WO2024252368A2 - Methods and compositions for treating ulcerative colitis - Google Patents

Methods and compositions for treating ulcerative colitis Download PDF

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Publication number
WO2024252368A2
WO2024252368A2 PCT/IB2024/055621 IB2024055621W WO2024252368A2 WO 2024252368 A2 WO2024252368 A2 WO 2024252368A2 IB 2024055621 W IB2024055621 W IB 2024055621W WO 2024252368 A2 WO2024252368 A2 WO 2024252368A2
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response marker
treatment
human subject
seq
level
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WO2024252368A3 (en
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Maria PARASKEVOPOULOU
Eleonora A.M. FESTEN
Emilia BIGAEVA
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G01N2800/065—Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Ulcerative colitis is an inflammatory bowel disease (IBD) of the colon characterized by the inflammation of colonic mucosa, with diarrhea and rectal bleeding as its main symptoms (Kaser, A., Zeissig, S. & Blumberg, R. S. Inflammatory bowel disease. Annu Rev Immunol 28, 573–621 (2010); Cui, G., Fan, Q., Li, Z., Goll, R. & Florholmen, J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers.
  • UC patients experience a significant decrease in their quality of life due to symptoms, endoscopies, and frequent hospital visits (Kappelman, M. D. et al. Utilization of healthcare resources by U.S. children and adults with inflammatory bowel disease. Inflamm Bowel Dis 17, 62–68 (2011)).
  • TNF- ⁇ anti-tumor necrosis factor alpha
  • Infliximab Infliximab
  • JAK Janus kinase
  • VDZ Vedolizumab
  • integrin receptor antagonists like Vedolizumab (VDZ)
  • VDZ Vedolizumab
  • US 4854-8046-9185v2 M. C., Maconi, G. & Ardizzone, S. An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis. J Clin Med 11, 2302 (2022)
  • One of the major problems in the treatment of IBD is that medical therapy often leads to a sustained remission in less than 50% of patients (Jairath, V. & Feagan, B. G. Global burden of inflammatory bowel disease. Lancet Gastroenterol Hepatol 5, 2–3 (2020)).
  • Non-response to therapy not only comes as a significant expense for healthcare system, but it also places a major socioeconomic burden on patients (Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol 12, 720–727 (2015)).
  • Anti-TNF ⁇ agents are often the first-line biologic treatment for moderate-to-severe ulcerative colitis (UC), with a response rate of ⁇ 60%, but sustained remission rate of 30% (Cui, G., Fan, Q., Li, Z., Goll, R. & Florholmen, J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers. EBioMedicine 66, 103329 (2021)).
  • VDZ vedolizumab
  • the growing evidence for VDZ to be equally effective and safer than anti-TNF ⁇ agents advocates for a shift in clinical practice towards using VDZ as a first-line biologic (Bohm, M. et al. Comparative safety and effectiveness of vedolizumab to tumour necrosis factor antagonist therapy for Crohn’s disease. Aliment Pharmacol Ther 52, 669– 681 (2020)).
  • the ability to predict which patients will respond to vedolizumab will spare the patients from enduring unsuccessful treatment and provide confidence in treatment plans or highlight the need for early modification of the treatment options.
  • VDZ Vedolizumab
  • UC moderate-to- severe ulcerative colitis
  • the present disclosure is based, at least in part, on the discovery of an association between certain cellular and molecular signatures (e.g., mRNA and/or protein biomarkers) and 2 WBD (US) 4854-8046-9185v2 response or non-response to VDZ in patients with UC.
  • certain cellular and molecular signatures e.g., mRNA and/or protein biomarkers
  • 2 WBD US
  • the methods and compositions provided herein are also useful for improving clinical care for a UC patient by enabling informed decisions regarding treatment options in a UC patient that is predicted to respond or not respond to treatment with VDZ.
  • the disclosure provides a method for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin, said method comprising determining an expression level of at least one response marker in a biological sample from the human subject, wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, wherein the human subject will respond to treatment if the level of the at least one response marker correlates with a reference level for a human subject who has responded to treatment with the humanized antibody, or wherein the human subject will not respond to treatment if the level of the at least one response marker correlates with a reference level for a human subject who has not responded to treatment with the humanized antibody, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin comprises the CDRs: light chain: CDR1 SEQ
  • the disclosure provides method for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin, said method comprising comparing the expression 3 WBD (US) 4854-8046-9185v2 level of at least one response marker in a biological sample from the human subject to a non- response control level of the at least one response marker; wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, and determining whether the level of the at least one response marker from the biological sample is equal to or higher than the level of the at least one response marker of a non- response control, wherein a higher level of the at least one response marker from the biological sample from the human subject relative to the level of the at least one response marker from the non-response control indicates that the human subject will respond to treatment, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody
  • the disclosure provides a method of treating ulcerative colitis in a human subject, said method comprising determining an expression level of at least one response marker in a biological sample from the human subject, wherein the human subject will respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin if the level of the at least one response marker correlates with a reference level for a human subject who has responded to treatment, wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, further comprising administering to the human subject the humanized antibody, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin comprises the CDRs: light chain: CDR1 SEQ ID NO: 4, CDR2 SEQ ID NO: 5, CDR3 SEQ ID NO: 6; heavy chain: CDR1 SEQ ID NO: 1; CDR2 SEQ ID NO: 2;
  • the biological sample is a peripheral blood sample or a gut mucosal biopsy sample from the human subject.
  • the sample comprises colonic inflammatory monocytes that express galectin-3 and CD68 at immunofluorescence staining.
  • the sample is collected within two weeks prior to treatment. 4 WBD (US) 4854-8046-9185v2
  • the expression level of the at least one response marker is determined by single-cell RNAseq.
  • the ulcerative colitis is moderately to severely active ulcerative colitis.
  • the human subject had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof.
  • the human subject previously received treatment with at least one corticosteroid.
  • response to treatment is assessed by Physician Global Assessment (PGA) score at 14 weeks after the start of treatment.
  • PGA Physician Global Assessment
  • the methods of the invention further comprises measuring the level of dendritic cells (DCs), innate lymphoid cells (ILCs), natural killer (NK) cells, and/or inflammatory monocytes in the sample from the human subject, wherein an increased level relative to a response control level of DCs, ILCs, NK cells, and/or inflammatory monocytes indicates that the human subject will not respond to treatment.
  • the at least one response marker is selected from a gene expressed in colonic inflammatory monocytes and involved in neutrophil mediated immunity, cellular response to lipopolysaccharide, the interferon-gamma-mediated signaling pathway, and/or the cytokine-mediated signaling pathway.
  • increased expression of the at least one response marker selected from a gene expressed in colonic inflammatory monocytes and involved in neutrophil mediated immunity, cellular response to lipopolysaccharide, the interferon-gamma-mediated signaling pathway, and/or the cytokine-mediated signaling pathway indicates that the human subject will respond to treatment.
  • the at least one response marker is selected from a gene expressed in colonic inflammatory monocytes and involved in the regulation of T cell apoptotic process, ribosome assembly and biogenesis, and/or cellular metabolic process.
  • increased expression of at least one response marker selected from a gene expressed in colonic inflammatory monocytes and involved in the regulation of T cell 5 WBD (US) 4854-8046-9185v2 apoptotic process, ribosome assembly and biogenesis, and/or cellular metabolic process indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN.
  • the at least one response marker is expressed in colonic inflammatory monocytes and selected from HIF1A, SOCS3, and/or IL1RN.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from HIF1A, SOCS3, and/or IL1RN indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 and/or IL1RN.
  • the at least one response marker is expressed in colonic mucosal macrophages and selected from RGS2 and/or MAFB. In another embodiment, increased expression of the at least one response marker expressed in colonic mucosal macrophages and selected from RGS2 and/or MAFB indicates that the human subject will respond to treatment. 6 WBD (US) 4854-8046-9185v2 In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and selected from TREM1 and/or TGM2. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from TREM1 and/or TGM2 indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and is selected from IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3 indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and is selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3 indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and selected from ADAM17 and/or TNF.
  • increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from ADAM17 and/or TNF indicates the human subject will respond to treatment.
  • the at least one response marker is expressed in inflammatory fibroblasts and is selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B.
  • increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and is selected from CCL5, CEBPB, IL23A, and/or DCHS2.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from CCL5, CEBPB, IL23A, and/or DCHS2 indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and is selected from SELE, LTB, OSM, and/or CXCL10. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from SELE, LTB, OSM, and/or CXCL10 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in IgG plasma cells and is SEC63. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells, wherein the at least one response marker is SEC63 indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in IgG plasma cells and is selected from TNFRSF17, TNFRSF13C, and/or SDC1. In another embodiment, the at least one response marker is expressed in IgG plasma cells and is SDC1. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells and selected from TNFRSF17, TNFRSF13C, and/or SDC1 indicates that the human subject will not respond to treatment. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells, wherein the at least one response marker is SDC1 indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2.
  • 8 WBD (US) 4854-8046-9185v2 the at least one response marker is expressed in colonic inflammatory monocytes and is ITGB1 and/or IL10RA.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2 indicates that the human subject will respond to treatment.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and wherein the at least one response marker is ITGB1 and/or IL10RA indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in colonic inflammatory monocytes and is IL1R1 and/or IL1RAP.
  • increased expression of the at least one response marker expressed in colonic inflammatory monocytes and wherein the at least one response marker is IL1R1 and/or IL1RAP indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CD40LG, IL18R1, IL10RA, IL7R, and/or TNFRSF14.
  • increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF indicates that the human subject will respond to treatment.
  • increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from CD40LG, IL18R1, IL10RA, IL7R, and/or TNFRSF14 indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is IL12RB, IL2RG, and/or TNFRSF1B.
  • increased expression of the at least one response marker expressed in regulatory T cells (Tregs) selected from IL12RB, IL2RG, and/or TNFRSF1B indicates that the human subject will not respond to treatment.
  • 9 WBD (US) 4854-8046-9185v2 the at least one response marker is expressed in inflammatory fibroblasts and is selected from IL-11, CXCL2, and/or CXCL14.
  • increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from IL-11, CXCL2, and/or CXCL14 indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in inflammatory fibroblasts and is selected from CXCL12, CXCL16, and/or CCL2.
  • increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from CXCL12, CXCL16, and/or CCL2 indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in IgG plasma cells and is selected from ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE.
  • increased expression of the at least one response marker expressed in IgG plasma cells and selected from ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in inflammatory monocytes and is selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD36, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, and/or FLT1.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25.
  • Tregs regulatory T cells
  • increased expression of the at least one response marker expressed in regulatory T cells indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in inflammatory fibroblasts and is selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74.
  • the at least one response marker is expressed in IgG plasma cells and is selected from CD44/SDC1, CD40, GLG1, and/or ITGA6.
  • increased expression of the at least one response marker expressed in IgG plasma cells and selected from CD44/SDC1, CD40, GLG1, and/or ITGA6 indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in inflammatory monocytes and is selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST.
  • increased expression of the at least one response marker expressed in inflammatory monocytes and selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6.
  • increased expression of the at least one response marker expressed in regulatory T cells indicates that the human subject will not respond to treatment.
  • Tregs regulatory T cells
  • the at least one response marker is expressed in inflammatory fibroblasts and is selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR.
  • increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in inflammatory monocytes and is selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CXCR4, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1.
  • the at least one response marker is expressed in inflammatory fibroblasts and is selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1.
  • Tregs regulatory T cells
  • increased expression of the at least one response marker expressed in regulatory T cells indicates that the human subject will respond to treatment.
  • the at least one response marker is expressed in inflammatory monocytes and is selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5.
  • increased expression of the at least one response marker expressed in inflammatory monocytes and selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5 indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in inflammatory fibroblasts and is selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK.
  • increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK indicates that the human subject will not respond to treatment.
  • the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4.
  • increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4 indicates that the human subject will not respond to treatment.
  • the mRNA expression level and/or protein expression level of the at least one response marker is determined.
  • the mRNA expression level is determined by in situ hybridization or RNA sequencing.
  • the protein expression level is determined by flow cytometry, mass cytometry, or immunohistochemistry.
  • a human subject that is determined to respond to treatment is administered the humanized antibody.
  • a human subject that is determined not to respond to treatment is further treated with a higher dose and/or more frequent administration of the humanized antibody.
  • a human subject that is determined not to respond to treatment is further treated with a combination therapy that includes the humanized antibody and a second agent.
  • the second agent is a JAK inhibitor, an anti-TNF ⁇ inhibitor, or an IL-23 inhibitor.
  • the second agent is infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, risankizumab, guselkumab, mirikizumab, or tofacitinib.
  • a response with reference to ulcerative colitis subjects refers to at least one response selected from the group consisting of a clinical response of a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding, endoscopic response, and mucosal healing.
  • a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission.
  • CSF corticosteroid-free
  • a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission and CSF endoscopic remission.
  • a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission, CSF endoscopic remission, and CSF histologic remission.
  • the humanized antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.
  • the humanized antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain comprising the amino acid sequence of SEQ ID NO: 8.
  • the humanized antibody is vedolizumab.
  • FIG.1A depicts reclustering of inflammatory monocytes captured in the mucosa of UC patients before the start of VDZ treatment (pre-VDZ). Shown is a UMAP representation of 1355 single-cell inflammatory monocytes (transcriptomes) shaded by the response status according to the PGA score.
  • FIG.1B depicts a Volcano plot showing the differential genes expressed by inflammatory monocytes derived from responders (left side of the plot) and non-responders (right side of the plot) prior to VDZ treatment. A gene was considered differentially expressed if the negative log10 FDR (adjusted p value) was greater than 0.05, and log2 fold change was either less than –0.25 or greater than 0.25.
  • FIG.1C shows overrepresented GO terms in the inflammatory monocytes based on 205 differentially expressed genes in responders and 277 genes in non-responders at baseline (pre-VDZ). Circle size corresponds to the proportion of tested genes annotated to a given term, while the shading indicates the level of significance from low (blue) to high (magenta) according to the -log10 of the adjusted p value.
  • FIG.1D depicts CellChat analysis of the intercellular communication network between 10 distinct cell types in the mucosa of the responders (on the left) and non-responders (on the right) at baseline (pre-VDZ). In the circle plots, lines represent predicted interaction between two cell types, and the thickness of each line is proportional to the number of interactions (i.e.
  • FIGS.1E-G depicts enriched pathways (in GO terms) that reflect functional state of the mucosal inflammatory monocytes, Tregs, and inflammatory fibroblasts.
  • Circle size corresponds to the proportion of tested genes annotated to a given term, while the shading indicates the level of significance from low (light shading) to high (darker shading) according to the -log10 of the adjusted p value.
  • FIG.1H depicts proportion of IgG+ (on the left) or IgA+ (on the right) plasma cells of the total number of captured plasma cells in each sample.
  • FIG.2A and FIG.2B show changes in immune cell composition of the mucosa in responders and non-responders to vedolizumab therapy.
  • FIG.2A depicts cell proportions within adaptive and innate immune cells (Cytek immunoprofiles) in the mucosa in responders and non-responders pre-VDZ and post-VDZ. Shown are stacked fractions of each cell subtype (y axis) divided by the total number of cells in each of the four sample groups (VDZ-R pre- and post-treatment, VDZ-NR pre- and post-treatment).
  • FIG.2B depicts identification of the innate cellular signature that distinguishes non-responders to VDZ prior to treatment. Shown are significant changes in cell frequency (y axis) for innate cell subsets in mucosal Cytek immunoprofiles in responders and non-responders pre-VDZ.
  • Each dot represents a single sample, cell frequency of each cell type divided by the total number of cells in a sample.
  • Statistical analysis was performed using Bayesian Multinomial Logistic Regression (the Pibble model) with 75% Credible Interval (# indicates significance detected at 75%, 90% or 95% CI).
  • VDZ vedolizumab
  • VDZ-R responders to vedolizumab
  • VDZ-NR non-responders to vedolizumab
  • CI Credible Interval.
  • FIG.3A and FIG.3B show mucosal expression of selected genes associated with cytokine signaling, monocyte-specific LPS and immune complex (IC) signatures, and genes that mark resident macrophages.
  • FIG.3A depicts heatmaps showing the average log2 fold change in cytokine expression in responders and non-responders over the course of 14 weeks of vedolizumab treatment (top panel), as well as average log2 fold change in cytokine expression between these two groups of patients at pre-VDZ and post-VDZ (bottom panel).
  • the single-cell RNAseq mucosal cells dataset was converted to a pseudo-bulk dataset to interrogate the expression of the cytokines across all cells together (left panels) or across only epithelial cells (right panels).
  • the dotted (“concrete”) pattern in the top panel represents a significant increase in gene expression of a cytokine post-VDZ compared to pre-VDZ, the diagonal line pattern in the top panel represents a significant decrease.
  • the crosshatch pattern in the bottom panel represents a significant increase in gene expression of a cytokine in responders, while the dotted (“sand”) pattern in the bottom panel represents a significant increase in non-responders. No pattern indicates no significant change.
  • a gene appears on the x axis if at least one of the tested 16 WBD (US) 4854-8046-9185v2 cytokines shows a significant change.
  • FIG.3B depicts heatmaps showing the average log2 fold change in the expression of selected genes in inflammatory monocytes and macrophages in the mucosa in responders and non-responders over the course of 14 weeks of vedolizumab treatment (top panel), as well as average log2 fold change in the expression between these two groups of patients at pre-VDZ and post-VDZ (bottom panel).
  • the diagonal patterns in the top panel represent a significant increase in gene expression of a cytokine post-VDZ compared to pre-VDZ
  • the hexagon pattern and dotted (“concrete”) pattern in the top panel represent a significant decrease.
  • the large-dotted pattern and crosshatch pattern in the bottom panel represents a significant increase in gene expression of a cytokine in responders
  • the small-dotted (“sand”) pattern, diagonal line pattern, and dashed diagonal line pattern in the bottom panel represents a significant increase in non-responders.
  • No pattern indicates no significant change.
  • a gene appears on the x axis if at least one of the tested cytokines shows a significant change.
  • LPS lipopolysaccharide
  • IC immune complex
  • VDZ vedolizumab
  • VDZ-R responder to vedolizumab treatment
  • VDZ-NR non-responder to vedolizumab treatment
  • pre-VDZ a study time point of 2 weeks before the start of the vedolizumab treatment
  • post-VDZ a study time point of 14 weeks after the start of the vedolizumab treatment.
  • FIG.4A and FIG.4B show a schematic illustration of the cell-cell interactions within the mucosal inflammatory module that underlie fundamentally different inflammatory mechanisms in responders and non-responders to vedolizumab.
  • the cell interaction networks were built for responders (FIG.4A) and non-responders (FIG.4B) based on genes differentially expressed by selected mucosal cell types at baseline which were analyzed using CellChat and NicheNet. Detailed information on the number of ligand-receptor pairs, identity of these pairs as well as predicted biological functions that the ligand-receptor pairs represent are shown in FIG.7.
  • FIG.5 depicts heatmaps showing the average log2 fold change in the expression of the genes previously reported to have the potential to distinguish non-responders to VDZ from responders.
  • the top panel shows changes over the course of 14 weeks of vedolizumab treatment, and the bottom panel shows changes in gene expression between responders and non-responders 17 WBD (US) 4854-8046-9185v2 at pre-VDZ and post-VDZ.
  • the single-cell RNAseq mucosal cells dataset was converted to a pseudo-bulk dataset to interrogate the expression of the cytokines across all cells together.
  • the bottom five fill patterns in the left log2FC legend represent a significant increase in gene expression post-VDZ compared to pre-VDZ
  • the top five fill patterns in the left avg log2FC legend represents a significant decrease.
  • the top three fill patterns in the right avg log2FC legend represent a significant increase in gene expression in responders
  • the bottom eight fill patterns in the right log2FC legend represent a significant increase in non-responders. No pattern indicates no significant change.
  • Statistical differential gene expression analysis was performed using the “MAST” method (“Seurat” R package) (adjusted p ⁇ 0.05 after Benjamini-Hochberg multiple test correction).
  • FIG.6A and FIG.6B , and FIG.6C depict a characterization of the functional state of circulating monocytes in responders and non-responders prior to vedolizumab treatment.
  • FIG. 6A shows a reclustering of the monocytes captured in the peripheral blood of UC patients before the start of VDZ treatment (pre-VDZ). Shown is the UMAP representation of 21,031 single-cell monocytes (transcriptomes, CD14+ and CD16+ monocytes combined) shaded by the PGA response.
  • FIG.6B is a Volcano plot showing the differential genes expressed by monocytes derived from responders (left side of the plot) and non-responders (right side of the plot) prior to VDZ treatment.
  • FIG.6C shows enriched pathways (in GO terms) that reflect the functional state of the circulating monocytes. Circle size corresponds to the proportion of tested genes annotated to a given term, while the shading indicates the level of significance from low to high according to the -log10 of the adjusted p value.
  • FIG.7 depicts differences in the mucosal cell-cell crosstalk of responders and non- responders prior to VDZ treatment.
  • FIG.7 is an overview of the changes in ligand- receptor interactions between a sender cell (inflammatory monocyte, Treg or inflammatory fibroblast) and a receiver cell in the mucosa in two groups of UC patients – responders (top row) and non-responders (bottom row). Numbers indicate the quantity of ligand-receptor pairs for each intercellular link. The loops indicate autocrine circuits. Analysis was done using CellChat. VDZ, vedolizumab; VDZ-R, responder to vedolizumab treatment; VDZ-NR, non-responder to vedolizumab treatment.
  • VDZ vedolizumab
  • VDZ-R responder to vedolizumab treatment
  • VDZ-NR non-responder to vedolizumab treatment.
  • Predicted responders can then be treated with standard treatment options, and the treatment options of predicted non-responders can be modified (e.g., increased dosing, increased dosing frequency, combination therapy).
  • Methods disclosed herein relate to the surprising discovery that there is an association between certain cellular and molecular signatures (e.g., mRNA and/or protein biomarkers) and response or non-response to vedolizumab in patients with ulcerative colitis.
  • Vedolizumab a humanized monoclonal antibody that binds specifically to the ⁇ 4 ⁇ 7 integrin, is indicated for the treatment of patients with moderately to severely active ulcerative colitis and Crohn’s disease.
  • Vedolizumab has a novel gut-selective mechanism of action that differs from that of other currently marketed biologic agents for the treatment for inflammatory bowel disease (IBD), including natalizumab and tumor necrosis factor- ⁇ (TNF- ⁇ ) antagonists.
  • IBD inflammatory bowel disease
  • TNF- ⁇ tumor necrosis factor- ⁇
  • vedolizumab blocks the interaction of a subset of memory gut-homing T lymphocytes with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on endothelial cells. Consequently, migration of these cells into inflamed intestinal tissue is inhibited.
  • MAdCAM-1 mucosal addressin cell adhesion molecule-1
  • vedolizumab The efficacy and safety of vedolizumab was demonstrated in patients with UC in the GEMINI 1 trial (ClinicalTrials.gov number, NCT00783718) and in patients with CD in the GEMINI 2 (ClinicalTrials.gov number, NCT00783692) and GEMINI 3 (ClinicalTrials.gov number, NCT01224171) trials.
  • the exposure-response (efficacy) relationships of vedolizumab in patients with UC and CD for induction and maintenance therapy have been presented elsewhere. I. Definitions In order that the present invention may be more readily understood, certain terms are first defined.
  • ⁇ 4 ⁇ 7 integrin or “ ⁇ 4 ⁇ 7” (used interchangeably throughout) is a heterodimer of an ⁇ 4 chain (CD49D, ITGA4) and a ⁇ 7 chain (ITGB7).
  • Human ⁇ 4-integrin and ⁇ 7-integrin genes GenBank (National Center for Biotechnology Information, Bethesda, Md.) RefSeq Accession numbers NM_000885 and NM_000889, respectively) are expressed by B and T lymphocytes, particularly memory CD4+ lymphocytes.
  • ⁇ 4 ⁇ 7 can exist in either a resting or activated state.
  • Ligands for ⁇ 4 ⁇ 7 include vascular cell adhesion molecule (VCAM), fibronectin and mucosal addressin (MAdCAM (e.g., MAdCAM-1)).
  • VCAM vascular cell adhesion molecule
  • MAdCAM mucosal addressin
  • An antibody that binds to ⁇ 4 ⁇ 7 integrin is referred to herein as an “anti- ⁇ 4 ⁇ 7 antibody”.
  • an antibody, or antigen-binding fragment thereof, that has "binding specificity for the ⁇ 4 ⁇ 7 complex" binds to ⁇ 4 ⁇ 7, but not to ⁇ 4 ⁇ 1 or ⁇ E B7.
  • Vedolizumab is an example of an antibody that has binding specificity for the ⁇ 4 ⁇ 7 complex.
  • antibody as used herein, is intended to refer to an immunoglobulin molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter- connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region (CH).
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain 20 WBD (US) 4854-8046-9185v2 constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the antibody has a fragment crystallizable (Fc) region.
  • the antibody is an IgG1 isotype and has a kappa light chain.
  • a "CDR” or “complementarity determining region” is a region of hypervariability interspersed within regions that are more conserved, termed "framework regions" (FR).
  • antigen binding fragment or “antigen binding portion” of an antibody refers to Fab, Fab', F(ab') 2 , and Fv fragments, single chain antibodies, functional heavy chain antibodies (nanobodies), as well as any portion of an antibody having specificity toward at least one desired epitope, that competes with the intact antibody for specific binding (e.g., an isolated portion of a complementarity determining or variable region having sufficient framework sequences so as to bind specifically to an epitope).
  • Antigen binding fragments can be produced by recombinant techniques, or by enzymatic or chemical cleavage of an antibody.
  • Fab or F(ab')2 fragments can be used to generate Fab or F(ab')2 fragments, respectively.
  • Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site.
  • a recombinant construct encoding the heavy chain of an F(ab')2 fragment can be designed to include DNA sequences encoding the CHI domain and hinge region of the heavy chain.
  • “Antigen binding fragments” of a humanized anti- ⁇ 4 ⁇ 7 antibody comprise at least the variable regions of the heavy and/or light chains of an anti- ⁇ 4 ⁇ 7 antibody (e.g., SEQ ID NOs: 9 and 10).
  • antigen binding fragments include Fab fragments, Fab′ fragments, scFv and F(ab′)2 fragments of a humanized immunoglobulin known in the art.
  • antigen binding fragments of an anti- ⁇ 4 ⁇ 7 antibody inhibit binding of ⁇ 4 ⁇ 7 integrin to one or more of its ligands (e.g., the mucosal addressin MAdCAM (e.g., MAdCAM-1), fibronectin).
  • MAdCAM mucosal addressin
  • fibronectin fibronectin
  • the patient to be treated herein 21 WBD (US) 4854-8046-9185v2 may have been diagnosed as having the disease or may be predisposed or susceptible to the disease.
  • the terms “patient” and “subject” are used interchangeably herein.
  • a patient is a human.
  • “Baseline” as used herein describes a value of a parameter which is measured prior to the initial dose of a therapeutic agent or initiation of a treatment. It can refer to a measurement on a sample obtained the same day, the day before, during the week before initial treatment, i.e., at a time period before the first dose when little change is expected until after the first dose and values of the measurement obtained after the first dose can be compared to this baseline value to represent the change caused by the dose.
  • determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin is intended to refer to an ability to assess the likelihood that treatment of a subject with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin will or will not be effective in (e.g., provide a measurable benefit to) the subject.
  • an ability to assess the likelihood that treatment will or will not be effective typically is exercised before treatment with the humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin is begun in the subject.
  • the term “expression” when used in connection with detecting the expression of a biomarker of the present disclosure can refer to detecting transcription of the gene encoding a biomarker protein and/or detecting translation of the biomarker protein.
  • To detect expression of a biomarker refers to the act of actively determining whether a biomarker is expressed or not.
  • To quantitate expression refers to the act of determining the level of the given biomarker, e.g., ng/ml.
  • Detecting and/or quantitating expression can include determining whether the biomarker expression is upregulated as compared to a known standard level, downregulated as compared to a known standard level, or substantially unchanged as compared to a known standard level.
  • the step of quantitating and/or detecting expression does not require that expression of the biomarker actually is upregulated or downregulated, but rather, can also include detecting no expression of the biomarker or detecting that the expression of the biomarker has not changed or is not different (i.e., detecting no significant expression of the biomarker or no significant change in expression of the biomarker as compared to a control). 22 WBD (US) 4854-8046-9185v2
  • level or “amount” of a biomarker refers to the measurable quantity of a biomarker, e.g., a transcript, a peptide, a protein (or polypeptide).
  • the amount may be either (a) an absolute amount as measured in molecules, moles or weight per unit volume or cells or (b) a relative amount.
  • the term “reference level” or “control level”, refers to an accepted or pre- determined level of a biomarker which is used to compare the biomarker level derived from the sample of a subject. The level of the biomarker may also be compared to a baseline level which is not accepted or pre-determined.
  • sample or “biological sample” as used herein refers to cells or tissue obtained from a subject.
  • the source of the tissue or cell sample may be solid tissue (as from a fresh, frozen and/or preserved organ or tissue sample or biopsy (e.g., mucosal biopsy) or aspirate); whole blood or any blood constituents (e.g., peripheral blood mononuclear cells (PBMCs)); or bodily fluids, such as serum, plasma, urine, feces, saliva, sweat or synovial fluid.
  • PBMCs peripheral blood mononuclear cells
  • inflammatory monocytes are cells that are characterized by cell type annotations set forth in Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019).
  • PGA Physical Global Assessment
  • SCCAI Simple Clinical Colitis Activity Index
  • endoscopic response defined as a decrease in total Mayo score by at least 3 points post-VDZ in the last three segments of the intestinal tract
  • serological and fecal markers such as C-Reactive Protein, hemoglobin, and calprotectin.
  • COS Composite Outcome Score
  • the present disclosure is based, at least in part, on the discovery that certain cellular and molecular signatures (e.g., mRNA and/or protein biomarkers) are associated with response or non-response to vedolizumab in patients with ulcerative colitis.
  • the markers described herein are mRNA markers and/or protein markers.
  • the disclosure provides biomarkers whose expression levels can be used to predict whether a subject with UC will respond or not respond to treatment with vedolizumab.
  • the disclosure relates to the use of differential expression of mRNA and/or protein response markers in a biological sample from a UC patient to predict/determine whether said patient will respond or not respond to treatment with vedolizumab.
  • the response markers that can be used in the compositions and methods disclosed herein include nucleic acid sequences (e.g., mRNA transcripts) that encode the following proteins, alone or in combination: CYP27A1: CYP27A1 (also known as Cytochrome P450 Family 27 Subfamily A Member 1; CYP27; CP27; CTX; Sterol 26-Hydroxylase, Mitochondrial; Vitamin D(3) 25-Hydroxylase; Cytochrome P-450C27/25; Sterol 27-Hydroxylase; Cytochrome P45027; 5-Beta-Cholestane-3- Alpha, 7-Alpha, 12-Alpha-Triol 26-Hydroxylase) encodes a member of the cytochrome P
  • the enzyme is known to catalyze the first step in the oxidation of the side chain of sterol intermediates in the bile acid synthesis pathway (Cali et al. J Biol Chem.1991 Apr 25;266(12):7774-8).
  • the amino acid sequence of CYP27A1 is SEQ ID NO: 11 and can be found under UniProt Accession No. Q02318.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 11 and/or the protein level thereof.
  • C4orf3 (also known as chromosome 4 open reading frame 3; ALN; HCVFTP1; uncharacterized protein C4orf3; HCV F-transactivated protein 1; another-regulin; hepatitis C virus F protein-transactivated protein 1) encodes a protein predicted to be located in the endoplasmic reticulum membrane and predicted to act upstream of or within negative regulation 24 WBD (US) 4854-8046-9185v2 of ATPase-coupled calcium transmembrane transporter activity and negative regulation of calcium ion binding activity.
  • the amino acid sequence of C4orf3 is SEQ ID NO: 12 and can be found under UniProt Accession No. Q8WVX3.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 12 and/or the protein level thereof.
  • IRAK3 also known as Interleukin-1 Receptor-Associated Kinase 3; IRAK-M; Inactive IL-1 Receptor-Associated Kinase 3; IL-1 Receptor-Associated Kinase M; ASRT5; IRAKM
  • IRAK3 also known as Interleukin-1 Receptor-Associated Kinase 3; IRAK-M; Inactive IL-1 Receptor-Associated Kinase 3; IL-1 Receptor-Associated Kinase M; ASRT5; IRAKM
  • the amino acid sequence of IRAK3 is SEQ ID NO: 13 and can be found under UniProt Accession No. Q9Y616.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 13 and/or the protein level thereof.
  • CXCL9 (also known as C-X-C Motif Chemokine Ligand 9; SCYB9; Crg-10; Humig; CMK; MIG; Monokine Induced By Gamma Interferon; Gamma-Interferon-Induced Monokine; Chemokine (C-X-C Motif) Ligand 9; Small-Inducible Cytokine B9) encodes a cytokine involved in immunoregulatory and inflammatory processes.
  • CXCL9 is known to be induced in THP-1 cells and in peripheral blood mononuclear cells by interferon-gamma but not by interferon-alpha or by lipopolysaccharide (Farber JM.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 14 and/or the protein level thereof.
  • SLCO4A1 also known as Solute Carrier Organic Anion Transporter Family Member 4A1; OATP4A1; OATP-E; SLC21A12; Solute Carrier Family 21 (Organic Anion Transporter), Member 12; Organic Anion Transporter Polypeptide-Related Protein 1; Sodium- Independent Organic Anion Transporter E; Solute Carrier Family 21 Member 12; Colon Organic Anion Transporter; OATPRP1; OATP1; POAT; Solute Carrier Organic Anion Transporter Family, Member 4A1; Organic Anion Transporting Polypeptide E) encodes a member of the solute carrier family and is predicted to enable sodium-independent organic anion transmembrane transporter activity and thyroid hormone transmembrane transporter activity.
  • the amino acid sequence of SLCO4A1 is SEQ ID NO: 15 and can be found under UniProt Accession No. Q96BD0.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 15 and/or the protein level thereof.
  • CLEC4E (also known as C-Type Lectin Domain Family 4 Member E; MINCLE; Macrophage-Inducible C-Type Lectin; CLECSF9; C-Type (Calcium Dependent, Carbohydrate-Recognition Domain) Lectin, Superfamily Member 9; C-Type Lectin Superfamily Member 9) encodes a C-type lectin receptor that acts as a pattern recognition receptor (PRR) of the innate immune system.
  • PRR pattern recognition receptor
  • TREM1 TREM1 (also known as Triggering Receptor Expressed On Myeloid Cells 1; TREM-1; CD354; CD354 Antigen) encodes a cell surface receptor expressed on neutrophils and 26 WBD (US) 4854-8046-9185v2 monocytes that amplifies inflammation induced by stimulation of pattern-recognition receptors (Arts et al.
  • TREM1 The amino acid sequence of TREM1 is SEQ ID NO: 17 and can be found under UniProt Accession No. Q9NP99.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 17 and/or the protein level thereof.
  • IL1B (also known as Interleukin 1 Beta; IL1F2; IL1-BETA; IL-1 Beta; Catabolin; Pro-Interleukin-1-Beta; Preinterleukin 1 Beta; Interleukin 1beta) encodes a key innate cytokine that is essential for immune activation and promoting the inflammatory process (Yaseen et al. Rev Med Virol.2023 Jan;33(1):e2400. doi: 10.1002/rmv.2400).
  • the amino acid sequence of IL1B is SEQ ID NO: 18 and can be found under UniProt Accession No. P01584.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 18 and/or the protein level thereof.
  • FLT1 FLT1 (also known as Fms Related Receptor Tyrosine Kinase 1; VEGFR1; Vascular Endothelial Growth Factor Receptor 1; Vascular Permeability Factor Receptor; FLT; Fms-Related Tyrosine Kinase 1 (Vascular Endothelial Growth Factor/Vascular Permeability Factor Receptor); Tyrosine-Protein Kinase Receptor FLT; Fms Related Tyrosine Kinase 1) encodes a tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and
  • the amino acid sequence of FLT1 is SEQ ID NO: 19 and can be found under UniProt Accession No. P17948.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 19 and/or the protein level thereof.
  • SOD2 also known as Superoxide Dismutase 2; GClnc1; IPOB; GC1; Superoxide Dismutase 2, Mitochondrial; MnSOD
  • SOD2 has antiapoptotic functions against inflammatory cytokines, oxidative stress, and ionizing radiation (Becuwe et al. Free Radic Biol Med.2014 Dec;77:139-51. doi: 10.1016/j.freeradbiomed.2014.08.026).
  • the amino acid sequence of SOD2 is SEQ ID NO: 20 and can be found under UniProt Accession No. P04179.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 20 and/or the protein level thereof.
  • HIF1A HIF1A (also known as Hypoxia-inducible factor 1-alpha; HIF-1-alpha; HIF-1A; HIF-1alpha; HIF1; HIF1-ALPHA; MOP1; PASD8; bHLHe78; hypoxia inducible factor 1 alpha subunit; hypoxia inducible factor 1 subunit alpha; HIF-1 ⁇ ) encodes a basic helix-loop-helix PAS domain containing protein that functions as a master transcriptional regulator of the adaptive response to hypoxia. It is known to induce expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons in monocytes (Codo et al.
  • HIF1A The amino acid sequence of HIF1A is SEQ ID NO: 21 and can be found under UniProt Accession No. Q16665.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 21 and/or the protein level thereof.
  • GBP2 GBP2 (also known as Guanylate Binding Protein 2; Interferon-Induced Guanylate-Binding Protein 2; Guanylate Binding Protein 2, Interferon-Inducible; Guanine Nucleotide-Binding Protein 2; Guanylate-Binding Protein 2) encodes an interferon-induced protein that can bind to guanine nucleotides.
  • Murine GBP2 is also known to be expressed in innate and adaptive immune cells (Praefcke GJK. Regulation of innate immune functions by guanylate-binding proteins. Int J Med Microbiol.2018 Jan;308(1):237-245).
  • the amino acid sequence of GBP2 is SEQ ID NO: 22 and can be found under UniProt Accession No. P32456. 28 WBD (US) 4854-8046-9185v2
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 22 and/or the protein level thereof.
  • SLAMF1 also known as Signaling Lymphocytic Activation Molecule Family Member 1; Signaling Lymphocytic Activation Molecule; CD150; SLAM; SLAM Family Member 1; CDw150; IPO-3; CD150 Antigen
  • SLAMF1 also known as Signaling Lymphocytic Activation Molecule Family Member 1; Signaling Lymphocytic Activation Molecule; CD150; SLAM; SLAM Family Member 1; CDw150; IPO-3; CD150 Antigen
  • SLAMF1 also known as Signaling Lymphocytic Activation Molecule Family Member 1; Signaling Lymphocytic Activation Molecule; CD150; SLAM; SLAM Family Member 1; CDw150; IPO-3; CD150 Antigen
  • DCs dendritic cells
  • the amino acid sequence of SLAMF1 is SEQ ID NO: 23 and can be found under UniProt Accession No. Q13291.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 23 and/or the protein level thereof.
  • IL1A (also known as Interleukin 1 Alpha; IL1F1; Hematopoietin-1; IL1-ALPHA; IL-1A; Pro-Interleukin-1-Alpha; Preinterleukin 1 Alpha; Interleukin-1 Alpha) encodes a member of the interleukin 1 cytokine family that functions as a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity (Cohen et al. Sci Rep.2015 Oct 6;5:14756. doi: 10.1038/srep14756).
  • the amino acid sequence of IL1A is SEQ ID NO: 24 and can be found under UniProt Accession No. P01583.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 24 and/or the protein level thereof.
  • PTGS2 also known as Prostaglandin-endoperoxide synthase 2; cyclooxygenase- 2; COX-2; COX2; GRIPGHS; PGG/HS; PGHS-2; PHS-2; hCox-2) encodes one of two cyclooxygenases in humans involved in the conversion of arachidonic acid to prostaglandin H2.
  • PTSG2 transcripts are highly induced in mesenchymal-derived inflammatory cells (Hla et al.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 25 and/or the protein level thereof.
  • BCL2L1 BCL2L1 (also known as Bcl-2-like protein 1; Bcl2l1; Bcl(X)L; Bcl-XL; Bcl2l; BclX; bcl-x; bcl2-L-1; BCL-XL/S; BCLXL; BCLXS; PPP1R52; bcl-xS; BCL2L; BCLX; Bcl-X; bcl-xL; BCL2 like 1) encodes Bcl-xL and Bcl-xS through alternative splicing that function as a regulators of apoptotic cell death (Korsmeyer SJ. Regulators of cell death.
  • Bcl-2-like protein 1 Bcl2l1; Bcl(X)L; Bcl-XL; Bcl2l; BclX; bcl-x; bcl2-L-1; BCL-XL/S; BCLXL;
  • Bcl-xS mRNA is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes (Boise et al. Cell.1993 Aug 27;74(4):597-608. doi: 10.1016/0092-8674(93)90508-n).
  • the amino acid sequence of BCL2L1 is SEQ ID NO: 26 and can be found under UniProt Accession No. Q07817.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 26 and/or the protein level thereof.
  • SOCS3 (also known as ATOD4; CIS3; Cish3; SOCS-3; SSI-3; SSI3; suppressor of cytokine signaling 3) encodes a cytokine-inducible negative regulator of cytokine signaling.
  • SOCS is thought to play a critical role in negative feedback control of JAK-STAT signaling pathway (Minamoto et al. Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochem Biophys Res Commun.1997 Aug 8;237(1):79-83. doi: 10.1006/bbrc.1997.7080).
  • the amino acid sequence of SOCS3 is SEQ ID NO: 27 and can be found under UniProt Accession No. O14543.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 27 and/or the protein level thereof.
  • DUSP7 also known as MKPX; PYST2; dual specificity phosphatase 7) encodes a dual specificity protein phosphatase that shows high activity towards MAPK1/ERK2 and lower activity towards MAPK14 and MAPK8 (Dowd et al. J Cell Sci.1998 Nov;111 ( Pt 22):3389-99).
  • DUSP7 The amino acid sequence of DUSP7 is SEQ ID NO: 28 and can be found under UniProt Accession No. Q16829.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 28 and/or the protein level thereof.
  • PLEK PLEK (also known as Pleckstrin; P47; PLEK1; Platelet 47 KDa Protein) encodes the major protein kinase C (PKC) substrate of platelets and functions in mediating cellular responses evoked by agonist-induced phosphoinositide turnover (Tyers et al. J Cell Biochem. 1989 Jun;40(2):133-45).
  • the amino acid sequence of PLEK is SEQ ID NO: 29 and can be found under UniProt Accession No. P08567.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 29 and/or the protein level thereof.
  • SPP1 also known as secreted phosphoprotein 1; Osteopontin; OPN; bone /sialoprotein I; BSP-1; BNSP; early T-lymphocyte activation; ETA-1) encodes a cytokine involved in enhancing production of interferon-gamma and interleukin-12 and reducing production of interleukin-10 and is essential in the pathway that leads to type I immunity.
  • SPP1 The amino acid sequence of SPP1 is SEQ ID NO: 30 and can be found under UniProt Accession No. P10451.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 30 and/or the protein level thereof.
  • TGM2 (also known as Transglutaminase 2; Tissue transglutaminase; G-ALPHA- h; GNAH; HEL-S-45; TG2; TGC; TG(C); transglutaminase 2; G(h); hTG2; tTG) encodes a 78- kDa, calcium-dependent enzyme of the transglutaminase family. Intracellularly, TGM2 is thought to function in apoptosis (McConkey et al. Biochem Biophys Res Commun.1997 Oct 31 WBD (US) 4854-8046-9185v2 20;239(2):357-66.
  • EGR2 also known as Early growth response protein 2; AT591; CMT1D; CMT4E; KROX20; early growth response 2; CHN1
  • EGR2 functions in osteoprogenitor maintenance and new bone formation (Chandra et al.
  • EGR2 The amino acid sequence of EGR2 is SEQ ID NO: 32 and can be found under UniProt Accession No. P11161.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 32 and/or the protein level thereof.
  • INHBA also known as Inhibin, beta A; EDF; FRP; inhibin beta A; inhibin beta A subunit; inhibin subunit beta A
  • INHBA encodes a preproprotein that is proteolytically processed to generate a subunit of the dimeric activin and inhibin protein complexes.
  • Activins and inhibins are structurally related members of the TGF-beta superfamily of growth and differentiation factors that regulate reproductive and other functions (Lewis et al. Nature.2000 Mar 23;404(6776):411-4).
  • the amino acid sequence of INHBA is SEQ ID NO: 33 and can be found under UniProt Accession No. P08476.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 33 and/or the protein level thereof.
  • IL1RN also known as interleukin-1 receptor antagonist protein; DIRA; ICIL- 1RA; IL-1RN; IL-1ra; IL-1ra3; IL1F3; IL1RA; IRAP; MVCD4; interleukin 1 receptor antagonist
  • the absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement (Aksentijevich et al. N Engl J Med.2009 Jun 4;360(23):2426-37. doi: 10.1056/NEJMoa0807865).
  • the amino acid sequence of IL1RN is SEQ ID NO: 34 and can be found under UniProt Accession No. P18510.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 34 and/or the protein level thereof.
  • PLAU also known as Urokinase; urokinase-type plasminogen activator; ATF; BDPLT5; QPD; UPA; URK; u-PA; plasminogen activator
  • PLAU regulates extracellular matrix remodeling by activating ubiquitous protease plasmin in many important physiological processes and is active in tumors where misregulation has been associated with the development of metastatic phenotype (Maduni ⁇ .
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 35 and/or the protein level thereof.
  • SMAD3 (also known as SMAD family member 3; Mothers against decapentaplegic homolog 3; HSPC193; HsT17436; JV15-2; LDS1C; LDS3; MADH3) encodes a member of the SMAD family of proteins that functions in mediating the signals initiated by the transforming growth factor beta (TGF- ⁇ ) superfamily of cytokines, which regulate cell proliferation, differentiation and death (Moustakas et al. J Cell Sci.2001 Dec;114(Pt 24):4359- 69. doi: 10.1242/jcs.114.24.4359).
  • TGF- ⁇ transforming growth factor beta
  • the amino acid sequence of SMAD3 is SEQ ID NO: 36 and can be found under UniProt Accession No. P84022.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 36 and/or the protein level thereof.
  • REV3L REV3L (also known as Protein reversionless 3-like; DNA polymerase zeta catalytic subunit; POLZ; REV3; REV3 like; DNA directed polymerase zeta catalytic subunit) encodes a catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (Murakumo et al. J Biol Chem.2001 Sep 21;276(38):35644-51.
  • the amino acid sequence of REV3L is SEQ ID NO: 37 and can be found under UniProt Accession No. O60673.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 37 and/or the protein level thereof.
  • HCAR3 (also known as Hydroxycarboxylic acid receptor 3; niacin receptor 2; NIACR2; GPR109B; HCA3; HM74; PUMAG; Puma-g) encodes a receptor for 3-OH-octanoid acid that mediates negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates.
  • HCAR3 is required for pertussis toxin-sensitive migration of primary human monocytes in response to lactic acid bacteria derived metabolites (Peters et al. PLoS Genet.2019 May 23;15(5):e1008145).
  • TLR8 TLR8 (also known as Toll-like receptor 8; CD288; cluster of differentiation 288; hIMD98) encodes an endosomal receptor that functions in innate and adaptive immunity. TLR8 is known to recognize viral ssRNA and endogenous RNA, such as microRNAs, resulting in the production of proinflammatory cytokines (Ishii et al.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 39 and/or the protein level thereof.
  • BMF also known as Bcl2 Modifying Factor; Bcl-2-Modifying Factor
  • Bcl-2-Modifying Factor encodes a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex.
  • BMF is thought to function to sense intracellular damage by their localization to distinct cytoskeletal structures (Puthalakath et al. Science.2001 Sep 7;293(5536):1829-32. doi: 10.1126/science.1062257).
  • the amino acid sequence of BMF is SEQ ID NO: 40 and can be found under UniProt Accession No. Q96LC9.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 40 and/or the protein level thereof.
  • APOL3 also known as Apolipoprotein L3; APOLIII; CG121; CG12_1; apoL- III encodes a potent bactericidal protein protecting multiple non-immune barrier cell types against infection when expressed in the gut (Gaudet et al. Science.2021 Jul 16;373(6552):eabf8113. doi: 10.1126/science.abf8113).
  • the amino acid sequence of APOL3 is SEQ ID NO: 41 and can be found under UniProt Accession No. O95236.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 41 and/or the protein level thereof.
  • ARHGEF10L ARHGEF10L (also known as Rho Guanine Nucleotide Exchange Factor 10 Like; GrinchGEF; Rho Guanine Nucleotide Exchange Factor 10-Like Protein; Rho Guanine Nucleotide Exchange Factor (GEF) 10-Like) encodes a protein that acts as a guanine nucleotide exchange factor (GEF) for RHOA, RHOB and RHOC.
  • Increased expression of ARHGEF10L is known to stimulate hepatocellular tumorigenesis by activating the RhoA-ROCK1- phospho ERM pathway and EMT (Tang et al. Exp Cell Res.2019 Jan 1;374(1):46-68. doi: 35 WBD (US) 4854-8046-9185v2 10.1016/j.yexcr.2018.11.007).
  • the amino acid sequence of ARHGEF10L is SEQ ID NO: 42 and can be found under UniProt Accession No. Q9HCE6.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 42 and/or the protein level thereof.
  • GSDMD also known as Gasdermin D; DF5L, DFNA5L, GSDMDC1, FKSG10) encodes a precursor of a pore-forming protein that functions in host defense against pathogen infection and promotes pyroptosis in response to microbial infection and danger signals (Shi et al. Nature.2015 Oct 29;526(7575):660-5. doi: 10.1038/nature15514).
  • the amino acid sequence of GSDMD is SEQ ID NO: 43 and can be found under UniProt Accession No. P57764.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 43 and/or the protein level thereof.
  • PDPN also known as Podoplanin; AGGRUS; GP36; GP40; Gp38; HT1A-1; OTS8; PA2.26; T1A; T1A-2; T1A2; TI1A; D2-40) encodes a type-I, integral membrane, O- glycosylated glycoprotein with mucin-type characteristics. Expression of mouse PDPN and its human homolog induces platelet aggregation without requiring plasma components.
  • the amino acid sequence of PDPN is SEQ ID NO: 44 and can be found under UniProt Accession No. Q86YL7.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 44 and/or the protein level thereof.
  • RGS2 also known as Regulator of G-protein signaling 2; G0S8; Cell Growth- Inhibiting Gene 31 Protein; G0/G1 Switch Regulatory Protein 8) encodes a regulator of G protein-coupled receptor signaling cascades.
  • RGS2 was found to bind to eIF2Bepsilon (eukaryotic initiation factor 2B epsilon subunit) and inhibit the translation of messenger RNA (mRNA) into new protein (Nguyen et al. J Cell Biol.2009 Sep 7;186(5):755-65.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 45 and/or the protein level thereof.
  • MAFB also known as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B; KRML; MCTO; MAF bZIP transcription factor B; DURS3 encodes a basic leucine zipper transcription factor that functions in the regulation of lineage-specific hematopoiesis.
  • MAFB is known to act as a transcriptional activator or repressor (Park et al. Am J Hum Genet. 2016 Jun 2;98(6):1220-1227. doi: 10.1016/j.ajhg.2016.03.023).
  • the amino acid sequence of MAFB is SEQ ID NO: 46 and can be found under UniProt Accession No. Q9Y5Q3.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 46 and/or the protein level thereof.
  • CCL2 also known as chemokine (C-C motif) ligand 2; monocyte chemoattractant protein 1; small inducible cytokine A2; GDCF-2; HC11; HSMCR30; MCAF; MCP-1; MCP1; SCYA2; SMC-CF) encodes a small cytokine primarily secreted by monocytes, macrophages, and dendritic cells.
  • CCL2 acts a major chemoattractant for monocytes and memory T cells by binding to its specific cell-surface receptor, CC-chemokine receptor-2 (CCR2) (Xia et al. Expert Opin Ther Pat.2009 Mar;19(3):295-303.
  • CCR2 CC-chemokine receptor-2
  • the amino acid sequence of CCL2 is SEQ ID NO: 47 and can be found under UniProt Accession No. P13500.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 47 and/or the protein level thereof.
  • ANXA1 also known as Annexin A1; lipocortin I; ANX1; LPC1; Phospholipase A2 Inhibitory Protein; Chromobindin-9) encodes a calcium-dependent phospholipid-binding protein.
  • ANXA1 functions as an anti-inflammatory protein that plays an important homeostatic role in innate immunity and contributes to the adaptive immune response by enhancing signaling 37 WBD (US) 4854-8046-9185v2 cascades that are triggered by T-cell activation (D'Acquisto et al. Blood.2007 Feb 1;109(3):1095-102. doi: 10.1182/blood-2006-05-022798).
  • the amino acid sequence of ANXA1 is SEQ ID NO: 48 and can be found under UniProt Accession No. P04083.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 48 and/or the protein level thereof.
  • ADAM17 (also known as A disintegrin and metalloprotease 17; tumor necrosis factor- ⁇ -converting enzyme; ADAM18; CD156B; CSVP; NISBD; NISBD1; TACE; ADAM metallopeptidase domain 17) encodes a 70 kDA enzyme that functions in the cleavage of the membrane bound precursor of TNF-alpha to its mature soluble form (Moss et al. Nature. 1997 Feb 20;385(6618):733-6. doi: 10.1038/385733a0).
  • the amino acid sequence of ADAM17 is SEQ ID NO: 49 and can be found under UniProt Accession No. P78536.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 49 and/or the protein level thereof.
  • TNF also known as Tumor necrosis factor; cachexin; cachectin; tumor necrosis factor alpha; TNF- ⁇ ; DIF; TNF-alpha; TNFA; TNFSF2; TNLG1F
  • TNF is known to function in the pathogenesis of several chronic inflammatory diseases (Szondy et al. Pharmacol Res.2017 Jan;115:124-132.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 50 and/or the protein level thereof.
  • CCL3 CCL3 (also known as Chemokine (C-C motif) ligand 3; macrophage inflammatory protein 1-alpha; MIP-1-alpha; G0S19-1; LD78ALPHA; MIP1A; SCYA3; C-C motif chemokine ligand 3) encodes a cytokine that binds to CCR1, CCR4 and CCR5.
  • CCL3 is 38 WBD (US) 4854-8046-9185v2 thought to CCL3 negatively regulate the proliferation of hematopoietic stem/progenitor cells (HSPCs) in addition to its proinflammatory activities (Baba, T., & Mukaida, N. (2014). Role of macrophage inflammatory protein (MIP)-1 ⁇ /CCL3 in leukemogenesis. Molecular & cellular oncology, 1(1), e29899).
  • the amino acid sequence of CCL3 is SEQ ID NO: 51 and can be found under UniProt Accession No. P10147.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 51 and/or the protein level thereof.
  • CCL4 also known as Chemokine (C-C motif) ligands 4; CCL4L1; AT744.2; CCL4L; LAG-1; LAG1; SCYA4L; SCYA4L1; MIP-1-beta; SCYA4L2; C-C motif chemokine ligand 4 like 1) encodes a small cytokine that binds to CCR5.
  • CCL4 is thought to promote tumor development and progression by recruiting regulatory T cells and pro-tumorigenic macrophages (Mukaida, N., Sasaki, S.
  • CCL4 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology, 1231, 23–32).
  • the amino acid sequence of CCL4 is SEQ ID NO: 52 and can be found under UniProt Accession No. P13236.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 52 and/or the protein level thereof.
  • CXCL2 also known as hemokine (C-X-C motif) ligand 2; CXCL2, CINC-2a, GRO2, GROb, MGSA-b, MIP-2a, MIP2, MIP2A, SCYB2, C-X-C motif chemokine ligand 2 encodes a small cytokine produced by activated monocytes and neutrophils and expressed at sites of inflammation.
  • CXCL2 is thought to rapidly mobilized hematopoietic stem cells into the peripheral blood in combination with the CXCR4 inhibitor plerixafor (Hoggatt J, et al. (January 2018). "Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell".
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 53 and/or the protein level thereof.
  • CXCL3 also known as Chemokine (C-X-C motif) ligand 3, CINC-2b, GRO3, GROg, MIP-2b, MIP2B, SCYB3, C-X-C motif chemokine ligand 3 encodes a small cytokine that signals through the G-protein coupled receptor, CXC receptor 2 and plays a role in inflammation and as a chemoattractant for neutrophils.
  • CXCL3 is thought to act as an arrest chemokine for monocyte adhesion on vascular cell adhesion molecule (VCAM)-1 under flow in the presence of P-selection (Smith et al. (2005).
  • VCAM vascular cell adhesion molecule
  • GRO family chemokines are specialized for monocyte arrest from flow. American journal of physiology. Heart and circulatory physiology, 289(5), H1976–H1984).
  • the amino acid sequence of CXCL3 is SEQ ID NO: 54 and can be found under UniProt Accession No. P19876.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 54 and/or the protein level thereof.
  • S10011A (also known as S100 calcium-binding protein A11, HEL-S-43, MLN70, S100C, S100 calcium binding protein A11) encodes a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs and is involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S10011A is also thought to function as a chemotactic agent in inflammatory disease (Zhang et al. (2021). The Calcium Binding Protein S100A11 and Its Roles in Diseases. Frontiers in cell and developmental biology, 9, 693262). The amino acid sequence of S10011A is SEQ ID NO: 55 and can be found under UniProt Accession No. P31949.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 55 and/or the protein level thereof.
  • S100A6 S100A6 (also known as 2A9, 5B10, CABP, CACY, PRA, S100 calcium binding protein A6, S10A6) encodes a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors (Donato, R., Sorci, G., & Giambanco, I. (2017).
  • S100A6 protein 40 WBD (US) 4854-8046-9185v2 functional roles. Cellular and molecular life sciences: CMLS, 74(15), 2749–2760).
  • the amino acid sequence of S100A6 is SEQ ID NO: 56 and can be found under UniProt Accession No. P06703.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 56 and/or the protein level thereof.
  • S100A4 S100A4 (also known as) encodes a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs and is thought to be involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation.
  • S100A4 may function as a calcium sensor and modular thereby contributing to cellular calcium signaling (Yamaguchi et al. (2012). S100 proteins modulate protein phosphatase 5 function: a link between CA2+ signal transduction and protein dephosphorylation. The Journal of biological chemistry, 287(17), 13787–13798).
  • the amino acid sequence of S100A4 is SEQ ID NO: 57 and can be found under UniProt Accession No. P26447.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 57 and/or the protein level thereof.
  • LGALS1 also known as GAL1, GBP, galectin 1 encodes a lectin that binds beta-galactoside and a wide array of complex carbohydrates. LGALS1 functions in regulating apoptosis, cell proliferation, and cell differentiation. Dendritic cells lacking LGALS1 have greater immunogenic potential and an impaired ability to halt inflammatory disease (Ilarregui et al. (2009). Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nature immunology, 10(9), 981–991). The amino acid sequence of LGALS1 is SEQ ID NO: 58 and can be found under UniProt Accession No. P09382.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 58 and/or the protein level thereof.
  • 41 WBD (US) 4854-8046-9185v2 LGALS3 LGALS3 (also known as CBP35, GAL3, GALBP, GALIG, L31, LGALS2, MAC2, lectin, galactoside binding soluble 3, galectin 3) encodes a 30kDa lectin that contains a carbohydrate recognition binding domain and binding beta-galactosides.
  • LGALS3 is known to be involved in cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis (Dumic, J.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 59 and/or the protein level thereof.
  • TIMP3 also known as HSMRK222, K222, K222TA2, SFD, TIMP metallopeptidase inhibitor 3) encodes an inhibitor of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix.
  • TIMP3 is thought to block the binding of VEGF to VEGF receptor-2 and inhibit downstream signaling and angiogenesis (Qi et al. (2003). A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature medicine, 9(4), 407– 415).
  • the amino acid sequence of TIMP3 is SEQ ID NO: 60 and can be found under UniProt Accession No. P35625.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 60 and/or the protein level thereof.
  • ADAMDEC1 also known as ADAM-like, decysin 1; A Disintegrin And Metalloproteinase Domain-Like Protein Decysin-1) encodes a secreted protein belonging to the disintegrin metalloproteinase family.
  • ADAMDEC1 is thought to function as a positive regulator of Epithelial Defense against Cancer (EDAC) that promotes apical extrusion of RasV12- transformed cells (Yako et al. ADAM-like Decysin-1 (ADAMDEC1) is a positive regulator of Epithelial Defense against Cancer (EDAC) that promotes apical extrusion of RasV12- transformed cells. Sci Rep.2018 Jun 25;8(1):9639.
  • the 42 WBD (US) 4854-8046-9185v2 amino acid sequence of ADAMDEC1 is SEQ ID NO: 61 and can be found under UniProt Accession No. O15204.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 61 and/or the protein level thereof.
  • CXCL14 (also known as SCYB14, BRAK, NJAC, bolekine, Kec, MIP-2g, BMAC, KS1, breast and kidney-expressed chemokine) encodes a non-ELR (glutamic acid- leucine-arginine) chemokine with a broad spectrum of biological activities and is thought to contribute to the regulation of immune cell migration and executing antimicrobial immunity (Lu et al. (2016). CXCL14 as an emerging immune and inflammatory modulator. Journal of inflammation (London, England), 13, 1).
  • the amino acid sequence of CXCL14 is SEQ ID NO: 62 and can be found under UniProt Accession No. O95715.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 62 and/or the protein level thereof.
  • AGT also known as O6-alkylguanine DNA alkyltransferase, Mgmt, AI267024, Agat, O-6-methylguanine-DNA methyltransferase
  • AGT encodes a protein important for genome stability as it repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription.
  • AGT is known to be inducible by glucocorticoids and genotoxins such as radiation and alkylating agents (Kaina, B., Christmann, M., Naumann, S., & Roos, W. P. (2007). MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA repair, 6(8), 1079–1099).
  • the amino acid sequence of AGT is SEQ ID NO: 63 and can be found under UniProt Accession No. P16455.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 63 and/or the protein level thereof.
  • LAMA4 (also known as CMD1JJ, LAMA3, LAMA4*-1, Laminin, alpha 4, laminin subunit alpha 4) encodes a member of a family of extracellular matrix glycoproteins implicated in cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Deletion of LAMA4 in mice results in impaired hematopoiesis regeneration following irradiation-induced stress (Cai et al. (2022). Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression. Blood, 139(20), 3040–3057).
  • the amino acid sequence of LAMA4 is SEQ ID NO: 64 and can be found under UniProt Accession No. Q16363.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 64 and/or the protein level thereof.
  • WNT2B WNT2B (also known as WNT13, Wnt family member 2B) encodes a ligand for members of the frizzled family of seven transmembrane receptors and functions in the canonical Wnt/beta-catenin signaling pathway. WNT2B is thought to act as a putative stem cell factor in the retina (Kubo, F., Takeichi, M., & Nakagawa, S.
  • Wnt2b controls retinal cell differentiation at the ciliary marginal zone. Development (Cambridge, England), 130(3), 587– 598).
  • the amino acid sequence of WNT2B is SEQ ID NO: 65 and can be found under UniProt Accession No. Q93097.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 65 and/or the protein level thereof.
  • CCL5 (also known as D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228, eoCP, C-C motif chemokine ligand 5) encodes a 8kDa protein acting as a chemotactic cytokine or chemokine.
  • CCL5 is mostly expressed in T-cells and monocytes (Zeng, Z., Lan, T., Wei, Y., & Wei, X. (2022).
  • the amino acid sequence of CCL5 is SEQ ID NO: 66 and can be found under UniProt Accession No. P13501.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 66 and/or the protein level thereof.
  • CEBPB also known as C/EBP-beta, IL6DBP, NF-IL6, TCF5, CCAAT/enhancer binding protein beta, CCAAT enhancer binding protein beta
  • CREB- mediated induction of Cebpb expression is thought to be required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration (Ruffell et al. (2009).
  • CEBPB A CREB- C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proceedings of the National Academy of Sciences of the United States of America, 106(41), 17475–17480).
  • the amino acid sequence of CEBPB is SEQ ID NO: 67 and can be found under UniProt Accession No. P17676.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 67 and/or the protein level thereof.
  • IL23A (also known as IL-23, IL-23A, IL23P19, P19, SGRF, Interleukin 23, interleukin 23 subunit alpha) encodes one of the two subunits of the cytokine Interleukin-23 and is an important in inflammatory responses against infection.
  • IL23 is thought to stimulate IFN- gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cell (Oppmann (2000). Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 13(5), 715–725).
  • the amino acid sequence of IL23A is SEQ ID NO: 68 and can be found under UniProt Accession No. Q9NPF7.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 68 and/or the protein level thereof.
  • DCHS2 DCHS2 (also known as CDH27, CDHJ, CDHR7, PCDH23, PCDHJ, dachsous cadherin-related 2) encodes a Calcium-dependent cell-adhesion protein.
  • WBD US
  • the amino acid sequence of DCHS2 is SEQ ID NO: 69 and can be found under UniProt Accession No. Q6V1P9.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 69 and/or the protein level thereof.
  • SELE also known as E-selectin, CD62E, ELAM, ELAM1, ESEL, LECAM2, selectin E, selectin-e encodes a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. SELE recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes (Jubeli, E., Moine, L., Vergnaud-Gauduchon, J., & Barratt, G. (2012). E-selectin as a target for drug delivery and molecular imaging. Journal of controlled release : official journal of the Controlled Release Society, 158(2), 194–206).
  • the amino acid sequence of SELE is SEQ ID NO: 70 and can be found under UniProt Accession No. P16581.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 70 and/or the protein level thereof.
  • LTB LTB (also known as TNFC, TNFSF3, p33, Lymphotoxin beta, TNLG1C) encodes a type II membrane protein of the TNF family that anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. It is thought to have a role in immune regulation distinct from the functions ascribed to TNF (Browning et al. (1993).
  • Lymphotoxin beta a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface.
  • the amino acid sequence of LTB is SEQ ID NO: 71 and can be found under UniProt Accession No. Q06643.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 71 and/or the protein level thereof.
  • OSM also known as OncoM, oncostatin M
  • OSM encodes a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines.
  • OSM exhibits many unique biological activities in inflammation, hematopoiesis, and development (Tanaka, M., & Miyajima, A. (2003). Oncostatin M, a multifunctional cytokine. Reviews of physiology, biochemistry and pharmacology, 149, 39–52).
  • the amino acid sequence of OSM is SEQ ID NO: 72 and can be found under UniProt Accession No. P13725.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 72 and/or the protein level thereof.
  • CXCL10 (also known as C7, IFI10, INP10, IP-10, SCYB10, crg-2, gIP-10, mob-1, C-X-C motif chemokine ligand 10, C-X-C motif chemokine 10) encodes a small cytokine belonging to the CXC chemokine family and is secreted by several cell types in response to IFN- ⁇ .
  • CXCL10 is thought to have a role in effector T cell generation and trafficking in vivo (Dufour, J. H., Dziejman, M., Liu, M. T., Leung, J. H., Lane, T. E., & Luster, A. D. (2002).
  • IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. Journal of immunology (Baltimore, Md. : 1950), 168(7), 3195–3204).
  • the amino acid sequence of CXCL10 is SEQ ID NO: 73 and can be found under UniProt Accession No. P02778.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 73 and/or the protein level thereof.
  • SEC63 (also known as DNAJC23, ERdj2, PRO2507, SEC63L, SEC63 homolog, protein translocation regulator, PCLD2) encodes a protein associate with the ribosome-free SEC61 complex and involved in protein translocation of the endoplasmic reticulum membrane (Jung, S. J., & Kim, H. (2021). Emerging View on the Molecular Functions of Sec62 and Sec63 in Protein Translocation. International journal of molecular sciences, 22(23), 12757). The amino acid sequence of SEC63 is SEQ ID NO: 74 and can be found under UniProt Accession No. Q9UGP8.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 74 and/or the protein level thereof.
  • TNFRSF17 also known as B-cell maturation antigen, BCM, BCMA, CD269, TNFRSF13A, tumor necrosis factor receptor superfamily member 17, TNF receptor superfamily member 17
  • BCM B-cell maturation antigen
  • BCMA BCMA
  • CD269 TNFRSF13A
  • TNF receptor superfamily member 17 encodes a cell surface receptor of the TNF receptor superfamily which recognizes B-cell activating factor that is expressed in mature B lymphocytes and may be important for B-cell development and autoimmune response.
  • TNFRSF17 is a receptor for the tumor necrosis factor family member TALL-1 (Shu, H.
  • B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1. Proceedings of the National Academy of Sciences of the United States of America, 97(16), 9156–9161).
  • the amino acid sequence of TNFRSF17 is SEQ ID NO: 75 and can be found under UniProt Accession No. Q02223.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 75 and/or the protein level thereof.
  • TNFRSF13C (also known as BAFF receptor, B-cell activating factor receptor, BLyS receptor 3, BAFF-R, BAFFR, BROMIX, CD268, CVID4, prolixin, tumor necrosis factor receptor superfamily member 13C, TNF receptor superfamily member 13C) encodes a membrane protein of the TNF receptor superfamily which recognizes BAFF, an essential factor for B cell maturation and survival.
  • TNFRSF13C is thought to down regulate cell apoptosis (Rauch, M., Tussiwand, R., Bosco, N., & Rolink, A. G. (2009). Crucial role for BAFF- BAFF-R signaling in the survival and maintenance of mature B cells.
  • TNFRSF13C The amino acid sequence of TNFRSF13C is SEQ ID NO: 76 and can found under UniProt Accession No. Q96RJ3.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 76 and/or the protein level thereof.
  • SDC1 is thought to negatively regulate dendritic cell migration (Averbeck, M., Kuhn, S., Bühligen, J., Götte, M., Simon, J. C., & Polte, T. (2017). Syndecan-1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens. Experimental dermatology, 26(11), 1060–1067).
  • the amino acid sequence of SDC1 is SEQ ID NO: 77 and can be found under UniProt Accession No. P18827.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 77 and/or the protein level thereof.
  • ITGB1 (also known as Integrin beta-1, CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA, VLAB, integrin subunit beta 1) encodes a cell surface receptor that associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen receptors. ITGB1 is involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metastatic diffusion of tumor cells (Hynes R. O. (1992). Integrins: versatility, modulation, and signaling in cell adhesion. Cell, 69(1), 11–25).
  • the amino acid sequence of ITGB1 is SEQ ID NO: 78 and can be found under UniProt Accession No. P05556.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 78 and/or the protein level thereof.
  • IL17RA also known as Interleukin 17 receptor A, CANDF5, CD217, CDw217, IL-17RA, IL17R, hIL-17R, IMD51
  • IL17RA is known to play a role in the development of asthma, and allergy (Nejman-Gryz, P., Papli ⁇ ska-Goryca, M., Proboszcz, M., Grabczak, M., Hermanowicz-Salamon, J., & Krenke, R. (2021).
  • the amino acid sequence of IL17RA is SEQ ID NO: 79 and can be found under UniProt Accession No. Q96F46.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 79 and/or the protein level thereof.
  • IL10RA also known as CD210, CD210a, CDW210A, HIL-10R, IL-10R1, IL10R, Interleukin 10 receptor, alpha subunit, interleukin 10 receptor subunit alpha
  • IL10RA is frequently reported as a monogenic inflammatory bowel disease gene (Nambu et al. (2022). A Systematic Review of Monogenic Inflammatory Bowel Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 20(4), e653–e663).
  • the amino acid sequence of IL10RA is SEQ ID NO: 80 and can be found under UniProt Accession No. Q13651.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 80 and/or the protein level thereof.
  • IFNGR1 (also known as CD119, IFNGR, IMD27A, IMD27B, interferon gamma receptor 1) encodes IFN- ⁇ R1, which is the ligand-binding chain (alpha) of the heterodimeric gamma interferon receptor, and is expressed on macrophages.
  • Germline mutations in the gene IFNGR1 encoding the IFN- ⁇ R1 cause a primary immunodeficiency that mainly leads to mycobacterial infections (van de Vosse, E., & van Dissel, J. T. (2017).
  • IFN- ⁇ R1 defects Mutation update and description of the IFNGR1 variation database. Human mutation, 38(10), 1286–1296).
  • IFNGR1 The amino acid sequence of IFNGR1 is SEQ ID NO: 81 and can be found under UniProt Accession No. P15260.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 81 and/or the protein level thereof.
  • IFNGR2 IFNGR2 (also known as Interferon gamma receptor 2 or IFN- ⁇ R2) encodes the non-ligand-binding beta chain of the gamma interferon receptor.
  • IFNGR2 is required for 50 WBD (US) 4854-8046-9185v2 interferon- ⁇ signalling and therefore plays a critical immunoregulatory role in innate and adaptive immunity against viral and also bacterial and protozoal infections (Mikuleck ⁇ et al. (2016). Crystal structure of human interferon- ⁇ receptor 2 reveals the structural basis for receptor specificity. Acta crystallographica. Section D, Structural biology, 72(Pt 9), 1017–1025). The amino acid sequence of IFNGR2 is SEQ ID NO: 82 and can be found under UniProt Accession No. P38484.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 82 and/or the protein level thereof.
  • IL1R1 also known as CD121A, D2S1473, IL-1R-alpha, IL1R, IL1RA, P80, Interleukin 1 receptor, type I, interleukin 1 receptor type 1) encodes a cytokine receptor for interleukin 1 alpha (IL1A), interleukin 1 beta (IL1B), and interleukin 1 receptor antagonist (IL1RA) and has a role in cytokine induced immune and inflammatory responses.
  • IL1R1 also known as CD121A, D2S1473, IL-1R-alpha, IL1R, IL1RA, P80, Interleukin 1 receptor, type I, interleukin 1 receptor type 1
  • IL1A interleukin 1 alpha
  • IL1B interleukin 1 beta
  • IL1RA interle
  • IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients (Latiano et al. (2013). Associations between genetic polymorphisms in IL-33, IL1R1 and risk for inflammatory bowel disease. PloS one, 8(4), e62144).
  • the amino acid sequence of IL1R1 is SEQ ID NO: 83 and can be found under UniProt Accession No. P14778.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 83 and/or the protein level thereof.
  • IL1RAP also known as C3orf13, IL-1RAcP, IL1R3, interleukin 1 receptor accessory protein
  • IL1RAP encodes an accessory protein that forms a complex at the cell membrane with an interleukin 1 receptor and interleukin 1 to induce synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress.
  • IL1RAP is reported to be upregulated in Acute Myeloid Leukemia (AML) (De Boer, B., Sheveleva, S., Apelt, K., Vellenga, E., Mulder, A. B., Huls, G., & Jacob Schuringa, J. (2021).
  • AML Acute Myeloid Leukemia
  • the IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis. Haematologica, 106(12), 3067–3078).
  • the amino acid 51 WBD (US) 4854-8046-9185v2 sequence of IL1RAP is SEQ ID NO: 84 and can be found under UniProt Accession No. Q9NPH3.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 84 and/or the protein level thereof.
  • TNFRSF1 also known as TNFRSF1A, CD120a, FPF, MS5, TBP1, TNF-R, TNF-R-I, TNF-R55, TNFAR, TNFR1, TNFR1-d2, TNFR55, TNFR60, p55, p55-R, p60, tumor necrosis factor receptor superfamily member 1A, TNF receptor superfamily member 1A) encodes one of the major receptors for the tumor necrosis factor-alpha and can activate the transcription factor NF- ⁇ B, mediate apoptosis, and function as a regulator of inflammation.
  • TNFRSF1 also known as TNFRSF1A, CD120a, FPF, MS5, TBP1, TNF-R, TNF-R-I, TNF-R55, TNFAR, TNFR1, TNFR1-d2, TNFR55, TNFR60, p55, p55-R, p60, tumor necrosis factor receptor superfamily member 1A, TNF
  • the R92Q variant of the TNFRSF1A gene was identified as a new susceptibility locus for multiple sclerosis (Brumpfel, T., & Hohlfeld, R. (2009). Multiple sclerosis. TNFRSF1A, TRAPS and multiple sclerosis. Nature reviews. Neurology, 5(10), 528–529).
  • the amino acid sequence of TNFRSF1 is SEQ ID NO: 85 and can be found under UniProt Accession No. P19438.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 85 and/or the protein level thereof.
  • CCR6 (also known as BN-1, C-C CKR-6, CC-CKR-6, CCR-6, CD196, CKR-L3, CKRL3, CMKBR6, DCR2, DRY6, GPR29, GPRCY4, STRL22, C-C motif chemokine receptor 6, CD196) encodes a protein belonging to family A of G protein-coupled receptor superfamily and is expressed on B-cells, immature dendritic cells (DC), T-cells (Th1, Th2, Th17, Treg), natural killer T cells (NKT cells) and neutrophils. CCR6 is thought to recruit immature dendritic cells to sites of injury (Dieu et al.1998).
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 86 and/or the protein level thereof.
  • CD80 also known as Cluster of differentiation 80, B7, B7-1, B7.1, BB1, CD28LG, CD28LG1, LAB7 encodes a B7, type I membrane protein and is expressed specifically on DC, activated B-cells, and macrophages, but also T-cells. Expression levels of CD80 on dendritic cells are modulated during progression from an immature to a mature state (Zheng, Y., Manzotti, C. N., Liu, M., Burke, F., Mead, K. I., & Sansom, D. M. (2004). CD86 and CD80 differentially modulate the suppressive function of human regulatory T cells.
  • CD40LG also known as CD154, CD40L, HIGM1, IGM, IMD3, T-BAM, TNFSF5, TRAP, gp39, hCD40L, CD40 ligand
  • CD40LG also known as CD154, CD40L, HIGM1, IGM, IMD3, T-BAM, TNFSF5, TRAP, gp39, hCD40L, CD40 ligand
  • CD40L has a central role in costimulation and regulation of the immune response via T cell priming and activation of CD40- expressing immune cells (Grewal, I. S., & Flavell, R. A. (1998). CD40 and CD154 in cell- mediated immunity. Annual review of immunology, 16, 111–135).
  • the amino acid sequence of CD40LG is SEQ ID NO: 88 and can be found under UniProt Accession No. P29965.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 88 and/or the protein level thereof.
  • IL2RG (also known as CD132, CIDX, IL-2RG, IMD4, P64, SCIDX, SCIDX1, interleukin 2 receptor subunit gamma) encodes a cytokine receptor subunit that is common to the receptor complexes for at least IL-2, IL-4, IL-7, IL-9, IL-15.
  • An increased circulating level of IL2RG is found in inflammatory bowel disease (Nielsen, O. H., Kirman, I., Johnson, K., Giedlin, M., & Ciardelli, T. (1998).
  • the amino acid sequence of IL2RG is SEQ ID NO: 89 and can be found under UniProt Accession No. P31785. 53 WBD (US) 4854-8046-9185v2
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 89 and/or the protein level thereof.
  • CD40 also known as Bp50, CDW40, TNFRSF5, p50, Cluster of differentiation 40
  • CD40 encodes a type I transmembrane protein found on antigen-presenting cells that is required for their activation.
  • CD40 interacts with its binding partner CD40L to play a role in promoting germinal center formation and the production of class-switched antibodies (Karnell, J.
  • the amino acid sequence of CD40 is SEQ ID NO: 90 and can be found under UniProt Accession No. P25942.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 90 and/or the protein level thereof.
  • IL2RB (also known as CD122, IL15RB, P70-75, interleukin 2 receptor subunit beta, IMD63) encodes a type I membrane protein subunit of the interleukin 2 receptor and has a role in T cell-mediated immune responses.
  • IL2RB is thought to play a role in tumorigenesis, tumor metabolism, and immunity (Li, G., Wang, Y., & Cheng, Y. (2022).
  • IL2RB Is a Prognostic Biomarker Associated with Immune Infiltrates in Pan-Cancer. Journal of oncology, 2022, 2043880).
  • the amino acid sequence of IL2RB is SEQ ID NO: 91 and can be found under UniProt Accession No.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 91 and/or the protein level thereof.
  • IL18R1 also known as CD218a, CDw218a, IL-1Rrp, IL18RA, IL1RRP, interleukin 18 receptor 1, IL-18R-alpha, IL18Ralpha2, IL-18Ralpha
  • IL18R1 encodes a cytokine receptor that belongs to the interleukin 1 receptor family and is essential for IL18 mediated signal transduction.
  • IL18R1 is repressed during Th2 development (Yu, Q., Chang, H. C., Ahyi, A.
  • IL18R1 The amino acid sequence of IL18R1 is SEQ ID NO: 92 and can be found under UniProt Accession No. Q13478.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 92 and/or the protein level thereof.
  • IL7R also known as interleukin-7 receptor, CD127, IL7RA, Soluble Interleukin-7 Receptor, IL7RA
  • IL7R encodes a heterodimer consisting of interleukin-7 receptor- ⁇ (CD127) and common- ⁇ chain receptor (CD132).
  • the interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase (Schlissel, M. S., Durum, S. D., & Muegge, K. (2000).
  • the interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase.
  • TNFRSF14 (also known as Herpesvirus entry mediator, ATAR, CD270, HVEA, HVEM, LIGHTR, TR2, tumor necrosis factor receptor superfamily member 14, TNF receptor superfamily member 14) encodes a member of the TNF-receptor superfamily.
  • TNFRSF14 is thought to regulate the persistence of T helper memory cell populations (Soroosh et al. (2011). Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations. The Journal of experimental medicine, 208(4), 797–809).
  • the amino acid sequence of TNFRSF14 is SEQ ID NO: 94 and can be found under UniProt Accession No. Q92956.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 94 and/or the protein level thereof.
  • IL12RB (also known as IL12RB1, CD212, IL-12R-BETA1, IMD30, Interleukin 12 receptor beta 1 subunit, IL12 receptor beta 1 subunit, interleukin 12 receptor subunit beta 1) encodes a subunit of the interleukin 12 receptor and the interleukin 23 receptor.
  • IL12RB is essential for mycobacterial disease resistance and T cell differentiation (Reeme, A. E., Claeys, T. A., Aggarwal, P., Turner, A. J., Routes, J. M., Broeckel, U., & Robinson, R. T. (2019).
  • Human IL12RB1 expression is allele-biased and produces a novel IL12 response regulator. Genes and immunity, 20(3), 181–197).
  • the amino acid sequence of IL12RB is SEQ ID NO: 95 and can be found under UniProt Accession No. P42701.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 95 and/or the protein level thereof.
  • TNFRSF1B (also known as CD120b, TBPII, TNF-R-II, TNF-R75, TNFBR, TNFR1B, TNFR2, TNFR80, p75, p75TNFR, tumor necrosis factor receptor superfamily member 1B, TNF receptor superfamily member 1B) encodes one of two membrane receptors that binds tumor necrosis factor-alpha (TNF ⁇ ).
  • TNFRSF1B is associated with antineutrophil cytoplasmic antibody, an important biomarker in inflammatory bowel disease (Li, D., Silverberg, M. S., Haritunians, T., Dubinsky, M. C., Landers, C., Stempak, J.
  • TNFRSF1B Is Associated with ANCA in IBD. Inflammatory bowel diseases, 22(6), 1346–1352).
  • the amino acid sequence of TNFRSF1B is SEQ ID NO: 96 and can be found under UniProt Accession No. P20333.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 96 and/or the protein level thereof.
  • IL-11 (also known as AGIF, IL-11, interleukin 11, adipogenesis inhibitory factor) encodes a cytokine thought to regulate adipogenesis, osteoclastogenesis, neurogenesis and platelet maturation.
  • IL-11 is thought to contribute to the pathogenesis of autoimmune inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory conditions such as periodontitis, asthma, chronic 56 WBD (US) 4854-8046-9185v2 obstructive pulmonary disease, psoriasis and colitis (Fung, K. Y., Louis, C., Metcalfe, R. D., Kosasih, C.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 97 and/or the protein level thereof.
  • CXCL12 also known as Stromal cell-derived factor 1, IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1, C-X-C motif chemokine ligand 12 encodes a chemokine protein that is strongly chemotactic for lymphocytes and ubiquitously expressed.
  • CXCL12 plays an important role in embryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration of hematopoietic progenitor and stem cells, endothelial cells and most leukocytes (Janssens, R., Struyf, S., & Proost, P. (2016).
  • CXCL12 is SEQ ID NO: 98 and can be found under UniProt Accession No. P48061.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 98 and/or the protein level thereof.
  • CXCL16 CXCL16 (also known as Chemokine (C-X-C motif) ligand 16, SCYB16, SR- PSOX, CXCLG16) encodes a small cytokine that is induced by IFN-gamma and TNF-alpha.
  • CXCL16 is linked to the development of numerous autoimmune diseases (Bao et al. (2023). Role of the CXCR6/CXCL16 axis in autoimmune diseases. International immunopharmacology, 121, 110530).
  • the amino acid sequence of CXCL16 is SEQ ID NO: 99 and can be found under UniProt Accession No. Q9H2A7.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 99 and/or the protein level thereof.
  • ICAM1 also known as BB2, CD54, P3.58, intercellular adhesion molecule 1 encodes a surface glycoprotein expressed on endothelial cells and cells of the immune system. ICAM1 has been proposed to be a ligant in many LFA-1-dependent adhesion reactions (Rothlein, R., Dustin, M. L., Marlin, S. D., & Springer, T. A. (1986). A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. Journal of immunology (Baltimore, Md. : 1950), 137(4), 1270–1274).
  • the amino acid sequence of ICAM1 is SEQ ID NO: 100 and can be found under UniProt Accession No. P05362.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 100 and/or the protein level thereof.
  • PECAM1 also known as CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM- 1, endoCAM, platelet and endothelial cell adhesion molecule 1, PCAM-1) encodes a cell-cell adhesion protein that plays a role in removing aged neutrophils from the body.
  • Myocyte- enhancer factor 2 has been shown to transcriptionally activate PECAM1 and CXCR4 to activate the B-cell and NF- ⁇ B signaling pathways, leading to inflammatory cell infiltration and pulpitis progression (Liu, Y., Zhang, Z., Li, W., & Tian, S. (2020).
  • PECAM1 Combines With CXCR4 to Trigger Inflammatory Cell Infiltration and Pulpitis Progression Through Activating the NF- ⁇ B Signaling Pathway. Frontiers in cell and developmental biology, 8, 593653).
  • the amino acid sequence of PECAM1 is SEQ ID NO: 101 and can be found under UniProt Accession No. P16284.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 101 and/or the protein level thereof.
  • CXCR4 CXCR4 (also known as CD184, D2S201E, FB22, HM89, HSY3RR, LAP-3, LAP3, LCR1, LESTR, NPY3R, NPYR, NPYRL, NPYY3R, WHIM, WHIMS, C-X-C motif chemokine receptor 4, WHIMS1) encodes an alpha-chemokine receptor specific for stromal- derived-factor-1.
  • Cancer cell CXCR4 overexpression has been shown to contribute to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance (Chatterjee, S., Behnam Azad, B., & Nimmagadda, S. (2014). The intricate role of CXCR4 in cancer. Advances 58 WBD (US) 4854-8046-9185v2 in cancer research, 124, 31–82).
  • the amino acid sequence of CXCR4 is SEQ ID NO: 102 and can be found under UniProt Accession No. P61073.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 102 and/or the protein level thereof.
  • CD44 (also known as CDW44, CSPG8, ECMR-III, HCELL, HUTCH-I, IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp) encodes a cell-surface glycoprotein that is known to have a role in lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis.
  • CD44 isoforms are also known to be functionally involved in immune responses (Wittig, B. M., Stallmach, A., Zeitz, M., & Günthert, U. (2002). Functional involvement of CD44 variant 7 in gut immune response.
  • the amino acid sequence of CD44 is SEQ ID NO: 103 and can be found under UniProt Accession No. P16070.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 103 and/or the protein level thereof.
  • PTPRC (also known as B220, CD45, CD45R, GP180, L-CA, LCA, LY5, T200, protein tyrosine phosphatase, receptor type C) encodes a type I transmembrane protein that is a member of the protein tyrosine phosphatase (PTP) family.
  • PTPRC is thought to be essential for the innate immune system, is expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation (Al Barashdi, M. A., Ali, A., McMullin, M. F., & Mills, K. (2021).
  • PTPRC Protein tyrosine phosphatase receptor type C
  • the amino acid sequence of PTPRC is SEQ ID NO: 104 and can be found under UniProt Accession No. P08575.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 104 and/or the protein level thereof.
  • ITGAE also known as CD103, HUMINAE, integrin subunit alpha E encodes an integrin protein that binds integrin beta 7 to form the heterodimeric integrin molecule ⁇ E ⁇ 7.
  • ITGAE has been shown to have a role in the development of autoimmune diabetes in non-obese diabetic mice (Barrie, E. S., Lodder, M., Weinreb, P. H., Buss, J., Rajab, A., Adin, C., Mi, Q. S., & Hadley, G. A. (2015). Role of ITGAE in the development of autoimmune diabetes in non- obese diabetic mice.
  • ITGAE The Journal of endocrinology, 224(3), 235–243).
  • the amino acid sequence of ITGAE is SEQ ID NO: 105 and can be found under UniProt Accession No. P38570.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 105 and/or the protein level thereof.
  • ITGA5 also known as CD49e, FNRA, VLA5A, VLA-5, integrin subunit alpha 5 5) encodes a member of the integrin adhesion molecule family and is implicated in cancer metastasis and oncogenesis.
  • ITGA5 has been found to engage in remolding glioma immune infiltration and immune microenvironment, manifested by higher immune cell infiltration when ITGA5 is highly expressed (Li, S., Zhang, N., Liu, S., Zhang, H., Liu, J., Qi, Y., Zhang, Q., & Li, X. (2022).
  • ITGA5 Is a Novel Oncogenic Biomarker and Correlates With Tumor Immune Microenvironment in Gliomas. Frontiers in oncology, 12, 844144).
  • ITGA5 has also been shown to be correlated with immune infiltration in gastrointestinal tumors (Zhu, H., Wang, G., Zhu, H., & Xu, A. (2021).
  • ITGA5 is a prognostic biomarker and correlated with immune infiltration in gastrointestinal tumors. BMC cancer, 21(1), 269).
  • the amino acid sequence of ITGA5 is SEQ ID NO: 106 and can be found under UniProt Accession No. P08648.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 106 and/or the protein level thereof.
  • HAVCR2 HAVCR2 (also known as HAVcr-2, KIM-3, TIM3, TIMD-3, TIMD3, Tim-3, CD366, hepatitis A virus cellular receptor 2, SPTCL) encodes a member of TIM immunoregulatory proteins family and is known to be a regulator of the immune response.
  • SPTCL hepatitis A virus cellular receptor 2, SPTCL
  • TIM-3 acts as an immune checkpoint and plays an aimportant role in autoimmune disease, chronic viral infections, and tumors (Zhao, L., Cheng, S., Fan, L., 60 WBD (US) 4854-8046-9185v2 Zhang, B., & Xu, S. (2021).
  • TIM-3 An update on immunotherapy. International immunopharmacology, 99, 107933).
  • the amino acid sequence of HAVCR2 is SEQ ID NO: 107 and can be found under UniProt Accession No. Q8TDQ0.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 107 and/or the protein level thereof.
  • CD36 also known as BDPLT10, CHDS7, FAT, GP3B, GP4, GPIV, PASIV, SCARB3
  • CD36 also known as BDPLT10, CHDS7, FAT, GP3B, GP4, GPIV, PASIV, SCARB3
  • CD36 a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate.
  • the amino acid sequence of CD36 is SEQ ID NO: 108 and can be found under UniProt Accession No. P16671.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 108.
  • PILRA also known as FDF03 or paired immunoglobin like type 2 receptor alpha encodes an inhibitory receptor that is mainly expressed on myeloid cells and negatively regulates neutrophil infiltration during inflammation. PILRA is thought to control monocyte mobility through regulating integrin signaling and inhibiting CD99-CD99 binding (Kohyama, M., Matsuoka, S., Shida, K., Sugihara, F., Aoshi, T., Kishida, K., Ishii, K. J., & Arase, H. (2016). Monocyte infiltration into obese and fibrilized tissues is regulated by PILR ⁇ . European journal of immunology, 46(5), 1214–1223).
  • the amino acid sequence of PILRA is SEQ ID NO: 109 and can be found under UniProt Accession No. Q9UKJ1.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 109 and/or the protein level thereof.
  • LILRB1 (also known as CD85J, ILT-2, ILT2, LIR-1, LIR1, MIR-7, MIR7, PIR- B, PIRB, leukocyte immunoglobulin like receptor B1) encodes a receptor that is a member of the leukocyte immunoglobulin-like receptor (LIR) family and is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response.
  • LILRB1 is thought to engage major histocompatibility complex (MHC) class I to regulate the effector function of innate immune cells (Barkal et al. (2016).
  • MHC major histocompatibility complex
  • LILRB1 Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nature immunology, 19(1), 76–84).
  • the amino acid sequence of LILRB1 is SEQ ID NO: 110 and can be found under UniProt Accession No. Q8NHL6.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 110 and/or the protein level thereof.
  • NECTIN2 (also known as Poliovirus receptor-related 2, CD112, HVEB, PRR2, PVRR2, PVRL2, nectin cell adhesion molecule 2) encodes a single-pass type I membrane glycoprotein that is is one of the plasma membrane components of adherens junctions. NECTIN2 is thought to influence cell apoptosis by regulating ANXA2 expression in neuroblastoma (Zhang, S., Jiang, C., Su, Y., Gui, J., Yue, Z., Jian, B., He, S., & Ma, X. (2023). Nectin2 is thought to influence cell apoptosis by regulating ANXA2 expression in neuroblastoma.
  • NECTIN2 is SEQ ID NO: 111 and can be found under UniProt Accession No. Q92692.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 111 and/or the protein level thereof.
  • PLXNB2 (also known as MM1, Nbla00445, PLEXB2, dJ402G11.3, plexin B2) encodes a transmembrane protein that acts as a receptor for angiogenin in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells (Yu et al. (2017). Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin. Cell, 171(4), 849– 864.e25).
  • PXNB2 is thought to orchestrate cytoskeletal tension and cell-cell/cell-matrix adhesion 62 WBD (US) 4854-8046-9185v2 (Alves et al. (2021). Plexin-B2 orchestrates collective stem cell dynamics via actomyosin contractility, cytoskeletal tension and adhesion. Nature communications, 12(1), 6019).
  • the amino acid sequence of PLXNB2 is SEQ ID NO: 112 and can be found under UniProt Accession No. O15031.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 112 and/or the protein level thereof.
  • TLR4 (also known as ARMD10, CD284, TLR-4, TOLL, toll like receptor 4) encodes a transmembrane protein whose activation leads to intracellular signaling pathway NF- ⁇ B and inflammatory cytokine production. Prolonged activation of TLR4 is thought to be linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer (Ciesielska, A., Matyjek, M., & Kwiatkowska, K. (2021). TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cellular and molecular life sciences : CMLS, 78(4), 1233–126).
  • TLR4 The amino acid sequence of TLR4 is SEQ ID NO: 113 and can be found under UniProt Accession No. O00206.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 113 and/or the protein level thereof.
  • ITGA4 ITGA4 (also known as CD49D, IA4, integrin subunit alpha 4) encodes an integrin alpha subunit that makes up half of ⁇ 4 ⁇ 1 lymphocyte homing receptor.
  • ITGA4 is thought to play an essential role in mediating both cell-cell and cell-matrix interactions in Chronic lymphocytic leukemia (CLL)-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages.
  • the amino acid sequence of ITGA4 is SEQ ID NO: 114 and can be found under UniProt Accession No. P13612.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 114 and/or the protein level thereof.
  • CD47 also known as integrin associated protein, IAP, MER6, OA3 encodes a transmembrane protein belonging to the immunoglobulin superfamily and plays important roles in immune and angiogenic responses.
  • CD47 is known to be upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis (Jaiwal et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138(2), 271–285).
  • the amino acid sequence of CD47 is SEQ ID NO: 115 and can be found under UniProt Accession No.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 115 and/or the protein level thereof.
  • NOTCH2 also known as Neurogenic locus notch homolog protein 2, AGS2, HJCYS, hN2, Notch-2, notch 2, notch receptor 2 encodes a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
  • NOTCH2 is thought to be involved in intestinal immunity, given that the fate of mast cells and a subset of DCs is regulated by Notch2 in the intestine (Sakata-Yanagimoto, M., & Chiba, S. (2012). Notch2 and immune function. Current topics in microbiology and immunology, 360, 151–161).
  • the amino acid sequence of NOTCH2 is SEQ ID NO: 116 and can be found under UniProt Accession No. Q04721.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 116 and/or the protein level thereof.
  • TGFBR2 also known as Transforming growth factor, beta receptor II (70/80kDa), AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2, RIIC, TAAD2, TGFR-2, TGFbeta- RII, transforming growth factor beta receptor 2, TBR-ii, TBRII
  • TGFBR2 also known as Transforming growth factor, beta receptor II (70/80kDa), AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2, RIIC, TAAD2, TGFR-2, TGFbeta- RII, transforming growth factor beta receptor 2, TBR-ii, TBRII
  • TGFBR2 also known as Transforming growth factor, beta receptor II (70/80kDa), AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2, RIIC, TAAD2, TGFR-2, TGFbeta- RII, transforming growth factor beta receptor 2, TBR-ii
  • TGFBR2 transforming growth factor- ⁇ receptor 2
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 117 and/or the protein level thereof.
  • NRP2 also known as Neuropilin 2, NP2, NPN2, PRO2714, VEGF165R2 encodes a family member of neuropilins, cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors.
  • NRP2 has been proposed to be a novel angiogenic player by promoting ITGA5-mediated endothelial cell adhesion and migration on fibronectin.
  • the amino acid sequence of NRP2 is SEQ ID NO: 118 and can be found under UniProt Accession No. O60462.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 118 and/or the protein level thereof.
  • CD99 also known as single-chain type-1 glycoprotein, HBA71, MIC2, MIC2X, MIC2Y, MSK5X
  • CD99 encodes an O-glycosylated transmembrane protein that is believed to be involved in T-cell adhesion and apoptosis of double positive T-cells.
  • Activation of CD99 is thought to inhibit cell-extracellular matrix adhesion by suppressing ⁇ (1) integrin affinity (Lee et al. (2012).
  • the activation of CD99 inhibits cell-extracellular matrix adhesion by suppressing ⁇ (1) integrin affinity.
  • the amino acid sequence of CD99 is SEQ ID NO: 119 and can be found under UniProt Accession No. P14209.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 119 and/or the protein level thereof.
  • TIGIT also known as T cell immunoreceptor with Ig and ITIM domains, VSIG9, VSTM3, WUCAM
  • TIGIT also known as T cell immunoreceptor with Ig and ITIM domains, VSIG9, VSTM3, WUCAM
  • TIGIT is known to interact with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions (Harjun internationaleä, H., & Guillerey, C. 65 WBD (US) 4854-8046-9185v2 (2020). TIGIT as an emerging immune checkpoint. Clinical and experimental immunology, 200(2), 108–119).
  • the amino acid sequence of TIGIT is SEQ ID NO: 120 and can be found under UniProt Accession No. Q495A1.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 120 and/or the protein level thereof.
  • IL6ST also known as Glycoprotein 130, CD130, CDW130, GP130, IL-6RB, interleukin 6 signal transducer
  • IL6ST encodes a transmembrane protein that acts as a signal transducing molecule following cytokine engagement.
  • IL6ST is thought to be a predictive biomarker in breast cancer (Mart ⁇ nez-Pérez, C., Leung, J., Kay, C., Meehan, J., Gray, M., Dixon, J. M., & Turnbull, A. K. (2021).
  • the Signal Transducer IL6ST (gp130) as a Predictive and Prognostic Biomarker in Breast Cancer. Journal of personalized medicine, 11(7), 618).
  • the amino acid sequence of IL6ST is SEQ ID NO: 121 and can be found under UniProt Accession No. P40189.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 121 and/or the protein level thereof.
  • TGFB2 TGFB2 (also known as LDS4, TGF-beta2, transforming growth factor beta 2, G- TSF, Glioblastoma-derived T-cell suppressor factor, Polyergin, Cetermin) encodes a secreted ligand of the TGF-beta family of proteins.
  • TGFB2 In mice, TGFB2 is known to be secreted from adipose issue in response to exercise and improves glucose tolerance (Takahashi et al. (2019). TGF- ⁇ 2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nature metabolism, 1(2), 291–303).
  • the amino acid sequence of TGFB2 is SEQ ID NO: 122 and can be found under UniProt Accession No. P61812.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 122 and/or the protein level thereof.
  • CD74 also known as HLA class II histocompatibility antigen gamma chain, HLA-DR antigens-associated invariant chain, DHLAG, HLADG, II, Ia-GAMMA, CD74 molecule, p33, CLIP
  • CD74 encodes a non-polymorphic type II transmembrane glycoprotein that plays important roles in many inflammatory diseases, such as liver fibrosis, type I diabetes, systemic lupus erythematosus, and Alzheimer disease (Su, H., Na, N., Zhang, X., & Zhao, Y. (2017).
  • the biological function and significance of CD74 in immune diseases such as liver fibrosis, type I diabetes, systemic lupus erythematosus.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 123 and/or the protein level thereof.
  • TNFRSF25 (also known as APO-3, DDR3, DR3, LARD, TNFRSF12, TR3, TRAMP, WSL-1, WSL-LR, tumor necrosis factor receptor superfamily member 25, TNF receptor superfamily member 25, GEF720, PLEKHG5) encodes a cell surface receptor of the tumor necrosis factor receptor superfamily which mediates apoptotic signalling and differentiation.
  • Tregs are known to express DR2 and demonstrate DR3-mediated activation of p38, ERK, and NF ⁇ B (Bittner, S., Knoll, G., & Ehrenschwender, M. (2017). Death receptor 3 signaling enhances proliferation of human regulatory T cells.
  • CD55 also known as Complement decay-accelerating factor, CR, CROM, DAF, TC, CD55 molecule (Cromer blood group), CHAPLE
  • CD55 encodes a glycoprotein involved in the regulation of the complement cascade.
  • CD55 is a major regulator of the alternative and classical pathways of complement activation and is expressed on all serum-exposed cells (Lea S. (2002).
  • CD55 Interactions of CD55 with non-complement ligands. Biochemical Society transactions, 30(Pt 6), 67 WBD (US) 4854-8046-9185v2 1014–1019).
  • the amino acid sequence of CD55 is SEQ ID NO: 125 and can be found under UniProt Accession No. P08174.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 125 and/or the protein level thereof.
  • NRP1 (also known as BDCA4, CD304, NP1, NRP, VEGF165R, Neuropilin 1) encodes a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor and semaphoring family members. NRP1 is thought to restrict CD8+ T cell reinvigoration in response to checkpoint inhibitors and act as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance (Chuckran, C. A., Liu, C., Bruno, T. C., Workman, C. J., & Vignali, D. A. (2020).
  • Neuropilin-1 a checkpoint target with unique implications for cancer immunology and immunotherapy. Journal for immunotherapy of cancer, 8(2), e000967).
  • the amino acid sequence of NRP1 is SEQ ID NO: 126 and can be found under UniProt Accession No. O14786.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 126 and/or the protein level thereof.
  • FGFR1 (also known as BFGFR, CD331, CEK, FGFBR, FGFR-1, FLG, FLT-2, FLT2, HBGFR, HH2, HRTFDS, KAL2, N-SAM, OGD, bFGF-R-1, ECCL, fibroblast growth factor receptor 1) encodes a member of the fibroblast growth factor receptor (FGFR) family that possesses tyrosine kinase activity.
  • FGFR-1 is known to be expressed during wound healing (Takenaka, H., Kishimoto, S., Tooyama, I., Kimura, H., & Yasuno, H. (1997). Protein expression of fibroblast growth factor receptor-1 in keratinocytes during wound healing in rat skin.
  • the amino acid sequence of FGFR1 is SEQ ID NO: 127 and can be found under UniProt Accession No. P11362.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 127 and/or the protein level thereof.
  • ITGAV is overexpressed in gastric cancer and is associated with poorer prognostic outcomes (Wang, H., Chen, H., Jiang, Z., Lin, Y., Wang, X., Xiang, J., & Peng, J. (2019). Integrin subunit alpha V promotes growth, migration, and invasion of gastric cancer cells. Pathology, research and practice, 215(9), 152531 ).
  • the amino acid sequence of ITGAV is SEQ ID NO: 128 and can be found under UniProt Accession No. P06756.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 128 and/or the protein level thereof.
  • JAM3 (also known as JAM-2, JAM-3, JAM-C, JAMC, junctional adhesion molecule 3, Junctional adhesion molecule C) encodes a member of the junctional adhesion molecule family, which has been linked to epithelial and cancer cell proliferation. JAM3 has been found to promote migration and suppresses apoptosis of renal carcinoma cell lines (Li, X., Yin, A., Zhang, W., Zhao, F., Lv, J., Lv, J., & Sun, J. (2018). Jam3 promotes migration and suppresses apoptosis of renal carcinoma cell lines. International journal of molecular medicine, 42(5), 2923–2929).
  • JAM3 The amino acid sequence of JAM3 is SEQ ID NO: 129 and can be found under UniProt Accession No. Q9BX67.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 129 and/or the protein level thereof.
  • JAM2 JAM2 (also known as C21orf43, CD322, JAM-B, JAMB, PRO245, VE-JAM, VEJAM, junctional adhesion molecule 2, IBGC8, Junctional adhesion molecule B) encodes a receptor that mediates JAM2 adhesion to T-cells. Upregulation of JAM3 protein on peripheral blood lymphocytes has been observed following activation (Arrate, M.
  • JAM3 human junctional adhesion molecule 3
  • the amino acid sequence of JAM2 is SEQ ID NO: 130 and can be found under UniProt Accession No. P57087. 69 WBD (US) 4854-8046-9185v2
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 130 and/or the protein level thereof.
  • F11R (also known as Junctional adhesion molecule A, 9130004G24, AA638916, ESTM33, JAM, JAM-1, JAM-A, Jcam, Jcam1, Ly106, CD321, JAM1, JAMA, KAT, PAM-1, F11 receptor) encodes a transmembrane glycoprotein of the immunoglobulin superfamily, which is mainly located in epithelial and endothelial cell tight junctions and also expressed on circulating platelets and leukocytes.
  • F11R has a role in the regulation of various biological processes, as diverse as paracellular permeability, tight junction formation and maintenance, leukocyte transendothelial migration, epithelial-to-mesenchymal transition, angiogenesis, reovirus binding, and platelet activation (Czubak-Prowizor, K., Babinska, A., & Swiatkowska, M. (2022).
  • the F11 Receptor (F11R)/Junctional Adhesion Molecule-A (JAM-A) (F11R/JAM-A) in cancer progression. Molecular and cellular biochemistry, 477(1), 79–98).
  • the amino acid sequence of F11R is SEQ ID NO: 131 and can be found under UniProt Accession No.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 131 and/or the protein level thereof.
  • PTPRM also known as Receptor-type tyrosine-protein phosphatase mu, PTPRL1, R-PTP-MU, RPTPM, RPTPU, hR-PTPu, protein tyrosine phosphatase, receptor type M, protein tyrosine phosphatase receptor type M) encodes a transmembrane receptor type tyrosine phosphatase.
  • PTPRM is thought to be a dysregulated candidate tumor suppressor gene in small intestinal neuroendocrine tumors (Barazeghi, E., Hellman, P., Westin, G., & St ⁇ lberg, P. (2019).
  • PTPRM a candidate tumor suppressor gene in small intestinal neuroendocrine tumors. Endocrine connections, 8(8), 1126–1135).
  • the amino acid sequence of PTPRM is SEQ ID NO: 132 and can be found under UniProt Accession No. P28827.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 132 and/or the protein level thereof.
  • ITGA8 also known as Integrin alpha-8 or integrin subunit alpha 8 encodes a single-pass type 1 membrane protein that plays an important role in wound-healing and organogenesis.
  • ITGA8 signalling is thought to attenuate chronic renal interstitial fibrosis by reducing fibroblast activation (Marek, I., Lichtneger, T., Cordasic, N., Hilgers, K. F., Volkert, G., Fahlbusch, F., Rascher, W., Hartner, A., & Menendez-Castro, C. (2016).
  • Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover. PloS one, 11(3), e0150471).
  • the amino acid sequence of ITGA8 is SEQ ID NO: 133 and can be found under UniProt Accession No. P53708.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 133 and/or the protein level thereof.
  • ACVR1 (also known as Activin A receptor type I, ACTRI, ACVR1A, ACVRLK2, ALK2, FOP, SKR1, TSRI, activin A receptor type 1) encodes a bone morphogenetic protein type I receptor of the TGF ⁇ receptor superfamily. ACVR1 overactivity has been found to result in increased macrophage inflammatory responses (Matsuo, K., Lepinski, A., Chavez, R. D., Barruet, E., Pereira, A., Moody, T. A., Ton, A. N., Sharma, A., Hellman, J., Tomoda, K., Nakamura, M. C., & Hsiao, E. C. (2021).
  • ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone, 153, 116129).
  • the amino acid sequence of ACVR1 is SEQ ID NO: 134 and can be found under UniProt Accession No. Q04771.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 134 and/or the protein level thereof.
  • BMPR2 (also known as Bone morphogenetic protein receptor type II, BMPR-II, BMPR3, BMR2, BRK-3, POVD1, PPH1, T-ALK, bone morphogenetic protein receptor type 2) encodes a a serine/threonine receptor kinase that binds binds bone morphogenetic proteins. Loss of function mutations in BMPR2 have been found to be the most common genetic factor in Pulmonary Arterial Hypertension (Dannewitz Prosseda, S., Ali, M. K., & Spiekerkoetter, E. (2020). Novel Advances in Modifying BMPR2 Signaling in PAH. Genes, 12(1), 8).
  • the amino 71 WBD (US) 4854-8046-9185v2 acid sequence of BMPR2 is SEQ ID NO: 135 and can be found under UniProt Accession No. Q13873.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 135 and/or the protein level thereof.
  • F2R also known as Proteinase-activated receptor 1, protease-activated receptor 1, CHTR, PAR-1, PAR1, TR, Coagulation factor II receptor, coagulation factor II thrombin receptor
  • GPCR G-protein-coupled receptor
  • F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NF ⁇ B signaling pathways.
  • the amino acid sequence of F2R is SEQ ID NO: 136 and can be found under UniProt Accession No. P25116.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 136 and/or the protein level thereof.
  • TGFBR1 also known as Transforming growth factor beta receptor I (activin A receptor type II-like kinase, 53kDa), AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1, LDS1A, LDS2A, MSSE, SKR4, TGFR-1, tbetaR-I, transforming growth factor beta receptor 1, TBRI, TBR-i) encodes a transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines.
  • TGFBR1 also known as Transforming growth factor beta receptor I (activin A receptor type II-like kinase, 53kDa), AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1, LDS1A, LDS2A, MSSE, SKR4, TGFR-1, t
  • Endothelial cells angiogenesis has been found to be suppressed by miR-210-3p through the suppression of TGFBR1 mRNA translation (Tang, H., Zhu, W., Cao, L., Zhang, J., Li, J., Ma, D., & Guo, C. (2022).
  • miR-210-3p protects against osteoarthritis through inhibiting subchondral angiogenesis by targeting the expression of TGFBR1 and ID4. Frontiers in immunology, 13, 982278).
  • the amino acid sequence of TGFBR1 is SEQ ID NO: 137 and can be found under UniProt Accession No. P36897.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 137 and/or the protein level thereof.
  • LRP1 also known as alpha-2-macroglobulin receptor, apolipoprotein E receptor, cluster of differentiation 91, A2MR, APOER, APR, CD91, IGFBP3R, LRP, LRP1A, TGFBR5, low density lipoprotein receptor-related protein 1, LDL receptor related protein 1, KPA, IGFBP3R1, IGFBP-3R
  • LRP1 also known as alpha-2-macroglobulin receptor, apolipoprotein E receptor, cluster of differentiation 91, A2MR, APOER, APR, CD91, IGFBP3R, LRP, LRP1A, TGFBR5, low density lipoprotein receptor-related protein 1, LDL receptor related protein 1, KPA, IGFBP3R1, IGFBP-3R
  • LRP1 A chameleon receptor of lung inflammation and repair.
  • Matrix biology journal of the International Society for Matrix Biology, 68-69, 366–381).
  • the amino acid sequence of LRP1 is SEQ ID NO: 138 and can be found under UniProt Accession No. Q07954.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 138 and/or the protein level thereof.
  • EDNRB also known as Endothelin receptor type B, ABCDS, ET-B, ET-BR, ETB, ETBR, ETRB, HSCR, HSCR2, WS4A, ETB1
  • EDNRB signaling has been found to promote proliferation and differentiation of melanocyte stem cells (Takeo, M., Lee, W., Rabbani, P., Sun, Q., Hu, H., Lim, C. H., Manga, P., & Ito, M. (2016). EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling.
  • EDNRB The amino acid sequence of EDNRB is SEQ ID NO: 139 and can be found under UniProt Accession No. P24530.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 139 and/or the protein level thereof.
  • ITGB5 is known to promote tumor development in several carcinomas (Wen, X., Chen, S., Chen, X., Qiu, H., Wang, W., Zhang, N., Liu, W., Wang, T., Ding, X., & Zhang, L. (2022). ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway. Frontiers in oncology, 12, 887068). The amino acid sequence of ITGB5 is SEQ ID NO: 140 and can be found under UniProt Accession No. P18084.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 140 and/or the protein level thereof.
  • ITGB8 also known as Integrin beta-8 or integrin subunit beta 8 encodes a single-pass type I membrane protein with a VWFA domain and four cysteine-rich repeats that is a member of the integrin beta chain family. ITGB8 is thought to mediate release of active TGF- ⁇ 1 from the latent TGF- ⁇ 1/GARP complex on T regulatory cells (Edwards, J. P., Thornton, A. M., & Shevach, E. M. (2014).
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 141 and/or the protein level thereof.
  • ACVRL1 (also known as Serine/threonine-protein kinase receptor R3, ACVRLK1, ALK-1, ALK1, HHT, HHT2, ORW2, SKR3, TSR-I, activin A receptor like type 1) encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands.
  • ACVRL1 is thought to suppress plasmacytoid DC development while enhancing that of CD8 ⁇ (+) DCs (Verma, R., Jaiswal, H., Chauhan, K. S., Kaushik, M., & Tailor, P. (2016). Cutting Edge: ACVRL1 Signaling Augments CD8 ⁇ + Dendritic Cell Development.
  • the amino acid sequence of ACVRL1 is SEQ ID NO: 142 and can be found under UniProt Accession No. P37023.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 142 and/or the protein level thereof.
  • GLG1 also known as Golgi apparatus protein 1, CFR-1, ESL-1, MG-160, MG160, golgi glycoprotein 1 encodes an intracellular fibroblast growth factor receptor.
  • GLG1 mRNA expression has been found to be upregulated by memantine, an NMDA antagonist, in a concentration dependent manner.
  • the amino acid sequence of GLG1 is SEQ ID NO: 143 and can be found under UniProt Accession No. Q92896.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 143 and/or the protein level thereof.
  • ITGA6 also known as Integrin alpha-6, CD49f, ITGA6B, VLA-6, integrin subunit alpha 6, JEB6 encodes a member of the integrin alpha chain family of proteins.
  • ITGA6 gene silencing by RNA interference modulates the expression of a large number of cell migration- related genes in human thymic epithelial cells. BMC genomics, 14 Suppl 6(Suppl 6), S3).
  • the amino acid sequence of ITGA6 is SEQ ID NO: 144 and can be found under UniProt Accession No. P23229.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 144 and/or the protein level thereof.
  • ALOX5 also known as Arachidonate 5-lipoxygenase, 5-lipoxygenase, 5-LOX, 5-LO encodes a member of the lipoxygenase family of enzymes.
  • Elevated levels of ALOX5 75 WBD (US) 4854-8046-9185v2 have been found to contribute to autophagy and ferroptosis in vitro and in vivo (Wang, M., Zeng, G., Xiong, B., Zhu, X., Guo, J., Chen, D., Zhang, S., Luo, M., Guo, L., & Cai, L. (2023).
  • ALOX5 promotes autophagy-dependent ferroptosis by activating the AMPK/mTOR pathway in melanoma. Biochemical pharmacology, 212, 115554).
  • the amino acid sequence of ALOX5 is SEQ ID NO: 145 and can be found under UniProt Accession No.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 145 and/or the protein level thereof.
  • CD4 also known as cluster of differentiation 4, OKT4D, IMD79
  • CD4 encodes a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR).
  • TCR T-cell receptor
  • the amino acid sequence of CD4 is SEQ ID NO: 146 and can be found under UniProt Accession No. P01730.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 146 and/or the protein level thereof.
  • CEACAM5 (also known as Carcinoembryonic antigen-related cell adhesion molecule 5, Cluster of Differentiation 66e, CD66e, CEA, carcinoembryonic antigen related cell adhesion molecule 5, CEA cell adhesion molecule 5) encodes a member of the carcinoembryonic antigen (CEA) gene family and has a role in adhesion between epithelial cells in the embryonic intestine and colon tumors (Benchimol, S., Fuks, A., Jothy, S., Beauchemin, N., Shirota, K., & Stanners, C. P. (1989).
  • CEA carcinoembryonic antigen
  • Carcinoembryonic antigen a human tumor marker, functions as an intercellular adhesion molecule. Cell, 57(2), 327–334).
  • the amino acid sequence of CEACAM5 is SEQ ID NO: 147 and can be found under UniProt Accession No. P06731.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 147 and/or the protein level thereof.
  • ITGAX also known as Integrin, alpha X (complement component 3 receptor 4 subunit), CD11C, SLEB6, integrin subunit alpha X) encodes a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst.
  • ITGAX has been found to regulate late stage T cell development in the thymus (Hou, L., & Yuki, K. (2022). CD11c regulates late-stage T cell development in the thymus. Frontiers in immunology, 13, 1040818).
  • the amino acid sequence of ITGAX is SEQ ID NO: 148 and can be found under UniProt Accession No. P20702.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 148 and/or the protein level thereof.
  • TNFRSF10B (also known as TRAIL receptor 2, CD262, DR5, KILLER, KILLER/DR5, TRAIL-R2, TRAILR2, TRICK2, TRICK2A, TRICK2B, TRICKB, ZTNFR9, tumor necrosis factor receptor superfamily member 10b, TNF receptor superfamily member 10b) encodes a receptor for the cytotoxic ligand TNFSF10/TRAIL and transduces an apoptosis signal.
  • TNFRSF10B has been shown to promote neuronal injury and motor dysfunction in Parkinson's disease (Dai, M., Yan, L., Yu, H., Chen, C., & Xie, Y. (2023).
  • TNFRSF10B is involved in motor dysfunction in Parkinson's disease by regulating exosomal ⁇ -synuclein secretion from microglia. Journal of chemical neuroanatomy, 129, 102249).
  • the amino acid sequence of TNFRSF10B is SEQ ID NO: 149 and can be found under UniProt Accession No. O14763.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 149 and/or the protein level thereof.
  • CSF3R (also known as granulocyte colony-stimulating factor receptor, Cluster of Differentiation 114, CD114, GCSFR, colony stimulating factor 3 receptor, SCN7) encodes a a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF).
  • G-CSF granulocyte colony-stimulating factor
  • CSF3R signaling involves the recruitment of non-receptor protein tyrosine kinases and their dependent signaling pathways of serine/threonine kinases, tyrosine phosphatases, and lipid second messengers (Mehta, H. M., & Corey, S. J. (2021).
  • G-CSF the guardian of granulopoiesis.
  • CSF3R The amino acid sequence of CSF3R is SEQ ID NO: 150 and can be found under UniProt Accession No. Q99062.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 150 and/or the protein level thereof.
  • CSF1R CSF1R (also known as Colony stimulating factor 1 receptor, C-FMS, CD115, CSF-1R, CSFR, FIM2, FMS, HDLS, M-CSF-R, BANDDOS, HDLS1) encodes.
  • CSF1R encodes a receptor that is highy expressed in myeloid cells and can be activated by colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34).
  • CSF1R has important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia (Stanley, E. R., & Chitu, V. (2014). CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor perspectives in biology, 6(6), a021857).
  • the amino acid sequence of CSF1R is SEQ ID NO: 151 and can be found under UniProt Accession No. P07333.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 151 and/or the protein level thereof.
  • LILRB3 also known as Leukocyte immunoglobulin-like receptor subfamily B member 3, CD85A, HL9, ILT-5, ILT5, LILRA6, LIR-3, LIR3, PIRB, PIR-B, leukocyte immunoglobulin like receptor B3 encodes a receptor expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response.
  • LILRB3 has been proposed as a putative immune cell surface receptor for APOE (Zhou, J., Wang, Y., Huang, G., Yang, M., Zhu, Y., Jin, C., Jing, D., Ji, K., & Shi, Y. (2023).
  • LilrB3 is a putative cell surface receptor of APOE4. Cell research, 33(2), 116–130).
  • the amino acid sequence of LILRB3 is SEQ ID NO: 152 and can be found under UniProt Accession No. Q6PI73.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 152 and/or the protein level thereof.
  • FPR3 also known as N-formyl peptide receptor 3, FML2_HUMAN, FMLPY, FPRH1, FPRH2, FPRL2, RMLP-R-I, FMLP-R-II, formyl peptide receptor 3 encodes a G protein-coupled receptor essential for neutrophil activation.
  • FPR3 has been identified as an important immune-related biomarker for predicting poor prognosis for breast cancer (Qi, J., Liu, Y., Hu, J., Lu, L., Dou, Z., Dai, H., Wang, H., & Yang, W. (2021).
  • FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer. Frontiers in pharmacology, 11, 593247).
  • the amino acid sequence of FPR3 is SEQ ID NO: 153 and can be found under UniProt Accession No. P25089.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 153 and/or the protein level thereof.
  • CD28 also known as Cluster of Differentiation 28, Tp44
  • CD28 encodes a B7 receptor that has a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation (Esensten, J. H., Helou, Y.
  • CD28 Costimulation From Mechanism to Therapy. Immunity, 44(5), 973–988).
  • the amino acid sequence of CD28 is SEQ ID NO: 154 and can be found under UniProt Accession No. P10747.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 154 and/or the protein level thereof.
  • CTLA4 also known as cytotoxic T-lymphocyte-associated protein 4, ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4, GSE, IDDM12, cytotoxic T-lymphocyte associated protein 4
  • CTLA4 has been found to inhibit CD28-dependent IL-2 production (Walunas, T. L., Bakker, C. Y., & Bluestone, J. A. (1996).
  • CTLA-4 ligation blocks CD28-dependent T cell activation. The Journal of experimental medicine, 183(6), 2541–2550).
  • the amino acid sequence of CTLA4 is SEQ ID NO: 155 and can be found under UniProt Accession No. P16410. 79 WBD (US) 4854-8046-9185v2
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 155 and/or the protein level thereof.
  • IGF2R also known as Insulin-like growth factor 2 receptor, cation-independent mannose-6-phosphate receptor, CD222, CIMPR, M6P-R, MPR1, MPRI, M6P/MPR 300, CI- M6PR, MPR300, insulin like growth factor 2 receptor
  • IGF2R also known as Insulin-like growth factor 2 receptor, cation-independent mannose-6-phosphate receptor, CD222, CIMPR, M6P-R, MPR1, MPRI, M6P/MPR 300, CI- M6PR, MPR300, insulin like growth factor 2 receptor
  • IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages. Science advances, 6(48), eabb7389).
  • IGF2R The amino acid sequence of IGF2R is SEQ ID NO: 156 and can be found under UniProt Accession No. P11717.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 156 and/or the protein level thereof.
  • ITGAL also known as Integrin alpha L, antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide, CD11A, LFA-1, LFA1A
  • ITGAL also known as Integrin alpha L, antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide, CD11A, LFA-1, LFA1A
  • ITGAL has been found to be positively associated with most immune checkpoint genes and cytokines (Li, R., Wu, X., Xue, K., & Li, J. (2022). ITGAL infers adverse prognosis and correlates with immunity in acute myeloid leukemia. Cancer cell international, 22(1), 268).
  • the amino acid sequence of ITGAL is SEQ ID NO: 157 and can be found under UniProt Accession No. P20701.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 157 and/or the protein level thereof.
  • RPSA Ribosomal protein SA
  • 37LRP 37LRP
  • 67LR ICAS
  • LAMBR LAMR1
  • LBP LBP/p40
  • LRP LRP/LR
  • NEM/1CHD4 SA
  • lamR p40
  • Ribosomal protein SA encodes a protein component of the small ribosomal subunit and acts as a cell surface receptor 80 WBD (US) 4854-8046-9185v2 for laminin.
  • RPSA governs critical cellular processes including growth, survival, migration, protein synthesis, development, and differentiation (DiGiacomo, V., & Meruelo, D. (2016).
  • laminin receptor critical discussion regarding the non-integrin 37/67-kDa laminin receptor/RPSA protein. Biological reviews of the Cambridge Philosophical Society, 91(2), 288– 310).
  • the amino acid sequence of RPSA is SEQ ID NO: 158 and can be found under UniProt Accession No. P08865.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 158 and/or the protein level thereof.
  • MYLK also known as kinase-related protein, AAT7, KRP, MLCK, MLCK1, MLCK108, MLCK210, MSTP083, MYLK1, smMLCK, myosin light chain kinase, MMIHS, MMIHS1, MYLK-L, telokin
  • MMIHS myosin light-chain kinase
  • MYLK-L telokin
  • MYLK promotes hepatocellular carcinoma progression through regulating cytoskeleton to enhance epithelial-mesenchymal transition. Clinical and experimental medicine, 18(4), 523–533).
  • the amino acid sequence of MYLK is SEQ ID NO: 159 and can be found under UniProt Accession No. Q15746.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 159 and/or the protein level thereof.
  • ITGA1 also known as CD49a, VLA1, integrin subunit alpha 1 encodes an integrin alpha subunit that makes up half of the ⁇ 1 ⁇ 1 integrin duplex.
  • ITGA1 has a role in matrix remodeling such as is seen during morphogenesis and wound healing (Carver, W., Molano, I., Reaves, T. A., Borg, T. K., & Terracio, L. (1995). Role of the alpha 1 beta 1 integrin complex in collagen gel contraction in vitro by fibroblasts. Journal of cellular physiology, 165(2), 425–437).
  • the amino acid sequence of ITGA1 is SEQ ID NO: 160 and can be found under UniProt Accession No. P56199.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 160 and/or the protein level thereof.
  • SDC4 also known as SYND4, syndecan 4) encodes a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling.
  • SDC4 functions as an independent receptor for heparin-binding growth factors, such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs) (Elfenbein, A., & Simons, M. (2013). Syndecan-4 signaling at a glance. Journal of cell science, 126(Pt 17), 3799–3804).
  • FGFs fibroblast growth factors
  • VEGFs vascular endothelial growth factors
  • PDGFs platelet-derived growth factors
  • the amino acid sequence of SDC4 is SEQ ID NO: 161 and can be found under UniProt Accession No. P31431.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 161.
  • ITGB2 (also known as CD18, LAD, LCAMB, LFA-1, MAC-1, MF17, MFI7, integrin subunit beta 2) encodes an integrin beta chain protein that has roles in cellular adhesion, cell surface signaling, and immune responses. ITGB2 has been found to influence immune cell infiltration into the tumor microenviroment of acute myeloid leukemia (Wei, J., Huang, X. J., Huang, Y., Xiong, M. Y., Yao, X. Y., Huang, Z. N., Li, S. N., Zhou, W. J., Fang, D. L., Deng, D. H., & Cheng, P. (2021).
  • ITGB2 Key immune-related gene ITGB2 as a prognostic signature for acute myeloid leukemia. Annals of translational medicine, 9(17), 1386).
  • the amino acid sequence of ITGB2 is SEQ ID NO: 162 and can be found under UniProt Accession No. P05107.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 162 and/or the protein level thereof.
  • TNFRSF10D (also known as Decoy receptor 2, TRAIL receptor 4, CD264, DCR2, TRAIL-R4, TRAILR4, TRUNDD, tumor necrosis factor receptor superfamily member 10d, TNF receptor superfamily member 10d) encodes a member of the TNF-receptor superfamily that has been shown to play an inhibitory role in TRAIL-induced cell apoptosis.
  • TNFRSF10D has been found to promote the anti-tumoral cytotoxic activity of ⁇ T cells (Tawfik, 82 WBD (US) 4854-8046-9185v2 D., Groth, C., Gundlach, J.
  • TRAIL-Receptor 4 Modulates ⁇ T Cell-Cytotoxicity Toward Cancer Cells. Frontiers in immunology, 10, 2044).
  • the amino acid sequence of TNFRSF10D is SEQ ID NO: 163 and can be found under UniProt Accession No. Q9UBN6.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 163 and/or the protein level thereof.
  • FPR2 FPR2 (also known as N-formyl peptide receptor 2, ALXR, FMLP-R-II, FMLPX, FPR2A, FPRH1, FPRH2, FPRL1, HM63, LXA4R, formyl peptide receptor 2, ALX) encodes a G-protein coupled receptor expressed on phagocytic leukocytes and involved in host defense and inflammation.
  • FPR2 has been proposed as a promising target for the treatment of influenza (Alessi, M. C., Cenac, N., Si-Tahar, M., & Riteau, B. (2017).
  • FPR2 A Novel Promising Target for the Treatment of Influenza. Frontiers in microbiology, 8, 1719).
  • the amino acid sequence of FPR2 is SEQ ID NO: 164 and can be found under UniProt Accession No. P25090.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 164 and/or the protein level thereof.
  • LIFR LIFR (also known as Cluster of Differentiation 118, CD118, LIF-R, SJS2, STWS, SWS, leukemia inhibitory factor receptor alpha, LIF receptor alpha, LIF receptor subunit alpha) encodes a subunit of a receptor for leukemia inhibitory factor.
  • LIFR is known to be down regulated in hepatocellular carcinoma (Yao et al. (2021).
  • a targetable LIFR-NF- ⁇ B-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature communications, 12(1), 7333).
  • the amino acid sequence of LIFR is SEQ ID NO: 165 and can be found under UniProt Accession No. P42702.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 165 and/or the protein level thereof.
  • AREG also known as AR, AREGB, CRDGF, SDGF, amphiregulin
  • EGF epidermal growth factor
  • AREG gene expression and release is induced by a plethora of stimuli including inflammatory lipids, cytokines, hormones, growth factors and xenobiotics (Berasain, C., & Avila, M. A. (2014). Amphiregulin. Seminars in cell & developmental biology, 28, 31–41).
  • the amino acid sequence of AREG is SEQ ID NO: 166 and can be found under UniProt Accession No. P15514.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 166 and/or the protein level thereof.
  • CD46 also known as membrane cofactor protein, AHUS2, MCP, MIC10, TLX, TRA2.10 encodes a ubiquitously expressed complement regulatory protein, serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells and plays roles in human reproduction, autophagy, modulating T cell activation and effector functions.
  • CD46 deficiencies are thought to contribute to inflammatory disorders (Liszewski, M. K., & Atkinson, J. P. (2021).
  • the amino acid sequence of CD46 is SEQ ID NO: 167 and can be found under UniProt Accession No. P15529.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 167 and/or the protein level thereof.
  • HBEGF also known as DTR, DTS, DTSF, HEGFL, heparin binding EGF like growth factor
  • HBEGF encodes a heparin-binding member of the EGF family that was initially identified in the conditioned medium of human macrophages.
  • HB-EGF has been implicated as a participant in a variety of normal physiological processes such as blastocyst implantation and wound healing, and in pathological processes such as tumor growth, SMC hyperplasia and atherosclerosis (Raab, G., & Klagsbrun, M. (1997). Heparin-binding EGF-like growth factor.
  • the amino acid sequence of HBEGF is SEQ ID NO: 168 and can be found under UniProt Accession No. Q99075.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 168 and/or the protein level thereof.
  • HLA-DRB1 HLA-DRB1 (also known as DRB1, DRw10, HLA-DR1B, HLA-DRB, SS1, major histocompatibility complex, class II, DR beta 1) encodes a beta chain of antigen- presenting major histocompatibility complex class II (MHCII) molecule.
  • DRB1 relies a beta chain of antigen- presenting major histocompatibility complex class II (MHCII) molecule.
  • MHCII major histocompatibility complex class II
  • the amino acid sequence of HLA-DRB1 is SEQ ID NO: 169 and can be found under UniProt Accession No. P01911.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 169 and/or the protein level thereof.
  • IL10 also known as human cytokine synthesis inhibitory factor, CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10) encodes an anti-inflammatory cytokine.
  • IL-10 is known to play important roles in sterile wound healing, autoimmunity, cancer, and homeostasis (Saraiva, M., Vieira, P., & O'Garra, A. (2020). Biology and therapeutic potential of interleukin-10. The Journal of experimental medicine, 217(1), e20190418).
  • the amino acid sequence of IL10 is SEQ ID NO: 170 and can be found under UniProt Accession No. P22301.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 170 and/or the protein level thereof.
  • SELL also known as L-selectin, CD62L, LAM1, LECAM1, LEU8, LNHR, LSEL, LYAM1, PLNHR, TQ1, selectin L encodes a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst.
  • the leukocytic cell adhesion receptor L-selectin is thought to 85 WBD (US) 4854-8046-9185v2 mediate the initial step of the adhesion cascade, the capture and rolling of leukocytes on endothelial cells, which enables leukocytes to migrate out of the vasculature into surrounding tissues during inflammation and immune surveillance (Wedepohl, S., Beceren-Braun, F., Riese, S., Buscher, K., Enders, S., Bernhard, G., Kilian, K., Blanchard, V., Dernedde, J., & Tauber, R. (2012). L-selectin--a dynamic regulator of leukocyte migration.
  • the amino acid sequence of SELL is SEQ ID NO: 171 and can be found under UniProt Accession No. P14151.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 171 and/or the protein level thereof.
  • TNFSF13B (also known as B-cell activating factor, BAFF, BLYS, CD257, DTL, TALL-1, TALL1, THANK, TNFSF20, ZTNF4, TNLG7A, tumor necrosis factor superfamily member 13b, TNF superfamily member 13b) encodes a cytokine that belongs to the tumor necrosis factor (TNF) ligand family.
  • TNFSF13B has been shown to be required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells (Schweighoffer, E., & Tybulewicz, V. L. (2021). BAFF signaling in health and disease.
  • CLL chronic lymphocytic leukaemia
  • the amino acid sequence of TNFSF13B is SEQ ID NO: 172 and can be found under UniProt Accession No. Q9Y275.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 172 and/or the protein level thereof.
  • BMP7 also known as osteogenic protein-1, OP-1, bone morphogenetic protein 7
  • BMP7 encodes a member of the TGF- ⁇ superfamily that plays roles in embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis.
  • BMP7 as been shown to counteract transforming growth factor-beta-mediated fibrosis (Patel, S.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 173 and/or the protein level thereof.
  • COL18A1 (also known as KNO, KNO1, KS, Collagen, type XVIII, alpha 1, collagen type XVIII alpha 1, collagen type XVIII alpha 1 chain, GLCC) encodes the alpha chain of type XVIII collagen.
  • COL18A1 has been identified as a candidate eye iridocorneal angle- closure gene in humans (Suri, F., Yazdani, S., Chapi, M., Safari, I., Rasooli, P., Daftarian, N., Jafarinasab, M.
  • COL18A1 is a candidate eye iridocorneal angle-closure gene in humans. Human molecular genetics, 27(21), 3772–3786).
  • the amino acid sequence of COL18A1 is SEQ ID NO: 174 and can be found under UniProt Accession No. P39060.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 174 and/or the protein level thereof.
  • CSF1 also known as macrophage colony-stimulating factor, CSF-1, MCSF, colony stimulating factor 1 encodes secreted a cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types.
  • CSF1 also known as macrophage colony-stimulating factor, CSF-1, MCSF, colony stimulating factor 1
  • CSF1 also known as macrophage colony-stimulating factor, CSF-1, MCSF, colony stimulating factor 1
  • CSF1 The amino acid sequence of CSF1 is SEQ ID NO: 175 and can be found under UniProt Accession No. P09603.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 175 and/or the protein level thereof.
  • CSF3 CSF3 (also known as Granulocyte colony-stimulating factor, C17orf33, CSF3OS, GCSF, colony stimulating factor 3) encodes a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.
  • CSF3 has been 87 WBD (US) 4854-8046-9185v2 shown to be involved in lipid metabolism and nonalcoholic fatty liver disease (NAFLD) (Zhang, Y., Zhou, X., Liu, P., Chen, X., Zhang, J., Zhang, H., Li, S., Chen, Y., Song, X., Wang, J., Zeng, H., Zhang, X., Tang, C., Yu, C., Li, Y., & Xu, C. (2021).
  • GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration. American journal of physiology.
  • CTGF also known as CCN2, HCS24, IGFBP8, NOV2, connective tissue growth factor, cellular communication network factor 2
  • CCN2 CCN2, HCS24, IGFBP8, NOV2
  • connective tissue growth factor cellular communication network factor 2
  • CTGF expression has been shown to be associated with tumor development and progression (Chu, C. Y., Chang, C. C., Prakash, E., & Kuo, M. L. (2008). Connective tissue growth factor (CTGF) and cancer progression. Journal of biomedical science, 15(6), 675–685).
  • the amino acid sequence of CTGF is SEQ ID NO: 177 and can be found under UniProt Accession No. P29279.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 177 and/or the protein level thereof.
  • FGF2 also known as basic fibroblast growth factor, BFGF, FGF-2, FGFB, HBGF-2, fibroblast growth factor 2 encodes a ligand that plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration.
  • FGF2 is known to play crucial roles in the growth and development of several tissues, including osteoclastogenesis (Wen, X., Hu, G., Xiao, X., Zhang, X., Zhang, Q., Guo, H., Li, X., Liu, Q., & Li, H. (2022).
  • FGF2 positively regulates osteoclastogenesis via activating the ERK-CREB pathway.
  • the amino acid sequence of FGF2 is SEQ ID NO: 178 and can be found under UniProt Accession No. P09038.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 178 and/or the protein level thereof.
  • HSPG2 also known as Perlecan, basement membrane-specific heparan sulfate proteoglycan core protein, HSPG, PLC, PRCAN, SJA, SJS, SJS1, heparan sulfate proteoglycan 2 encodes a multifunctional proteoglycan that preserves the integrity of extracellular matrices, patrols tissue borders, and controls various signaling pathways affecting cellular phenotype. Because of the role of HSPG2 in several fundamental processes, mutations to the gene in organisms are relatively rare (Martinez, J. R., Dhawan, A., & Farach-Carson, M. C. (2016).
  • Modular Proteoglycan Perlecan/HSPG2 Mutations, Phenotypes, and Functions. Genes, 9(11), 556).
  • the amino acid sequence of HSPG2 is SEQ ID NO: 179 and can be found under UniProt Accession No. P98160.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 179 and/or the protein level thereof.
  • LAMA2 LAMA2 (also known as Laminin subunit alpha-2, LAMM, Laminin, alpha 2, MDC1A) encodes the ⁇ 2 subunit of laminins.
  • LAMA2 has been found to regulate osteogenesis and adipogenesis of MSCs by modulating the hedgehog signaling pathway (Zhu, Y., Zhang, X., Gu, R., Liu, X., Wang, S., Xia, D., Li, Z., Lian, X., Zhang, P., Liu, Y., & Zhou, Y. (2020).
  • LAMA2 regulates the fate commitment of mesenchymal stem cells via hedgehog signaling. Stem cell research & therapy, 11(1), 135).
  • the amino acid sequence of LAMA2 is SEQ ID NO: 180 and can be found under UniProt Accession No. P24043.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 180 and/or the protein level thereof.
  • 89 WBD (US) 4854-8046-9185v2 LAMB2 LAMB2 (also known as LAMS, NPHS5, Laminin, beta 2, laminin subunit beta 2, PIERS) encodes the ⁇ 2 subunit of laminins. High concentrations of glucose have been found to reduce expression of this laminin subunit at the translational level (Schaeffer, V., Hansen, K. M., Morris, D. R., LeBoeuf, R. C., & Abrass, C. K. (2012).
  • RNA-binding protein IGF2BP2/IMP2 is required for laminin- ⁇ 2 mRNA translation and is modulated by glucose concentration.
  • the amino acid sequence of LAMB2 is SEQ ID NO: 181 and can be found under UniProt Accession No. P55268.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 181 and/or the protein level thereof.
  • MIF MIF (also known as GIF, GLIF, Macrophage migration inhibitory factor (glycosylation-inhibiting factor), macrophage migration inhibitory factor, L-dopachrome isomerase, phenylpyruvate tautomerase) encodes an inflammatory cytokine that participates in innate and adaptive immune responses and contributes to the resistance against infection agents, but also to the cellular and tissue damage in infectious, autoimmune, and allergic diseases. MIF is known to regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signaling (Kang, I., & Bucala, R. (2019). The immunobiology of MIF: function, genetics and prospects for precision medicine. Nature reviews.
  • the amino acid sequence of MIF is SEQ ID NO: 182 and can be found under UniProt Accession No. P14174.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 182 and/or the protein level thereof.
  • NAMPT (also known as 1110035O14Rik, PBEF, PBEF1, VF, VISFATIN, nicotinamide phosphoribosyltransferase, pre-B-cell colony-enhancing factor 1) encodes a protein that catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD.
  • NAMPT is thought to influence oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation 90 WBD (US) 4854-8046-9185v2 and insulin resistance (Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., & Kiess, W. (2015). Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nature reviews. Endocrinology, 11(9), 535–546).
  • the amino acid sequence of NAMPT is SEQ ID NO: 183 and can be found under UniProt Accession No. P43490.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 183 and/or the protein level thereof.
  • NRG1 also known as ARIA, GGF, GGF2, HGL, HRG, HRG1, HRGA, MST131, MSTP131, NDF, NRG1-IT2, SMDF, neuregulin 1
  • ARIA ARIA
  • GGF GGF2, HGL
  • HRG HRG1, HRGA
  • MST131 MSTP131
  • NDF NRG1-IT2
  • SMDF neuregulin 1
  • NRG1 is known to be secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury (Dugaucquier, L., Feyen, E., Mateiu, L., Bruyns, T. A. M., De Keulenaer, G. W., & Segers, V. F. M. (2020).
  • ECs cardiac endothelial cells
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 184 and/or the protein level thereof.
  • TNC also known as Tenascin C, 150-225, DFNA56, GMEM, GP, HXB, JI, TN, TN-C
  • ECM extracellular matrix
  • TNC is known to have a role in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy (Imanaka-Yoshida K.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 185 and/or the protein level thereof.
  • TSLP also known as thymic stromal lymphopoietin
  • TSLP encodes a cytokine that has been shown to be a key factor in maintaining immune homeostasis and regulating inflammatory responses at mucosal barriers.
  • Anti-TSLP agents have been proposed for the treatment of a variety of inflammatory conditions (Corren, J., & Ziegler, S. F. (2019).
  • TSLP from allergy to cancer. Nature immunology, 20(12), 1603–1609).
  • the amino acid sequence of TSLP is SEQ ID NO: 186 and can be found under UniProt Accession No. Q969D9.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 186 and/or the protein level thereof.
  • VEGFA also known as MVCD1, VEGF, VPF, vascular endothelial growth factor A
  • VEGFA encodes a growth factor active in angiogenesis, vasculogenesis and endothelial cell growth.
  • VEGFA induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels.
  • VEGFA is a therapeutic target in ovarian cancer (OVCA) (Jang, K., Kim, M., Gilbert, C. A., Simpkins, F., Ince, T.
  • VEGFA activates an epigenetic pathway upregulating ovarian cancer- initiating cells.
  • the amino acid sequence of VEGFA is SEQ ID NO: 187 and can be found under UniProt Accession No. P15692.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 187 and/or the protein level thereof.
  • WNT5A (also known as Wingless-Type MMTV Integration Site Family, Member 5A and hWnt family member 5A) encodes a signaling molecule expressed embryonically during gastrulation in various developing body regions including the caudal mesoderm of the primitive streak, lateral mesoderm, cranial neural crest cells, midbrain, frontal face region, limb buds, mammary gland mesenchyme, caudal region, genital primordia and 92 WBD (US) 4854-8046-9185v2 tailbud (Chu, E. Y., Hens, J., Andl, T., Kairo, A., Yamaguchi, T.
  • WNT5A has oncogenic and tumor suppressive activities (Wang, K., Ma, F., Arai, S., Wang, Y., Varkaris, A., Poluben, L., Voznesensky, O., Xie, F., Zhang, X., Yuan, X., & Balk, S. P. (2023).
  • WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth. Cancer research, 83(7), 1016–1030).
  • the amino acid sequence of WNT5A is SEQ ID NO: 188 and can be found under UniProt Accession No. P41221.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 188 and/or the protein level thereof.
  • BTLA also known as B- and T-lymphocyte attenuator, CD272, BTLA1, B and T lymphocyte associated
  • PD-1 programmed cell death-1
  • CTLA-4 cytotoxic T lymphocyte associated antigen-4
  • BTLA has been found to participate in numerous physiopathological processes, such as tumor, inflammatory diseases, autoimmune diseases, infectious diseases, and transplantation rejection (Ning, Z., Liu, K., & Xiong, H. (2021). Roles of BTLA in Immunity and Immune Disorders. Frontiers in immunology, 12, 654960).
  • the amino acid sequence of BTLA is SEQ ID NO: 189 and can be found under UniProt Accession No. Q7Z6A9.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 189 and/or the protein level thereof.
  • SEMA4D SEMA4D (also known as C9orf164, CD100, M-sema-G, SEMAJ, coll-4, semaphorin 4D, COLL4, A8, GR3, BB18) encodes a homodimeric protein belonging to the semaphorin family of axonal guidance proteins.
  • SEMA4D has been described to have immune functions and serves important roles in T cell priming, antibody production, and cell-to-cell adhesion (Maleki, K. T., Cornillet, M., & Björkström, N. K. (2016). Soluble SEMA4D/CD100: 93 WBD (US) 4854-8046-9185v2 A novel immunoregulator in infectious and inflammatory diseases. Clinical immunology (Orlando, Fla.), 163, 52–59).
  • the amino acid sequence of SEMA4D is SEQ ID NO: 190 and can be found under UniProt Accession No. Q92854.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 190 and/or the protein level thereof.
  • LRP6 also known as Low-density lipoprotein receptor-related protein 6, ADCAD2, STHAG7, LDL receptor related protein 6) encodes a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Clinical studies have implicated LRP6 in various kinds of cancer, including bladder and breast cancer (Alrefaei, A. F., & Abu-Elmagd, M. (2022). LRP6 Receptor Plays Essential Functions in Development and Human Diseases.
  • ADGRE5 also known as Cluster of differentiation 97, BL-Ac[F2], TM7LN1, CD97, adhesion G protein-coupled receptor E5 encodes a member of the EGF-TM7 family of adhesion G protein-coupled receptors (GPCRs) broadly expressed on leukocytes.
  • ADGRE5 has been found to promote spleen dendritic cell homeostasis through the mechanosensing of red blood cells (Liu, D., Duan, L., Rodda, L. B., Lu, E., Xu, Y., An, J., Qiu, L., Liu, F., Looney, M. R., Yang, Z., Allen, C. D. C., Li, Z., Marson, A., & Cyster, J. G. (2022).
  • CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells. Science (New York, N.Y.), 375(6581), eabi5965).
  • the amino acid sequence of ADGRE5 is SEQ ID NO: 192 and can be found under UniProt Accession No. P48960.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 192 and/or the protein level thereof.
  • APOE gene and neuropsychiatric disorders and endophenotypes A comprehensive review. Am J Med Genet B Neuropsychiatr Genet.2018 Mar;177(2):126-142.).
  • the amino acid sequence of APOE is SEQ ID NO: 193 and can be found under UniProt Accession No. P02649.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 193 and/or the protein level thereof.
  • COL1A2 COL1A2 (also known as Collagen alpha-2(I) chain, OI4, collagen type I alpha 2, collagen type I alpha 2 chain, EDSCV, EDSARTH2) encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues.
  • COL1A2 has been found to mediate the pro- and anti-migratory effects of TBX3 in chondrosarcoma and fibrosarcoma cells respectively (Omar R, Cooper A, Maranyane HM, Zerbini L, Prince S.
  • COL1A2 is a TBX3 target that mediates its impact on fibrosarcoma and chondrosarcoma cell migration. Cancer Lett. 2019 Sep 10;459:227-239).
  • the amino acid sequence of COL1A2 is SEQ ID NO: 194 and can be found under UniProt Accession No. P08123.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 194 and/or the protein level thereof.
  • COL4A2 (also known as Collagen alpha-2(IV) chain, ICH, POREN2, collagen type IV alpha 2, collagen type IV alpha 2 chain, BSVD2) encodes one of the six subunits of type IV collagen, the major structural component of basement membranes.
  • COL4A2 in the ECM has been found to promote osteogenic differentiation of PDLSCs through negative regulation of the Wnt/ ⁇ -catenin pathway (Wen Y, Yang H, Wu J, Wang A, Chen X, Hu S, Zhang Y, Bai D, Jin Z.
  • COL4A2 in the tissue-specific extracellular matrix plays important role on osteogenic differentiation of periodontal ligament stem cells. Theranostics.2019 May 31;9(15):4265-4286).
  • COL4A2 The amino acid sequence of COL4A2 is SEQ ID NO: 195 and can be found under UniProt Accession No. P08572.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 195 and/or the protein level thereof.
  • COL6A1: COL6A1 also known as Collagen alpha-1(VI) chain, OPLL, BTHLM1, UCHMD1, collagen type VI alpha 1, collagen type VI alpha 1 chain
  • COL6A1 has been found to stimulate tumor growth in vivo (Wan F, Wang H, Shen Y, Zhang H, Shi G, Zhu Y, Dai B, Ye D. Upregulation of COL6A1 is predictive of poor prognosis in clear cell renal cell carcinoma patients. Oncotarget.2015 Sep 29;6(29):27378-87).
  • the amino acid sequence of COL6A1 is SEQ ID NO: 196 and can be found under UniProt Accession No. P12109.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 196 and/or the protein level thereof.
  • COL6A2 (also known as Collagen alpha-2(VI) chain, PP3610, BTHLM1, UCMD1, collagen type VI alpha 2, collagen type VI alpha 2 chain) encodes a collagen VI subunit.
  • High expression of COL6A2 has been found to be associated with glioma proliferation, migration, invasion, and immunity (Hong X, Zhang J, Zou J, Ouyang J, Xiao B, Wang P, Peng X. Role of COL6A2 in malignant progression and temozolomide resistance of glioma. Cell Signal. 2023 Feb;102:110560).
  • the amino acid sequence of COL6A2 is SEQ ID NO: 197 and can be found under UniProt Accession No.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 197 and/or the protein level thereof.
  • COL6A3 also known as Collagen alpha-3(VI) chain, DYT27, BTHLM1, UCMD1, collagen type VI alpha 3, collagen type VI alpha 3 chain
  • COL6A3 encodes an alpha chain of type VI collagen that aids in microfibril formation.
  • Increased adipocyte COL6A3 expression has 96 WBD (US) 4854-8046-9185v2 been found to be associated with insulin resistance in humans (Dankel SN, Svärd J, Mattotro S, Claussnitzer M, Klöting N, Glunk V, Fandalyuk Z, Grytten E, Solsvik MH, Nielsen HJ, Busch C, Hauner H, Blüher M, Skurk T, Sagen JV, Mellgren G. COL6A3 expression in adipocytes associates with insulin resistance and depends on PPAR ⁇ and adipocyte size. Obesity (Silver Spring).2014 Aug;22(8):1807-13).
  • the amino acid sequence of COL6A3 is SEQ ID NO: 198 and can be found under UniProt Accession No. P12111.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 198 and/or the protein level thereof.
  • FGF7 also known as Keratinocyte growth factor, HBGF-7, KGF, fibroblast growth factor 7 encodes a protein that acts as a potent mitogen on epithelial cells, through interaction with the FGF7-specific receptor FGFR2/IIIb.
  • FGF7 has been found to have a role in initiating invasion of prostatic epithelial cells in humans (Ropiquet F, Huguenin S, Villette JM, Ronflé V, Le Brun G, Maitland NJ, Cussenot O, Fiet J, Berthon P. FGF7/KGF triggers cell transformation and invasion on immortalised human prostatic epithelial PNT1A cells. Int J Cancer.1999 Jul 19;82(2):237-43).
  • the amino acid sequence of FGF7 is SEQ ID NO: 199 and can be found under UniProt Accession No. P21781.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 199 and/or the protein level thereof.
  • HLA-E HLA-E (also known as HLA class I histocompatibility antigen, alpha chain E, MHC class I antigen E, EA1.2, EA2.1, HLA-6.2, MHC, QA1, major histocompatibility complex, class I, E) encodes a heterodimer involved in immune self-nonself discrimination.
  • HLA-E is thought to be a ligand for the innate and adaptive immune system (Kraemer T, Blasczyk R, Bade-Doeding C.
  • HLA-E a novel player for histocompatibility. J Immunol Res. 2014;2014:352160. doi: 10.1155/2014/352160. Epub 2014 Oct 20).
  • the amino acid sequence of HLA-E is SEQ ID NO: 200 and can be found under UniProt Accession No. P13747. 97 WBD (US) 4854-8046-9185v2
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 200 and/or the protein level thereof.
  • IL6 (also known as BSF2, HGF, HSF, IFNB2, IL-6, BSF-2, CDF, IFN-beta-2, interleukin 6) encodes an interleukin that acts as both a pro-inflammatory cytokine and an anti- inflammatory myokine.
  • IL-6 blockade has been proposed as a therapeutic strategy for acute systemic and chronic inflammatory diseases (Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL-6) Immunotherapy. Cold Spring Harb Perspect Biol.2018 Aug 1;10(8):a028456).
  • the amino acid sequence of IL6 is SEQ ID NO: 201 and can be found under UniProt Accession No. P05231.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 201 and/or the protein level thereof.
  • LAMB1 also known as Laminin subunit beta-1, CLM, LIS5, Laminin, beta 1, laminin subunit beta 1 encodes the beta chain of laminin, an extracellular matrix protein.
  • LAMB1 is involved in attachment, migration, and organization during development, and its elevated expression has been associated with several cancers including gastric cancer (Lee H, Kim WJ, Kang HG, Jang JH, Choi IJ, Chun KH, Kim SJ. Upregulation of LAMB1 via ERK/c- Jun Axis Promotes Gastric Cancer Growth and Motility.
  • LAMC1 (also known as Laminin subunit gamma-1, LAMB2, Laminin, gamma 1, laminin subunit gamma 1) encodes the gamma chain of laminin, an extracellular matrix protein.
  • LAMC1 has been proposed as a prognostic factor and a therapeutic target in gastric cancer (Xi D, Jia Q, Liu X, Zhang L, Xu B, Ma Z, Ma Y, Yu Y, Zhang F, Chen H.
  • LAMC1 is a Novel Prognostic Factor and a Potential Therapeutic Target in Gastric Cancer.
  • the amino acid sequence of LAMC1 is SEQ ID NO: 203 and can be found under UniProt Accession No. P11047.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 203 and/or the protein level thereof.
  • THBS2 THBS2 (also known as TSP2 and thrombospondin 2) encodes a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.
  • THBS2 has been implicated in poor prognosis and immune infiltration of gastric cancer (Zhang S, Yang H, Xiang X, Liu L, Huang H, Tang G.
  • THBS2 is Closely Related to the Poor Prognosis and Immune Cell Infiltration of Gastric Cancer. Front Genet.2022 Feb 3;13:803460).
  • the amino acid sequence of THBS2 is SEQ ID NO: 204 and can be found under UniProt Accession No. P35442.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 204 and/or the protein level thereof.
  • ALOXA5AP also known as Arachidonate 5-lipoxygenase-activating protein, 5-lipoxygenase activating protein, FLAP) encodes an integral protein within the nuclear membrane and is necessary for the synthesis of leukotriene, which are lipid mediators of inflammation.
  • ALOX5AP is known to be present in adipose tissue and associated with inflammation and insulin resistance (Kaaman M, Rydén M, Axelsson T, Nordström E, Sicard A, Bouloumié A, Langin D, Arner P, Dahlman I. ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance. Int J Obes (Lond).2006 Mar;30(3):447-52).
  • the amino acid sequence of ALOXA5AP is SEQ ID NO: 205 and can be found under UniProt Accession No. P20292.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 205 and/or the protein level thereof.
  • Calmodulin 2 Facilitates Angiogenesis and Metastasis of Gastric Cancer via STAT3/HIF-1A/VEGF-A Mediated Macrophage Polarization. Front Oncol.2021 Sep 15;11:727306. doi: 10.3389/fonc.2021.727306).
  • the amino acid sequence of CALM2 is SEQ ID NO: 206 and can be found under UniProt Accession No. P0DP24.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 206 and/or the protein level thereof.
  • LGALS9 also known as Galectin-9, HUAT, LGALS9A, galectin 9) encodes a 36 kDa beta-galactoside lectin protein. High LGALS9 expression has been found to be correlated with poor prognosis in multiple human cancers (Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, Yan M, Chang WC, Hsu JM, Cha JH, Hsu JL, Chou CW, Sun X, Deng Y, Chou CK, Yu D, Hung MC. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun.2021 Feb 5;12(1):832).
  • the amino acid sequence of LGALS9 is SEQ ID NO: 207 and can be found under UniProt Accession No. O00182.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 207 and/or the protein level thereof.
  • CDH1 also known as Arc-1, CD324, CDHE, ECAD, LCAM, UVO, cadherin 1, BCDS1, E-cadherin, uvomorulin
  • CDH1 also known as Arc-1, CD324, CDHE, ECAD, LCAM, UVO, cadherin 1, BCDS1, E-cadherin, uvomorulin
  • Germline mutations of CDH1 have been found to be associated with the development of multiple cancers (Corso G. Pleiotropic cancer manifestations of germline CDH1 mutations: Risks and management. J Surg Oncol.2022 Jun;125(8):1326-1331. doi: 100 WBD (US) 4854-8046-9185v2 10.1002/jso.26847. Epub 2022 Mar 12).
  • the amino acid sequence of CDH1 is SEQ ID NO: 208 and can be found under UniProt Accession No. P55287.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 208 and/or the protein level thereof.
  • IL22 (also known as Interleukin-22, IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL- 23, TIFa, zcyto18, interleukin 22) encodes an ⁇ -helical cytokine.
  • IL22 has been proposed as a therapeutic target in diseases of the intestine, including inflammatory bowel disease, GvHD, and cancer (Keir M, Yi Y, Lu T, Ghilardi N. The role of IL-22 in intestinal health and disease. J Exp Med.2020 Feb 13;217(3):e20192195).
  • the amino acid sequence of IL22 is SEQ ID NO: 209 and can be found under UniProt Accession No. Q9GZX6.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 209 and/or the protein level thereof.
  • HLA-F also known as HLA class I histocompatibility antigen, alpha chain F, CDA12, HLA-5.4, HLA-CDA12, major histocompatibility complex, class I, F
  • HLA-F encodes a ⁇ 40- 41 kDa non-classical heavy chain anchored to the membrane and forming a heterodimer with a ⁇ -2 microglobulin light chain.
  • HLA-F is thought to be involved in viral infections, cancer immunology, and may have a role in fertility and reproduction (Persson G, J ⁇ rgensen N, Nilsson LL, Andersen LHJ, Hviid TVF. A role for both HLA-F and HLA-G in reproduction and during pregnancy? Hum Immunol.2020 Apr;81(4):127-133).
  • the amino acid sequence of HLA-F is SEQ ID NO: 210 and can be found under UniProt Accession No. P30511.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 210 and/or the protein level thereof.
  • ANGPTL2 (also known as Angiopoietin-related protein 2, angiopoietin-like protein 2, ARP2, HARP, angiopoietin like 2) encodes a member of the vascular endothelial growth factor family that maintains tissue homeostasis by promoting adaptive inflammation and 101 WBD (US) 4854-8046-9185v2 subsequent tissue reconstruction.
  • ANGPTL2 has been found to regulate autophagy and affect the progression of renal fibrosis in diabetic nephropathy (Huang H, Ni H, Ma K, Zou J.
  • ANGPTL2 regulates autophagy through the MEK/ERK/Nrf-1 pathway and affects the progression of renal fibrosis in diabetic nephropathy. Am J Transl Res.2019 Sep 15;11(9):5472-5486).
  • the amino acid sequence of ANGPTL2 is SEQ ID NO: 211 and can be found under UniProt Accession No. Q9UKU9.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 211 and/or the protein level thereof.
  • DLL1 also known as Delta-like protein 1, DELTA1, DL1, Delta, Delta-like 1, delta like canonical Notch ligand 1, NEDBAS
  • DLL1 also known as Delta-like protein 1, DELTA1, DL1, Delta, Delta-like 1, delta like canonical Notch ligand 1, NEDBAS
  • DLL1 encodes a human homolog of the Notch Delta ligand and is a member of the delta/serrate/jagged family that plays a role in mediating cell fate decisions during hematopoiesis (Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H. Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2. Mol Cell Biol.
  • the amino acid sequence of DLL1 is SEQ ID NO: 212 and can be found under UniProt Accession No. O00548.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 212 and/or the protein level thereof.
  • JAG1 (also known as Jagged1, ABE2, Gsfabe2, Htu, Ozz, Ser-1, AGS, AHD, AWS, CD339, HJ1, JAGL1, jagged 1, AGS1, DCHE, jagged canonical Notch ligand 1, CMT2HH) encodes a ligand that interact with four receptors in the mammalian Notch signaling pathway which helps to determine cellular fate and is active during many developmental stages.
  • JAG1 has been proposed as a marker of immunotherapy resistance in lung adenocarcinoma (He J, Li L, Lv L, Chen X, Ge M, Ren Y, Tang X, Liu P, Gao W.
  • JAG1 is correlated to suppressive immune microenvironment and predicts immunotherapy resistance in lung adenocarcinoma. Front Oncol.2023 Feb 27;13:1091488).
  • the amino acid sequence of JAG1 is SEQ ID NO: 213 and can be found under UniProt Accession No. P78504.
  • 102 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 213 and/or the protein level thereof.
  • JAG2 (also known as Jagged-2, HJ2, SER2, jagged 2, jagged canonical Notch ligand 2, LGMDR27) encodes a ligand that interact with four receptors in the mammalian Notch signaling pathway which helps to determine cellular fate and is active during many developmental stages. JAG2 overexpression has been found to correlate with poor outcomes in oral squamous cell carcinoma (Hatano K, Saigo C, Kito Y, Shibata T, Takeuchi T. Overexpression of JAG2 is related to poor outcomes in oral squamous cell carcinoma. Clin Exp Dent Res.2020 Apr;6(2):174-180).
  • the amino acid sequence of JAG2 is SEQ ID NO: 214 and can be found under UniProt Accession No. Q9Y219.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 214 and/or the protein level thereof.
  • TGFB1 also known as Transforming growth factor beta 1, CED, DPD1, LAP, TGFB, TGFbeta, transforming growth factor beta 1, IBDIMDE, TGF-beta1 encodes a secreted protein member of the transforming growth factor beta superfamily of cytokines that is involved in cell growth, cell proliferation, cell differentiation, and apoptosis.
  • TGFB1 has been found to enhance intestinal regeneration (Chen L, Dupre A, Qiu X, Pellon-Cardenas O, Walton KD, Wang J, Perekatt AO, Hu W, Spence JR, Verzi MP. TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration. bioRxiv [Preprint].2023 Jan 13:2023.01.13.523825).
  • the amino acid sequence of TGFB1 is SEQ ID NO: 215 and can be found under UniProt Accession No. P01137.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 215 and/or the protein level thereof.
  • TGFB3 (also known as Transforming growth factor beta-3, ARVD, ARVD1, RNHF, TGF-beta3, Transforming growth factor, beta 3, LDS5, transforming growth factor beta 103 WBD (US) 4854-8046-9185v2 3, TGF beta 3) encodes encodes a secreted protein member of the transforming growth factor beta superfamily of cytokines that is involved in cell differentiation, embryogenesis and development.
  • TGFB3 has been identified as a potential mitgator of radiation and chemotherapy induced toxicity (Hanson I, Pitman KE, Edin NFJ. The Role of TGF- ⁇ 3 in Radiation Response. Int J Mol Sci.2023 Apr 20;24(8):7614).
  • VEGFC also known as Vascular endothelial growth factor C, Flt4-L, LMPH1D, VRP, vascular endothelial growth factor C, LMPHM4 encodes a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family that functions to promote the growth of lymphatic vessels.
  • VEGFC Macrophage produced VEGFC has been found to ameliorate cardiac injury and inflammation (Glinton KE, Ma W, Lantz C, Grigoryeva LS, DeBerge M, Liu X, Febbraio M, Kahn M, Oliver G, Thorp EB. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation. J Clin Invest.2022 May 2;132(9):e140685).
  • the amino acid sequence of VEGFC is SEQ ID NO: 217 and can be found under UniProt Accession No. P49767.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 217 and/or the protein level thereof.
  • PGF PGF (also known as D12S1900, PGFL, PLGF, PlGF-2, SHGC-10760, Placental growth factor, PIGF) encodes a member of the VEGF (vascular endothelial growth factor) sub- family and plays a key role in angiogenesis and vasculogenesis. High levels of PGF has been associated with diabetic retinopathy in the vitreous of patients (Nguyen QD, De Falco S, Behar- Cohen F, Lam WC, Li X, Reichhart N, Ricci F, Pluim J, Li WW.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 218 and/or the protein level thereof.
  • IL18 (also known as Interleukin-18, IGIF, IL-18, IL-1g, IL1F4, interleukin 18, interferon-gamma inducing factor) encodes a proinflammatory cytokine.
  • IL18 was originally discovered as a factor that enhanced IFN- ⁇ production from anti-CD3-stimulated Th1 cells (Yasuda K, Nakanishi K, Tsutsui H. Interleukin-18 in Health and Disease. Int J Mol Sci.2019 Feb 2;20(3):649. doi: 10.3390/ijms20030649).
  • the amino acid sequence of IL18 is SEQ ID NO: 219 and can be found under UniProt Accession No. Q14116.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 219 and/or the protein level thereof.
  • APP also known as Amyloid-beta precursor protein, AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II, PN2, amyloid beta precursor protein, preA4, alpha-sAPP
  • APP also known as Amyloid-beta precursor protein, AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II, PN2, amyloid beta precursor protein, preA4, alpha-sAPP
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 220 and/or the protein level thereof.
  • TNFSF15 (also known as TL1, TL1A, VEGI, VEGI192A, Vascular endothelial growth inhibitor, TNLG1B, tumor necrosis factor superfamily member 15, TNF superfamily member 15) encodes an anti-angiogenic protein that belongs to the tumor necrosis factor superfamily. It is the sole ligand of death receptor 3 (Wang EC. On death receptor 3 and 105 WBD (US) 4854-8046-9185v2 its ligands. Immunology.2012 Sep;137(1):114-6).
  • the amino acid sequence of TNFSF15 is SEQ ID NO: 221 and can be found under UniProt Accession No. O95150.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 221 and/or the protein level thereof.
  • VCAM1 also known as Vascular cell adhesion protein 1, cluster of differentiation 106, CD106, INCAM-100, vascular cell adhesion molecule 1
  • VCAM1 also known as Vascular cell adhesion protein 1, cluster of differentiation 106, CD106, INCAM-100, vascular cell adhesion molecule 1
  • VCAM1 also known as Vascular cell adhesion protein 1, cluster of differentiation 106, CD106, INCAM-100, vascular cell adhesion molecule 1
  • VCAM1 has been found to be expressed in a subpopulation of mesenchymal stem cells with unique immunomodulatory properties (Yang ZX, Han ZB, Ji YR, Wang YW, Liang L, Chi Y, Yang SG, Li LN, Luo WF, Li JP, Chen DD, Du WJ, Cao XC, Zhuo GS, Wang T, Han ZC.
  • CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties.
  • the amino acid sequence of VCAM1 is SEQ ID NO: 222 and can be found under UniProt Accession No. P19320.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 222 and/or the protein level thereof.
  • ITGAM also known as CD11B, CR3A, MAC-1, MAC1A, MO1A, SLEB6, integrin subunit alpha M
  • ITGAM encodes one protein subunit that forms heterodimeric integrin alpha-M beta-2 ( ⁇ M ⁇ 2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3).
  • ITGAM is known to be highly expressed on the surface of innate immune cells, including macrophages and neutrophils (Khan SQ, Khan I, Gupta V.
  • the amino acid sequence of ITGAM is SEQ ID NO: 223 and can be found under UniProt Accession No. P11215.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 223 and/or the protein level thereof.
  • FGF2 also known as basic fibroblast growth factor (bFGF), BFGF, FGF-2, FGFB, HBGF-2, fibroblast growth factor 2 encodes a growth factor and signaling protein involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.
  • FGF2 is known to interact with APoptosis Inhibitor 5 (API5) to regulate mRNA export (Bong SM, Bae SH, Song B, Gwak H, Yang SW, Kim S, Nam S, Rajalingam K, Oh SJ, Kim TW, Park S, Jang H, Lee BI.
  • API5 Apoptosis Inhibitor 5
  • POSTN POSTN (also known as OSF-2, OSF2, PDLPN, periostin) encodes a ligand for alpha-V/beta-3 and alpha-V/beta-5 integrins to support adhesion and migration of epithelial cells.
  • POSTN has been found to be expressed by mesenchymal stromal cells (Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J. Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells. J Biol Chem.2008 Jun 27;283(26):17991-8001 ).
  • the amino acid sequence of POSTN is SEQ ID NO: 225 and can be found under UniProt Accession No. Q15063.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 225 and/or the protein level thereof.
  • LAMA5 also known as Laminin subunit alpha-5, Laminin, alpha 5, laminin subunit alpha 5 encodes the alpha subunit of laminin which is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It has been found to play a role in skeletogenesis (Barad M, Csukasi F, Bosakova M, Martin JH, Zhang W, Paige Taylor S, Lachman RS, Zieba J, Bamshad M, Nickerson D, Chong JX, Cohn DH, Krejci P, Krakow D, Duran I.
  • LAMA5 Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a 107 WBD (US) 4854-8046-9185v2 distinct bent bone dysplasia. EBioMedicine.2020 Dec;62:103075).
  • the amino acid sequence of LAMA5 is SEQ ID NO: 226 and can be found under UniProt Accession No. O15230.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 226 and/or the protein level thereof.
  • LAMB3 (also known as BM600-125KDA, LAM5, LAMNB1, AI1A, Laminin, beta 3, laminin subunit beta 3, JEB1B, JEB1A) encodes the beta subunit of laminin which is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
  • LAMB3 has been identified as a potential therapeutic target in colorectal cancer that can be targeted by BET inhibitors and MEK inhibitors (Zhu Z, Song J, Guo Y, Huang Z, Chen X, Dang X, Huang Y, Wang Y, Ou W, Yang Y, Yu W, Liu CY, Cui L.
  • LAMB3 promotes tumour progression through the AKT-FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer. Oncogene.2020 Jun;39(24):4666-4680).
  • the amino acid sequence of LAMB3 is SEQ ID NO: 227 and can be found under UniProt Accession No. Q13751.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 227 and/or the protein level thereof.
  • GZMA also known as Granzyme A, CTLA3, HuTPS, T-cell associated protease 1, cytotoxic T lymphocyte serine protease, TSP-1, T-cell derived serine proteinase encodes a proinflammatory protease that promotes colorectal cancer development.
  • Extracellular GzmA has been found to induce NF- ⁇ B-dependent IL-6 production in macrophages (Santiago L, Castro M, Sanz-Pamplona R, Garzón M, Ramirez-Labrada A, Tapia E, Moreno V, Layunta E, Gil-Gómez G, Garrido M, Pe ⁇ a R, Lanuza PM, Comas L, Jaime-Sanchez P, Uranga-Murillo I, Del Campo R, Pelegr ⁇ n P, skyr E, Mart ⁇ nez-Lostao L, Mu ⁇ oz G, Uranga JA, Alcalde A, Galvez EM, Ferrandez A, Bird PI, Metkar S, Arias MA, Pardo J.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 228 and/or the protein level thereof.
  • PRSS3 (also known as MTG, PRSS4, T9, TRY3, TRY4, protease, serine 3, serine protease 3) encodes trypsinogen, which is a member of the trypsin family of serine proteases.
  • PRSS3 has been proposed as a biomarker for invasive ductal carcinoma of the breast (Qian L, Gao X, Huang H, Lu S, Cai Y, Hua Y, Liu Y, Zhang J. PRSS3 is a prognostic marker in invasive ductal carcinoma of the breast. Oncotarget.2017 Mar 28;8(13):21444-21453).
  • SERPING1 also known as C1-inh, C1 esterase inhibitor, C1IN, C1INH, C1NH, HAE1, HAE2, serpin family G member 1 encodes a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems.
  • SERPING1 Recombinant SERPING1 is used in the treatment of hereditary angioedema (Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B. C1 inhibitor: molecular and clinical aspects. Springer Semin Immunopathol.2005 Nov;27(3):286-98. doi: 10.1007/s00281- 005-0001-4. Epub 2005 Nov 11.).
  • the amino acid sequence of SERPING1 is SEQ ID NO: 230 and can be found under UniProt Accession No. P05155.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 230 and/or the protein level thereof.
  • EDN1 (also known as preproendothelin-1, ARCND3, ET1, HDLCQ7, QME, endothelin 1, PPET1) encodes a potent vasoconstrictor peptide produced by vascular endothelial cells and is proteolytically processed to release endothelin 1.
  • EDN1 has been found to be sensitive to glucose and glutamine deprivations (Minchenko DO, Khita OO, Tsymbal DO, 109 WBD (US) 4854-8046-9185v2 Viletska YM, Sliusar MY, Yefimova YV, Levadna LO, Krasnytska DA, Minchenko OH.
  • ERN1 knockdown modifies the impact of glucose and glutamine deprivations on the expression of EDN1 and its receptors in glioma cells.
  • the amino acid sequence of EDN1 is SEQ ID NO: 231 and can be found under UniProt Accession No. P05305.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 231 and/or the protein level thereof.
  • EDN3 (also known as ET-3, ET3, HSCR4, PPET3, WS4B, endothelin 3) encodes an endothelium-derived vasoactive peptide.
  • EDN3 is a frequent target of epigenetic inactivation in human breast cancer and has been proposed to act as a natural tumor suppressor in the human mammary gland (Wiesmann F, Veeck J, Galm O, Hartmann A, Esteller M, Knüchel R, Dahl E. Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer.
  • HLA.DRA HLA.DRA (also known as HLA-DRA, HLA class II histocompatibility antigen, DR alpha chain, HLA-DRA1, MLRW, major histocompatibility complex, class II, DR alpha) encodes the alpha subunit of HLA-DR, which plays a central role in the immune system by presenting peptides derived from extracellular proteins.
  • HLA-DRA has been proposed to identify immuno-hot tumors and predict the therapeutic response to anti-PD-1 immunotherapy in NSCLC (Mei J, Jiang G, Chen Y, Xu Y, Wan Y, Chen R, Liu F, Mao W, Zheng M, Xu J.
  • HLA class II molecule HLA-DRA identifies immuno-hot tumors and predicts the therapeutic response to anti-PD-1 immunotherapy in NSCLC.
  • the amino acid sequence of HLA.DRA is SEQ ID NO: 233 and can be found under UniProt Accession No. P01903.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 233 and/or the protein level thereof.
  • CD1D also known as CD1A, R3, R3G1
  • CD1D encodes a member of the family of glycoproteins expressed on the surface of various human antigen-presenting cells.
  • CD1d- deficient macrophages have been found to exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import (Brailey PM, Evans L, López-Rodr ⁇ guez JC, Sinadinos A, Tyrrel V, Kelly G, O'Donnell V, Ghazal P, John S, Barral P. CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses. Nat Commun.2022 Nov 7;13(1):6723. doi: 10.1038/s41467-022-34532-x).
  • the amino acid sequence of CD1D is SEQ ID NO: 234 and can be found under UniProt Accession No. P15813.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 234 and/or the protein level thereof.
  • TNFSF10 also known as APO2L, Apo-2L, CD253, TL2, TRAIL, TNLG6A, tumor necrosis factor superfamily member 10, TNF superfamily member 10) encodes a cytokine that is produced and secreted by most normal tissue cells and is involved in the apoptosis of tumor cells.
  • TNFSF10 has been found to be a prognostic and immune infiltration marker in skin cutaneous melanoma (Xue L, Zhang W, Ju Y, Xu X, Bo H, Zhong X, Hu Z, Zheng C, Fang B, Tang S. TNFSF10, an autophagy related gene, was a prognostic and immune infiltration marker in skin cutaneous melanoma. J Cancer.2023 Jul 31;14(13):2417-2430. doi: 10.7150/jca.86735).
  • the amino acid sequence of TNFSF10 is SEQ ID NO: 235 and can be found under UniProt Accession No. P50591.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 235 and/or the protein level thereof.
  • 111 WBD US 4854-8046-9185v2 VWF: VWF (also known as F8VWD and von Willebrand factor) encodes a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF in endothelium, megakaryocytes, and subendothelial connective tissue (Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem.1998;67:395-424. doi: 10.1146/annurev.biochem.67.1.395.).
  • the amino acid sequence of VWF is SEQ ID NO: 236 and can be found under UniProt Accession No. P04275.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 236 and/or the protein level thereof.
  • LIF also known as CDF, DIA, HILDA, MLPLI, leukemia inhibitory factor, interleukin 6 family cytokine, LIF interleukin 6 family cytokine
  • LIF encodes an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation.
  • LIF expression has been linked to hallmarks of cancer, such as proliferation, metastasis, and chemoresistance, as well as overall patient survival (Jorgensen MM, de la Puente P. Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer. Biomolecules.2022 Jan 27;12(2):217. doi: 10.3390/biom12020217).
  • the amino acid sequence of LIF is SEQ ID NO: 237 and can be found under UniProt Accession No. P15018.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 237 and/or the protein level thereof.
  • ADAM12 also known as Disintegrin and metalloproteinase domain- containing protein 12, Meltrin, ADAM12-OT1, CAR10, MCMP, MCMPMltna, MLTN, MLTNA, ADAM metallopeptidase domain 12 encodes a membrane-anchored protein implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, such as fertilization, muscle development, and neurogenesis. High expression of ADAM12 has been implicated in poor prognosis for patients with primary liver cancer (Du S, Sun L, Wang Y, Zhu W, Gao J, Pei W, Zhang Y. ADAM12 is an independent predictor of poor prognosis in liver cancer.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 238 and/or the protein level thereof.
  • HLA-DQB1 also known as Major histocompatibility complex, class II, DQ beta 1, CELIAC1, HLA-DQB, IDDM1, major histocompatibility complex, class II, DQ beta 1, HLA-DRB1 encodes one of two proteins that are required to form the DQ heterodimer, a cell surface receptor essential to the function of the immune system.
  • HLA-DQB1 polymorphisms have been found to be associated with rheumatoid arthritis (Wu J, Li J, Li S, Zhang TP, Li LJ, Lv TT, Pan HF, Ye DQ.
  • HLA-DQB1 polymorphisms with rheumatoid arthritis: a meta-analysis. Postgrad Med J.2017 Oct;93(1104):618-625. doi: 10.1136/postgradmedj-2016- 134724. Epub 2017 Apr 28).
  • the amino acid sequence of HLA-DQB1 is SEQ ID NO: 239 and can be found under UniProt Accession No. P01920.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 239 and/or the protein level thereof.
  • GZMB GZMB (also known as CCPI, CGL-1, CGL1, CSP-B, CSPB, CTLA1, CTSGL1, HLP, SECT, granzyme B, C11) encodes a serine protease expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells.
  • CTL cytotoxic T lymphocytes
  • NK natural killer cells.
  • GZMB expression is known to be elevated in chronic disease and inflammatory skin disorders, such as diabetic ulcers, hypertrophic scarring, autoimmune skin disorders, cutaneous leishmaniasis and aging skin (Turner CT, Lim D, Granville DJ. Granzyme B in skin inflammation and disease. Matrix Biol.2019 Jan;75-76:126- 140. doi: 10.1016/j.matbio.2017.12.005.
  • GZMB The amino acid sequence of GZMB is SEQ ID NO: 240 and can be found under UniProt Accession No. P10144.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 240 and/or the protein level thereof.
  • CCL20 also known as CKb4, Exodus, LARC, MIP-3-alpha, MIP-3a, MIP3A, SCYA20, ST38, chemokine (C-C motif) ligand 20, C-C motif chemokine ligand 20, Macrophage Inflammatory Protein-3, liver activation regulated chemokine
  • CCL20 has been found to be primarily produced by epithelial cells and inflammatory conditions are known to increase its expression (Meitei HT, Jadhav N, Lal G.
  • CCR6-CCL20 axis as a therapeutic target for autoimmune diseases.
  • the amino acid sequence of CCL20 is SEQ ID NO: 241 and can be found under UniProt Accession No. P78556.
  • the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 241 and/or the protein level thereof.
  • the response markers are selected from any one of (or a combination of, or combinations of) CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A
  • a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty- five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty
  • a human subject having moderately-to-severely active ulcerative colitis is predicted not to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least 116 WBD (US)
  • the present invention includes the individual markers described herein, as well as marker combinations, and their use in methods, composition and systems described herein.
  • the methods may include the measurement of at least one additional marker to facilitate identifying a subject having ulcerative colitis who will respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • Determining whether a level of a biomarker in a biological sample derived from a “test” subject is different from the level of the biomarker present in a control (e.g., non-response control) subject may be ascertained by comparing the level of the biomarker in the sample from the “test” subject with a suitable control of the same biomarker.
  • a suitable control may be a biological sample derived from a known subject (e.g., a non-response control, or e.g., a standard control level, or e.g., a known standard, or, e.g., a reference level).
  • a control level can result from measurement of the level of a marker in a non-inflamed sample from the patient, such as a non-inflamed colonic biopsy distal from the site where an inflamed biopsy is harvested.
  • a suitable control may also be a reference standard.
  • a reference standard serves as a reference level for comparison, such that test samples can be compared to the reference standard in order to predict if a UC patient will respond or not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • a reference standard may be representative of the level of one or more biomarkers in a sample from a known subject, e.g., a subject known to respond to treatment or a subject known to not respond to 118 WBD (US) 4854-8046-9185v2 treatment with an antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • a reference standard may be representative of the level of one or more biomarkers in a population of known subjects, e.g., a population of subjects known to respond to treatment or a population of subjects known to not respond to treatment with an antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • the reference standard may be obtained, for example, by pooling samples from a plurality of individuals and determining the level of a biomarker in the pooled samples, to thereby produce a standard over an averaged population. Such a reference standard represents an average level of a biomarker among a population of individuals.
  • a reference standard may also be obtained, for example, by averaging the level of a biomarker determined to be present in individual samples obtained from a plurality of individuals. Such a standard is also representative of an average level of a biomarker among a population of individuals.
  • a reference standard may also be a collection of values each representing the level of a biomarker in a known subject in a population of individuals.
  • test samples may be compared against such a collection of values in order to determine if a subject with UC will respond or not respond to treatment with an antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • the reference standard is an absolute value.
  • test samples may be compared against the absolute value in order to determine if a subject with UC will respond or not respond to treatment with an antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • a comparison between the level of at least one biomarker in a sample relative to a suitable control is made by executing a software classification algorithm. The skilled person can readily envision additional suitable controls that may be appropriate depending on the assay in question.
  • a human subject having ulcerative colitis is determined to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin if the level of the at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S100
  • a human subject having ulcerative colitis is determined to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin if the level of the at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, T
  • a human subject having ulcerative colitis is treated by determining an expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, C
  • a human subject having ulcerative colitis is treated by determining an expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, C
  • the humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin is given in combination with another agent such as a JAK inhibitor, an anti-TNF ⁇ inhibitor, or an IL-23 inhibitor.
  • the other agent given in combination with the humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin is infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, risankizumab, guselkumab, mirikizumab, or tofacitinib to treat a UC patient predicted to not respond to treatment with an anti- ⁇ 4 ⁇ 7 integrin antibody.
  • the human subject having ulcerative colitis has not previously received an anti- ⁇ 4 ⁇ 7 integrin antibody for treatment.
  • the human subject having ulcerative colitis is treatment na ⁇ ve or not previously exposed to biologic therapy.
  • the failure of anti-TNF ⁇ agents may lead to increased immunogenicity, which might affect the efficacy of a subsequent biological treatment such as vedolizumab.
  • the human subject having ulcerative colitis had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof.
  • Subsets of PBMCs may include myeloid cells, including monocytes, natural killer cells (NKs) and innate lymphoid cells (ILCs), B cells, and T cells, including regulatory T cells (Tregs).
  • PBMCs may include myeloid cells, including monocytes, natural killer cells (NKs) and innate lymphoid cells (ILCs), B cells, and T cells, including regulatory T cells (Tregs).
  • PBMCs may include CD4+ T cells, such as CD4+ na ⁇ ve cells, CD4+ TCM cells, CD4+ TEM cells, CD4+ CTL cells, CD4+ proliferating cells, and/or Tregs.
  • PBMCs may include CD8+ T cells, such as CD8+ na ⁇ ve cells, CD8+ TCM cells, CD8+ TEM cells, CD8+ proliferating cells, and/or MAIT cells.
  • PBMCs may include Gamma delta ( ⁇ ) T cells and/or CD3+CD4 ⁇ CD8 ⁇ T cells (double- negative T cells; DNT cells).
  • PBMCs may include B cells, such as na ⁇ ve 125 WBD (US) 4854-8046-9185v2 B cells, intermediate B cells, memory B cells, and/or plasmablasts.
  • PBMCs may include NK cells, such as CD56bright NK cells and/or proliferating NK cells.
  • PBMCs may include myeloid cells, such as conventional type 1 dendritic cells (cDC1s), conventional type 2 dendritic cells (cDC1s), plasmacytoid dendritic cells (pDCs), ASDCs (AXL+SIGLEC6+ dendritic cells), CD14+ monocytes, and/or CD16+ monocytes.
  • PBMCs may include erythrocytes, hematopoietic stem and progenitor cells (HSPCs), and/or platelet cells.
  • HSPCs hematopoietic stem and progenitor cells
  • Subsets of gut mucosal biopsy cells may include epithelial cells, including M cells, fibroblasts, including inflammatory fibroblasts, myeloid cells, including dendritic cells and inflammatory monocytes, B cells, and T cells, including Tregs and CD8 positive/IL17 positive T cells, NKs, and ILCs.
  • M cells microfold cells
  • fibroblasts including inflammatory fibroblasts, myeloid cells, including dendritic cells and inflammatory monocytes, B cells, and T cells, including Tregs and CD8 positive/IL17 positive T cells, NKs, and ILCs.
  • M cells microfold cells
  • Secretory CD8 positive/IL17 positive T cells make pro-inflammatory cytokine IL17A.
  • gut mucosal biopsy cells may include T cells, such as CD4+ activated Fos-hi cells, CD4+ activated Fos-lo cells, CD4+ memory cells, CD+ PD1+ cells, Tregs, CD8+ intraepithelial intestinal lymphocytes (IELs), CD8+ IL17+ cells, CD8+ lymphocyte-predominant (LP) cells, and/or cycling cells.
  • gut mucosal biopsy cells may include B cells, such as follicular B cells, germinal center (GC) B cells, and/or cycling B cells.
  • gut mucosal biopsy cells may include IgA cells, IgG cells, IgM cells, or Ig-negative cells.
  • gut mucosal biopsy cells may include myeloid cells, NK cells, and/or ILCs.
  • gut mucosal biopsy cells may include CD69- mast cells, CD69+ mast cells, macrophages, inflammatory monocytes, DC1 cells, DC2 cells, pDC cells.
  • gut mucosal biopsy cells may include enterocytes, for example, BEST4+ enterocytes.
  • gut mucosal biopsy cells may include enterocyte progenitors, immature enterocytes 1, and/or immature enterocytes 2.
  • gut mucosal biopsy cells may include secretory cells, such as enteroendocrine cells, goblet cells, immature goblet cells, tuft cells, Paneth-like cells, and M cells.
  • gut mucosal biopsy cells may include stem cells, transit-amplifying (TA) 1 cells, transit-amplifying (TA) 2 cells, secretory TA cells, and/or cycling TA cells.
  • gut mucosal cells may include post-capillary venules, microvascular cells, endothelial cells, and/or pericytes.
  • gut mucosal cells 126 WBD (US) 4854-8046-9185v2 may include myofibroblasts, WNT5B+ 2 cells, WNT5B+ 1 cells, WNT2B+ Fos-lo 1 cells, WNT2B+ Fos-lo 2 cells, WNT2B+ Fos-hi cells, RSPO3+ cells, and/or inflammatory fibroblasts.
  • gut mucosal cells may include glia.
  • the inflammatory monocytes express galectin-3 and CD68 at immunofluorescence staining.
  • cell-types e.g., inflammatory monocytes as described herein are based on the annotations described in Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019).
  • the expression level of at least one response marker selected from RGS2 and MAFB is determined in colonic mucosal macrophages. In certain embodiments, the expression level of at least one response marker selected from RGS2 and MAFB is determined in colonic mucosal macrophages and the human subject is determined to respond to treatment.
  • the expression level of at least one response marker selected from the group consisting of ADAM17, TNF, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, TNFRSF25, HLA-F, SEMA4D, BTLA, ITGB2, ITGAL, CD28, CD46, ITGA4, LTB, CD44, IL1R2, IL1R1, IL12RB, CXCR4, ITGB1, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, ALOXA5AP, CALM2, AREG, and/or HLA-E is determined in regulatory T cells (Tregs).
  • the expression level of at least one response marker selected from the group consisting of IL12RB, IL2RG, TNFRSF1B, CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, CCR6, ALOXA5AP, CALM2, AREG, and/or HLA-E is determined in Tregs and the human subject is determined to not respond to treatment.
  • the expression level of at least one response marker is determined in cells from a subject with UC 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days prior to treatment.
  • response is evaluated at 14 weeks after the start of treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin, such as vedolizumab.
  • response is evaluated by Physician Global Assessment (PGA).
  • PGA incorporates clinical response, endoscopic response and biochemical measurements such as C-Reactive Protein, hemoglobin, and calprotectin.
  • PGA is scored by three independent physicians.
  • response is evaluated by Mayo score (i.e., Mayo Scoring System for Assessment of Ulcerative Colitis Activity).
  • a response with reference to ulcerative colitis subjects refers to a reduction in complete Mayo score of 3 or greater points and 30% from baseline, (or a partial Mayo score of 2 or greater points and 25% or greater from 131 WBD (US) 4854-8046-9185v2 baseline, if the complete Mayo score was not performed at the visit) with an accompanying decrease in rectal bleeding subscore of 1 or greater points or absolute rectal bleeding score of 1 or less point.
  • clinical remission as used herein with reference to ulcerative colitis subjects refers to a complete Mayo score of 2 or less points and no individual subscore greater than 1 point.
  • clinical remission with reference to ulcerative colitis subjects refers to a stool frequency (SF) subscore ⁇ 1, a rectal bleeding subscore (RBS) of 0, and an endoscopic subscore of ⁇ 1.
  • the SF subscore, rectal bleeding subscore, and endoscopic subscore refer to the subscores used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. This is also referred to as “clinical remission per Adapted Mayo Score”.
  • a response with reference to ulcerative colitis subjects refers to a decrease from baseline in the Adapted Mayo score ⁇ 2 points and ⁇ 30% from baseline accompanied by a decrease in RBS ⁇ 1 or an absolute RBS ⁇ 1.
  • a response with reference to ulcerative colitis subjects refers to at least one response selected from the group consisting of a clinical response of a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding, endoscopic response, and mucosal healing.
  • a responder has corticosteroid-free [CSF] symptomatic remission.
  • a responder has corticosteroid-free [CSF] symptomatic remission and corticosteroid-free [CSF] endoscopic remission.
  • a responder has corticosteroid-free [CSF] symptomatic remission, corticosteroid-free [CSF] endoscopic remission, and corticosteroid-free [CSF] histologic remission.
  • CSF endoscopic remission is defined as Mayo Endoscopic Score [MES] ⁇ 1
  • CSF histologic remission is defined as Geboes score ⁇ 2B.0.
  • the level of one or more mRNA biomarkers in a biological sample may be determined by any suitable method. Any reliable method for measuring the level or amount of mRNA in a sample may be used.
  • mRNA can be detected and quantified from a sample (including fractions thereof), such as samples of isolated RNA by various methods known for mRNA, including, for example, amplification-based methods (e.g., Polymerase Chain Reaction (PCR), 132 WBD (US) 4854-8046-9185v2 Real-Time Polymerase Chain Reaction (RT-PCR), Quantitative Polymerase Chain Reaction (qPCR), rolling circle amplification, etc.), hybridization-based methods (e.g., hybridization arrays (e.g., microarrays), NanoString analysis, Northern Blot analysis, branched DNA (bDNA) signal amplification, in situ hybridization, etc.), and sequencing-based methods (e.g., transcriptome sequencing via next-generation sequencing methods, for example, using a MGI2000 sequencer or Illumina or IonTorrent platforms).
  • amplification-based methods e.g., Polymerase Chain Reaction (PCR), 132 WBD (US) 4854-8046-9185v2 Real-Time Poly
  • RNA is converted to DNA (cDNA) prior to analysis.
  • cDNA can be generated by reverse transcription of isolated mRNA using conventional techniques. Other exemplary techniques include ribonuclease protection assay (RPA) and mass spectroscopy.
  • RPA ribonuclease protection assay
  • the level of the mRNA in a sample is determined using quantitative PCR (qPCR) or a Northern blot.
  • qPCR quantitative PCR
  • the protein product of one or more biomarkers in a biological sample may be determined by any suitable method.
  • an antibody binding assay is used to detect a protein biomarker; e.g., a sample from the subject is contacted with an antibody reagent that binds the biomarker analyte, a reaction product (or complex) comprising the antibody reagent and analyte is generated, and the presence (or absence) or amount of the complex is determined.
  • the antibody reagent useful in detecting biomarker analytes can be monoclonal, polyclonal, chimeric, recombinant, or a fragment of the foregoing, and the step of detecting the reaction product can be carried out with any suitable immunoassay.
  • an antibody reagent that binds specifically to the biomarker protein product to be detected, and not to other proteins
  • an antibody reagent can be used to detect the expression of the biomarker of interest in a cellular sample from the subject, or a preparation derived from the cellular sample, using standard antibody-based techniques known in the art, such as flow cytometry (e.g., Fluorescence-Activated Cell Sorting (FACS); multi-color flow cytometry), mass cytometry (CyTOF), immunohistochemistry, oligonucleotide sequencing (e.g., CITE-Seq), ELISA and the like.
  • flow cytometry e.g., Fluorescence-Activated Cell Sorting (FACS); multi-color flow cytometry), mass cytometry (CyTOF), immunohistochemistry, oligonucleotide sequencing (e.g., CITE-Seq), ELISA and the like.
  • the protein product of one or more biomarkers in a biological sample is determined by flow cytometry (e.g., FACS). 133 WBD (US) 4854-8046-9185v2 In one embodiment, the protein product of one or more biomarkers in a biological sample is determined by mass cytometry (e.g., CyTOF). In one embodiment, the protein product of one or more biomarkers in a biological sample is determined by immunohistochemistry. In certain embodiments, the present invention involves detection of biomarkers by in situ hybridization. In certain embodiments, the present invention involves single cell RNA sequencing (scRNAseq).
  • scRNAseq single cell RNA sequencing
  • the invention involves high-throughput single-cell RNA-seq where the RNAs from different cells are tagged individually, allowing a single library to be created while retaining the cell identity of each read.
  • the molecular signatures identified by single cell RNAseq can include cytokines gene signatures, transcription factors gene signatures, lipopolysaccharide (LPS) signatures, immune complexes (IC) signatures, and resident macrophage genes signatures.
  • LPS lipopolysaccharide
  • IC immune complexes
  • resident macrophage genes signatures cytokines gene signatures
  • cytokines gene signatures transcription factors gene signatures
  • LPS lipopolysaccharide
  • IC immune complexes
  • resident macrophage genes signatures resident macrophage genes signatures.
  • a human subject having ulcerative colitis is determined to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin based on measurements of cell level.
  • the level of dendritic cells (DCs), innate lymphoid cells (ILCs), natural killer (NK) cells, and/or inflammatory monocytes is measured.
  • DCs dendritic cells
  • ILCs innate lymphoid cells
  • NK natural killer cells
  • inflammatory monocytes is measured.
  • an increased level of DCs, ILCs, NK cells, and/or inflammatory monocytes in a biological sample from a human subject with UC relative to a response control indicates that the human subject will not respond to treatment with vedolizumab.
  • mucosal inflammatory monocytes of non- responders to vedolizumab have aberrant phenotypes, which could be a causally related to non- response to therapy.
  • increased abundance of NK cells, monocytes, ILCs and DCs at baseline is associated with non-response to treatment.
  • Analysis of cell level or cell abundance can be performed, for example, using scRNAseq data or high-dimension flow cytometry (e.g., Cytek Aurora analysis).
  • non-response to treatment with vedolizumab is associated with Tregs that do not send signals to inflammatory monocytes or IgG cells, whereas response to treatment with vedolizumab is associated with Tregs that do send signals to inflammatory monocytes or IgG cells.
  • response to treatment with vedolizumab is associated with IL-10 mediated self-regulation of inflammatory monocytes, whereas non-response to treatment with vedolizumab is associated with the lack of IL-10 mediated self-regulation of inflammatory monocytes.
  • a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from a gene based on gene ontology (GO) analysis.
  • the marker, or group of markers is selected from a gene involved in neutrophil mediated immunity (GO:0002446), cellular response to lipopolysaccharide (GO:0071222), the interferon-gamma-mediated signaling pathway (GO:0060333), and/or the cytokine-mediated signaling pathway (GO:0019221).
  • increased expression of gene involved in neutrophil mediated immunity indicates that a UC patient will respond to treatment.
  • upregulation of a gene in immune-mediating pathways in mucosal T regulatory cells e.g., inflammatory response (GO:0006954), humoral immune response (GO:0006959) and/or defense response to other organism (GO:0098542), indicates that a UC patient will respond to treatment.
  • upregulation of a gene in fibroblast pathways in mucosal inflammatory fibroblasts indicates that a UC patient will respond to treatment.
  • a human subject having moderately-to-severely active ulcerative colitis is predicted not to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response 136 WBD (US) 4854-8046-9185v2 marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from a gene involved in the regulation of T cell apoptotic process (GO:0070232), ribosome assembly and biogenesis (GO:0042255), and/or cellular metabolic process (GO:0044267).
  • a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN.
  • the marker, or group of markers is selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1,
  • increased expression of the at least one response marker in colonic inflammatory monocytes selected from HIF1A, SOCS3, and/or IL1RN indicates that the human subject will respond to treatment.
  • a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 and/or IL1RN.
  • the marker, or group of markers is selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E,
  • a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from RGS2 and/or MAFB.
  • the marker, or group of markers is selected from RGS2 and/or MAFB.
  • increased expression of RGS2 and/or MAFB in colonic mucosal macrophages indicates that the human subject will respond to treatment.
  • a human subject having moderately-to-severely active ulcerative colitis is predicted not to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TREM1 and/or TGM2.
  • the marker, or group of markers is selected from TREM1 and/or TGM2.
  • increased expression of TREM1 and/or TGM2 in colonic inflammatory monocytes indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF.
  • the marker, or group of markers is selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF.
  • increased expression of IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF in colonic inflammatory monocytes indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ADAM17 and/or TNF.
  • the marker, or group of markers is selected from ADAM17 and/or TNF.
  • increased expression of ADAM17 and/or TNF in regulatory T cells (Tregs) indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining 138 WBD (US) 4854-8046-9185v2 an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from those indicative of a pro- inflammatory macrophage profile.
  • increased expression of IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3 in inflammatory monocytes indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B.
  • increased expression of TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B in inflammatory fibroblasts indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CCL5, CEBPB, IL23A, and/or DCHS2.
  • increased expression of CCL5, CEBPB, IL23A, and/or DCHS2 in colonic inflammatory monocytes indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from SELE, LTB, OSM, and/or CXCL10.
  • the marker, or group of markers is selected from SELE, LTB, OSM, and/or CXCL10.
  • increased expression of SELE, LTB, OSM, and/or 139 WBD (US) 4854-8046-9185v2 CXCL10 in colonic inflammatory monocytes indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the at least one response marker is SEC63.
  • increased expression of SEC63 in IgG plasma cells indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TNFRSF17, TNFRSF13C, and/or SDC1.
  • the marker, or group of markers is selected from TNFRSF17, TNFRSF13C, and/or SDC1.
  • increased expression of TNFRSF17, TNFRSF13C, and/or SDC1 in IgG plasma cells indicates that the human subject will not respond to treatment.
  • increased expression of SDC1 in IgG plasma cells indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2.
  • the marker, or group of markers is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2.
  • increased expression of IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2 in colonic inflammatory monocytes indicates that the human subject will respond to treatment.
  • increased expression of ITGB1 or IL10RA in colonic inflammatory monocytes indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is IL1R1 and/or IL1RAP.
  • increased expression of IL1R1 and/or IL1RAP in colonic inflammatory monocytes indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF.
  • TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF in regulatory T cells (Tregs) indicates that the human subject will respond to treatment.
  • increased expression of CD40LG, IL18R1, IL10RA, IL7R, or TNFRSF14 in Tregs indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is IL12RB, IL2RG, and/or TNFRSF1B.
  • the marker, or group of markers is IL12RB, IL2RG, and/or TNFRSF1B.
  • increased expression of IL12RB, IL2RG, and/or TNFRSF1B in regulatory T cells (Tregs) indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL-11, CXCL2, and/or CXCL14.
  • the marker, or group of markers is selected from IL-11, CXCL2, and/or CXCL14.
  • increased expression of IL-11, CXCL2, and/or CXCL14 in inflammatory fibroblasts indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CXCL12, CXCL16, and/or CCL2.
  • the marker, or group of markers is selected from CXCL12, CXCL16, and/or CCL2.
  • increased expression of CXCL12, CXCL16, and/or CCL2 in inflammatory fibroblasts indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human 141 WBD (US) 4854-8046-9185v2 subject, wherein the marker, or group of markers, is selected from ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE.
  • ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD36, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, and/or FLT1.
  • the marker, or group of markers is selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25.
  • increased expression of CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25 in regulatory T cells (Tregs) indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74.
  • the marker, or group of markers is selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, N
  • TNFRSF1A CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, 142 WBD (US) 4854-8046-9185v2 PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74 in inflammatory fibroblasts indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CD44/SDC1, CD40, GLG1, and/or ITGA6.
  • the marker, or group of markers is selected from CD44/SDC1, CD40, GLG1, and/or ITGA6.
  • increased expression of CD44/SDC1, CD40, GLG1, and/or ITGA6 in IgG plasma cells indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST.
  • increased expression of ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST in inflammatory monocytes indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6.
  • increased expression of CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6 in regulatory T cells (Tregs) indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the 143 WBD (US) 4854-8046-9185v2 human subject, wherein the marker, or group of markers, is selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR.
  • increased expression of MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR in inflammatory fibroblasts indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1.
  • the marker, or group of markers is selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV.
  • the marker, or group of markers is selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human 144 WBD (US) 4854-8046-9185v2 subject, wherein the marker, or group of markers, is selected from BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1.
  • increased expression of BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1 in regulatory T cells (Tregs) indicates that the human subject will respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5.
  • the marker, or group of markers is selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5.
  • increased expression of ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5 in inflammatory monocytes indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK.
  • increased expression of APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK in inflammatory fibroblasts indicates that the human subject will not respond to treatment.
  • a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4.
  • the marker, or group of markers is selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4.
  • increased expression of ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4 in regulatory T cells (Tregs) indicates that the human subject will not respond to treatment.
  • upregulation of a gene in a pathway in mucosal inflammatory fibroblasts that actively promote immune cell functions e.g. chemokine-mediated signaling 145 WBD (US) 4854-8046-9185v2 pathway (GO:0070098), extracellular matrix disassembly (GO:0022617) and/or response to type II interferon (GO:0034341), which enables them to regulate migration and chemotaxis of leukocytes, mononuclear cells and granulocytes indicates that a UC patient will not respond to treatment with a humanized antibody having binding specificity for human ⁇ 4 ⁇ 7 integrin.
  • the invention relates to a method of treating UC in a subject identified as a responder using the methods disclosed.
  • the responder patient is administered an anti- ⁇ 4 ⁇ 7 antibody in an amount effective to treat UC.
  • the human subject may be an adult (e.g., 18 years or older), an adolescent, or a child.
  • the anti- ⁇ 4 ⁇ 7 antibody used to treat a responder can bind to an epitope on the ⁇ 4 chain (e.g., humanized MAb 21.6 (Bendig et al., U.S. Pat.
  • the antibody binds a combinatorial epitope on the ⁇ 4 ⁇ 7 complex, but does not bind an epitope on the ⁇ 4 chain or the ⁇ 7 chain unless the chains are in association with each other.
  • the association of ⁇ 4 integrin with ⁇ 7 integrin can create a combinatorial epitope for example, by bringing into proximity residues present on both chains which together comprise the epitope or by conformationally exposing on one chain, e.g., the ⁇ 4 integrin chain or the ⁇ 7 integrin chain, an epitopic binding site that is inaccessible to antibody binding in the absence of the proper integrin partner or in the absence of integrin activation.
  • the anti- ⁇ 4 ⁇ 7 antibody binds both the ⁇ 4 integrin chain and the ⁇ 7 integrin chain, and thus, is specific for the ⁇ 4 ⁇ 7 integrin complex.
  • Antibodies can bind ⁇ 4 ⁇ 7 but not bind ⁇ 4 ⁇ 1, and/or not bind ⁇ E ⁇ 7, for example.
  • the anti- ⁇ 4 ⁇ 7 antibody binds to the same or substantially the same epitope as the Act-1 antibody (Lazarovits, A. I. et al., J. Immunol., 133(4): 1857-1862 (1984), Schweighoffer et al., J. Immunol., 151(2): 717-729, 1993; Bednarczyk et al., J. Biol. Chem., 269(11): 8348-8354, 1994).
  • Murine ACT-1 Hybridoma cell line which produces the murine Act-1 monoclonal antibody, was deposited under the provisions of the Budapest Treaty on Aug.22, 2001, on behalf of Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Mass.02139, U.S.A., at the American Type Culture Collection, 10801 University Boulevard, Manassas, Va.20110- 146 WBD (US) 4854-8046-9185v2 2209, U.S.A., under Accession No. PTA-3663.
  • the anti- ⁇ 4 ⁇ 7 antibody is a human antibody or an ⁇ 4 ⁇ 7 binding protein using the CDRs provided in U.S. Patent Application Publication No.2010/0254975.
  • the anti- ⁇ 4 ⁇ 7 antibody inhibits binding of ⁇ 4 ⁇ 7 to one or more of its ligands (e.g. the mucosal addressin, e.g., MAdCAM (e.g., MAdCAM-1), fibronectin, and/or vascular addressin (VCAM)).
  • MAdCAM mucosal addressin
  • VCAM vascular addressin
  • Primate MAdCAMs are described in the PCT publication WO 96/24673, the entire teachings of which are incorporated herein by this reference.
  • the anti- ⁇ 4 ⁇ 7 antibody inhibits binding of ⁇ 4 ⁇ 7 to MAdCAM (e.g., MAdCAM-1) and/or fibronectin without inhibiting the binding of VCAM.
  • the anti- ⁇ 4 ⁇ 7 antibody used in the therapeutics methods disclosed herein is a humanized version of the mouse Act-1 antibody. Suitable methods for preparing humanized antibodies are well-known in the art.
  • the humanized anti- ⁇ 4 ⁇ 7 antibody will contain a heavy chain that contains the 3 heavy chain complementarity determining regions (CDRs, CDR1 SEQ ID NO:1; CDR2 SEQ ID NO:2; and CDR3 SEQ ID NO:3) of the mouse Act-1 antibody and suitable human heavy chain framework regions; and also contain a light chain that contains the 3 light chain CDRs (CDR1 SEQ ID NO:4, CDR2 SEQ ID NO:5, CDR3 SEQ ID NO:6) of the mouse Act-1 antibody and suitable human light chain framework regions.
  • CDRs 3 heavy chain complementarity determining regions
  • the humanized Act-1 antibody can contain any suitable human framework regions, including consensus framework regions, with or without amino acid substitutions.
  • one or more of the framework amino acids can be replaced with another amino acid, such as the amino acid at the corresponding position in the mouse Act-1 antibody.
  • the human constant region or portion thereof if present, can be derived from the ⁇ or ⁇ light chains, and/or the ⁇ (e.g., ⁇ 1, ⁇ 2, ⁇ 3, ⁇ 4), ⁇ , ⁇ (e.g., ⁇ 1, ⁇ 2), ⁇ or ⁇ heavy chains of human antibodies, including allelic variants.
  • a particular constant region (e.g., IgG1), variant or portions thereof can be selected in order to tailor effector function.
  • a mutated constant region can be incorporated into a fusion protein to minimize binding to Fc receptors and/or ability to fix complement (see e.g., Winter et al., GB 2,209,757 B; Morrison et al., WO 89/07142; Morgan et al., WO 94/29351, Dec.22, 1994).
  • Humanized versions of Act-1 antibody were described in PCT publications nos. WO98/06248 and WO07/61679, the entire teachings of each of which are incorporated herein by this reference. 147 WBD (US) 4854-8046-9185v2
  • the anti- ⁇ 4 ⁇ 7 antibody is vedolizumab.
  • Vedolizumab (also called MLN0002, ENTYVIOTM or KYNTELESTM) is a humanized immunoglobulin (Ig) G1 mAb directed against the human lymphocyte integrin ⁇ 4 ⁇ 7. Vedolizumab binds the ⁇ 4 ⁇ 7 integrin, antagonizes its adherence to MAdCAM-1 and as such, impairs the migration of gut homing leukocytes into GI mucosa.
  • Vedolizumab is an integrin receptor antagonist indicated for adult patients with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator, or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
  • TNF tumor necrosis factor
  • vedolizumab is for inducing and maintaining clinical response, inducing and maintaining clinical remission, improving endoscopic appearance of the mucosa, and/or achieving corticosteroid-free remission.
  • the humanized anti- ⁇ 4 ⁇ 7 antibody for use in the treatment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.
  • the humanized light chain of vedolizumab e.g., Chemical Abstract Service (CAS, American Chemical Society) Registry number 943609-66-3
  • CAS American Chemical Society
  • LDP-02 has the somewhat hydrophobic, flexible alanine 114 and a hydrophilic site (Aspartate 115) that is replaced in vedolizumab with the slightly hydrophilic hydroxyl-containing threonine 114 and hydrophobic, potentially inward facing valine 115 residue.
  • Vedolizumab may be administered by any suitable method, such as by one or more of intravenous injection, subcutaneous injection, or infusion. In some embodiments, vedolizumab is administered at a dose of 50 mg, 100 mg, 180 mg, 300 mg, or 600 mg. In some embodiments, the vedolizumab is administered, for example subcutaneously, at a dose of 108 mg.
  • Vedolizumab may be administered once per day, per week, per month, or per year.
  • a vedolizumab dosing regimen may have an initial or induction phase and a maintenance phase.
  • An induction phase may be one or more than one, e.g., two, three or four doses, of high amounts or without long times, such as only one week, two weeks, three weeks or four weeks between each dose.
  • an induction regimen may have two doses, one at day (week) zero and one at week 2 (day 14).
  • a maintenance phase e.g., to maintain remission of the IBD, may have lower doses or doses further apart than in the induction phase.
  • the 148 WBD (US) 4854-8046-9185v2 vedolizumab is administered at zero, two and six weeks, and then every two weeks, four weeks or every eight weeks thereafter. Patients with IBD refractory to other therapies may need longer induction periods, e.g., 8, 10 or 12 weeks, before beginning maintenance therapy.
  • vedolizumab is administered intravenously at zero, two and six weeks, then every eight weeks thereafter.
  • vedolizumab is administered one or more times, and then at least one month, at least six months, or at least one year later, vedolizumab is again administered one or more times.
  • 300 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at four weeks intervals or eight week intervals thereafter. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero and two weeks, and then at six weeks and at two-, three- or four-week intervals, 108 mg of vedolizumab may be administered subcutaneously. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at two-, three- or four-week intervals, 108 mg of vedolizumab may be administered subcutaneously.
  • High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab (VDZ) therapy in ulcerative colitis (UC) Summary
  • VDZ vedolizumab
  • UC ulcerative colitis
  • 159,188 mucosal and 95,057 PBMC transcriptomes were generated, and results were validated using Cytek immunoprofiles of additional 797,670 CD45+ mucosal cells and 900,000 PBMCs.
  • Response to VDZ at week 14 manifested through a partial recovery of the epithelial and stromal compartments, and by depleted T cells (CD8+IL17+ and CD4+PD1+ subsets) and innate immune cells (dendritic cells, NKs and inflammatory monocytes) in the colon mucosa.
  • This Example shows that primary non-response to VDZ is marked by active, innate immune cell-mediated inflammation that is present prior to and persists throughout the treatment, and that can be detected in peripheral blood before start of treatment.
  • the aim of this study was to identify cellular and molecular signatures that mark (non-) response to VDZ in UC patients, and thus, gain a better understanding of the mechanism of 150 WBD (US) 4854-8046-9185v2 action of VDZ by performing high-resolution single-cell transcriptomic and surface protein profiling of gut mucosal and peripheral blood cells.
  • Methods Patients included patients with UC that were undergoing ileocolonoscopy to determine the extent of active disease before the start of treatment with VDZ.
  • Sample collection and cryopreservation Patients underwent ileocolonoscopy 2 weeks before the start of VDZ treatment (hereafter named pre-VDZ) and at week 14 after the start of VDZ treatment (hereafter named post-VDZ).
  • pre-VDZ ileocolonoscopy 2 weeks before the start of VDZ treatment
  • post-VDZ ileocolonoscopy 2 weeks before the start of VDZ treatment
  • mucosal biopsies and 10 mL of peripheral blood (EDTA) were obtained.
  • EDTA peripheral blood
  • paired biopsies from inflamed and non-inflamed regions of the colon were collected from the same patient.
  • the biopsies were collected in RPMI1640 supplemented with 10% FCS at 4°C, and were preserved in cold freezing medium containing 90% fetal calf serum (FCS) with 10% dimethyl sulfoxide (DMSO) after collection.
  • FCS fetal calf serum
  • DMSO dimethyl s
  • the gut mucosal biopsies were dissociated using the 'one-step collagenase' protocol, as described previously (Uniken Venema, W. T. C. et al. Gut mucosa dissociation protocols influence cell type proportions and single-cell gene expression levels. Sci Rep 12, 9897 (2022)).
  • biopsies were washed with cold thawing solution, and incubated for 30 minutes in the digestion medium (RPMI1640 supplemented with GlutaMax, 200 iU/mL collagenase IV C1889, 10 iU/mL DNAse II D8764, 35 iU/mL SUPERaseIn AM2694, 2% heat-inactivated FCS), pipette-strained after 10 minutes, and after 30 minutes of incubation, shortly incubated in TrypLE, filtered over a 70 ⁇ m filter and washed using cold wash buffer (PBS -/- supplemented with 0.4% BSA and 10 iU/mL DNase II).
  • the digestion medium RPMI1640 supplemented with GlutaMax, 200 iU/mL collagenase IV C1889, 10 iU/mL DNAse II D8764, 35 iU/mL SUPERaseIn AM2694, 2% heat-inactivated FCS
  • pipette-strained after 10
  • the main response outcome was scored according to Physician Global Assessment (PGA), which incorporates clinical response, endoscopic response and biochemical measurements such as C-Reactive Protein, hemoglobin, and calprotectin.
  • Response by PGA was scored by three independent physicians (one treating, and two unrelated); in cases of dispute, the majority votes were considered.
  • the table further details the assessment of clinical response, endoscopic 155 WBD (US) 4854-8046-9185v2 response and mucosal healing.
  • Clinical response was defined as a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding.
  • Endoscopic response was defined as a decrease in total Mayo score by at least 3 points post-VDZ in the last three segments of the intestinal tract.
  • Clinical response was defined as a decrease in Simple Clinical Colitis Activity Index (SCCAI) by at least 3 points post-VDZ with no reported rectal bleeding (Walmsley, R. S., Ayres, R. C., Pounder, R. E. & Allan, R. N. A simple clinical colitis activity index. Gut 43, 29–32 (1998)).
  • Endoscopic response was defined as a decrease in total Mayo score by at least 3 points post-VDZ in the last three segments of the intestinal tract.
  • Mucosal healing was recognized when a maximum one segment of the intestinal tract received a maximum Mayo score of 1 during post-VDZ (week 14) endoscopy. Since SCCAI scores showed high heterogeneity, and week 14 is generally a too early time point to confidently call endoscopic response or mucosal healing, patients were stratified into responders and non-responders to VDZ based on PGA for all downstream analyses.
  • Cell hashing Cells were labeled with barcoded antibodies (“cell hashing”) using TotalSeq A oligo- conjugated hashtag antibodies (Biolegend) according to the manufacturer's protocol to overcome the challenge of batch effects (Stoeckius, M. et al.
  • cDNA library prep was done according to the 10x manual CG000185 Rev D, and hashtag and antibody-derived libraries were prepared using the manufacturer's protocol (BioLegend TotalSeq-A Antibodies and Cell Hashing with 10x Single Cell 3' Reagent Kit v3.1 (Dual Index) Protocol) (B). Libraries were indexed using 10x PN-120262 Chromium i7 Multiplex Kit. Sequencing was performed by BGI (Hong Kong) on an MGI2000 sequencer, featuring 100bp paired-end reads.
  • High-dimension flow cytometry staining was performed using the CytekTM Aurora machine in the UMCG based on a 40-color flow cytometry-based panel (Park, L. M., Lannigan, J. & Jaimes, M. C. OMIP-069: Forty-Color Full Spectrum Flow Cytometry Panel for Deep Immunophenotyping of Major Cell Subsets in Human Peripheral Blood. Cytometry A 97, 1044– 1051 (2020)). Two panels were designed based on the Cytek Immunomonitoring panel (ref OMIP-069) with adjustments made for our study with support of Cytek. A portion of cells extracted from both peripheral blood and biopsies was visualized using antibodies against cell surface markers with this panel.
  • Seurat object (satijalab.org) was generated, HTO metadata were integrated and the data was filtered based on the HTO assignment (ref G). In cases where the cell was HTO- negative, the Souporcell assignment was used instead. Batch 1 and 2 objects were subsequently merged. The generated data were normalized through the SCTransform method implemented in Seurat and filtered for cells with a fraction of mitochondrial genes expressed (MT) higher than 70%. Next, PCA was performed considering the first 30 components through the RunPCA function in Seurat. Finally, FindNeighbors and FindClusters functions (default parameters) were used to identify cell-based clusters.
  • MT mitochondrial genes expressed
  • the Seurat object was subdivided into three different compartments based on epithelial (EPCAM+), immune (CD45+), and stromal (THY1, SOX10, MADCAM1) markers. Because of the usually lower MT content of immune cells, the immune compartment was further filtered for MT content over 20%. The previously described preprocessing steps were then repeated for the three compartments separately. The aforementioned processing steps used in the biopsy data processing were also followed during the processing of PBMCs scRNA-sequencing data. However, for the filtering of MT content a threshold of 15% was used, and there was no division into different compartments.
  • the Azimuth cell type annotation method in Seurat was used to automatically annotate the cell types within each compartment based on a reference single-cell dataset, where cells in the query dataset are annotated by labeling them based on their closest projected reference cell (cell-cell).
  • the training dataset of Smillie et al. was used for the biopsy data and the human PBMCs Azimuth dataset [the human PBMC dataset is available from the NIH Human Biomolecular Atlas Project (HuBMAP) Azimuth web application] was used for the PBMC data.
  • Pibble (fido package, V 1.0.2) and scCODA v() were chosen considering results significant at credible intervals over or equal to 75% and FDR no greater than 0.3 respectively (Büttner, M., Ostner, J., Müller, C. L., Theis, F. J. & Schubert, B. scCODA is a Bayesian model for compositional single-cell data analysis. Nat Commun 12, 6876 (2021)). Additionally, the non-parametric Mann-Whitney test was performed on the proportions of each cell type in different comparisons. DE analysis and pathway analysis The Seurat implementation of MAST was used to perform differential gene expression analysis at a single-cell level.
  • the statistically significant identified features were divided into positive and negative genes and used as input for enrichment pathway analysis.
  • the Enrichr V 3.1 function that based its GO terms identification on the “GO_Biological_Process_2018” database was used to identify enrichment of specific pathways.
  • Cell-cell interaction analysis Cell-cell communication analysis was performed through the integration of two different cell- cell communication methods. Data was first interrogated using the R package Cellchat (1.4.0), a public database containing information on ligand-receptor interactions and able to provide a first overview of the single cell interaction per specific condition. The investigation was focused on cell-cell communication in responders and non-responders at baseline and after treatment. Further cell-cell communication analysis was performed using NicheNet through the R package nichenetr (1.1.0).
  • NicheNet analysis provides an in-depth understanding of intercellular interactions by using a background set of differentially expressed (DE) genes, which allowed prediction of potential ligand-receptor interactions and determination if specific cell-cell 159 WBD (US) 4854-8046-9185v2 interactions resulted in variations in downstream gene expression.
  • DE genes selection was performed based on the gene presence in at least 10% of the specific cell types, an absolute LFC of 0.25, and a Bonferroni p-value adjusted of 0.05.
  • Nichenet pairwise analysis was performed on a previously selected group of interesting cell-types, which comprises inflammatory monocytes, Tregs, inflammatory fibroblasts, Tc17 cells, IgG+ plasma cells, NKs, DCs M cells and activated endothelial cells. 160 WBD (US) 4854-8046-9185v2 Table 3.
  • Subset of markers for cell communication in responders prior to vedolizumab treatment (subset showing ligands or receptors that are unique to responders)
  • Cell type Sender cell or receiver cell Marker Inflammatory monocytes Sender cell ANXA1 Inflammatory monocytes Sender cell AREG Inflammatory monocytes Sender cell CCL2 Inflammatory monocytes Sender cell CCL3 Inflammatory monocytes Sender cell CCL4 Inflammatory monocytes Sender cell CD46 Inflammatory monocytes Sender cell CXCL10 Inflammatory monocytes Sender cell CXCL3 Inflammatory monocytes Sender cell HBEGF Inflammatory monocytes Sender cell HLA-DRB1 Inflammatory monocytes Sender cell ICAM1 Inflammatory monocytes Sender cell IL10 Inflammatory monocytes Sender cell IL1A Inflammatory monocytes Sender cell IL1B Inflammatory monocytes Sender cell IL1RN Inflammatory monocytes Sender cell SELL
  • Subset of markers for cell communication in non-responders prior to vedolizumab treatment (subset showing ligands or receptors that are unique to non- responders)
  • Cell type Sender cell or receiver cell Marker Inflammatory monocytes Sender cell ADGRE5 Inflammatory monocytes Sender cell CD99 Inflammatory monocytes Sender cell HLA-E Inflammatory monocytes Sender cell ITGB2 Inflammatory monocytes Receiver cell ALOX5 Inflammatory fibroblasts Sender cell APOE Inflammatory fibroblasts Sender cell CCL2 Inflammatory fibroblasts Sender cell CD99 Inflammatory fibroblasts Sender cell COL1A2 Inflammatory fibroblasts Sender cell COL4A2 Inflammatory fibroblasts Sender cell COL6A1 Inflammatory fibroblasts Sender cell COL6A2 Inflammatory fibroblasts Sender cell COL6A3 Inflammatory fibroblasts Sender cell CXCL12 Inflammatory fibroblasts
  • FCS files were imported to the OMIQ program. Compensation was performed on the Cytek Aurora, and standard scaling settings were applied to the data. The data were manually gated to exclude doublets, dead cells, aggregates and CD45+ cells or EPCAM+ cells were selected. For biopsies, CD45+ colonic cells were the focus. In PBMCs, files were selected with a target count of 10,000 randomly selected cells per file, leading to 900,000 cells for analyses. One sample was excluded based on a lack of cells. In the biopsy data, all 797,670 cells were selected for downstream analysis. Afterwards, a Uniform Manifold Approximation and Projection (UMAP) algorithm was run to produce two- dimensional embeddings of the data for visualization.
  • UMAP Uniform Manifold Approximation and Projection
  • Metaclusters were manually grouped into populations using a combination of surface marker intensity, population location, heatmaps based on cell type defining markers (CD38, CD19, CD27, CD8, CD14, CD56, CD4) and prior manual annotation.
  • PBMCs myeloid cells
  • NKs natural killer cells
  • ILCs innate lymphoid cells
  • B cells B cells
  • T cells T cells
  • UMAP and metaclustering were repeated for each subset to obtain the final cell type annotation.
  • cell type annotation was checked by multiple users. Analyses When possible, cell types were grouped into populations that match the cell type annotation performed in the scRNAseq data. Counts of each cell type population at pre-VDZ and post-VDZ were exported. These counts of different subsets were combined into one dataframe for further analyses.
  • Metadata about time point and PGA response were also exported. Given the compositional aspect of the data, a combined approach of Pibble and Wilcoxon Rank Sum test was used. For analysis, no minimal cell count number was applied. Data were grouped into pre- VDZ and post-VDZ and subsequently in response and non-response. Identifying integrin expression changes To determine the differential expression of integrins on peripheral and colonic immune cells by scRNA-seq, the MAST function as built into the Seurat package was used. All p values were Benjamini-Hochberg corrected for multiple testing. In OMIQ positive populations of cell types expressing individual integrins were selected in both the peripheral blood and colonic immune cells based on blanco staining controls.
  • the original biopsy dataset was subdivided into three different compartments through specific markers.
  • the epithelial compartment was isolated selecting the cells showing an average gene expression of EPCAM>3.
  • the stromal compartment was extracted using THY>0.3 (fibroblasts), SOX10>2 (glia) and MADCAM> 1 (endothelial) as markers.
  • the remaining CD45+ and CD27+ cells were deemed the immune compartment.
  • a total of 71,547 cells and 16 cell types were identified using Azimuth with the Smillie reference set.
  • Paneth-like cells were assigned based on marker expression (LYZ, REG3A, module score > 2).
  • marker expression For the immune compartment, a total of 68,809 cells and 25 cell types were identified using Azimuth with the Smillie reference set (ref). Again, specific marker gene expression was used to assign additional biologically relevant cell types.
  • the plasma compartment was further subdivided into IgA (IGHA1> 250), IgG (IGHG1> 80), IgM (IGHM>900), and Ig-negative cell types.
  • pDCs plasmacytoid dendritic cells
  • PBMCs Single cell profiling of CD45+ cells from biopsies and PBMCs using Cytek Flow cytometry data of the PBMCs of the 25 UC patients were included in the study.
  • myeloid cells were subsampled to include all 188.146 cells.
  • CD14+Cd16 Non-classical monocytes (CD14+Cd16), intermediate monocytes (CD14+CD16+), classical monocytes (CD14+CD16-) and classical monocytes 2 (CD14dCD16d).
  • DCs were annotated based on CD14-CD16d cells.
  • CD123+ pDCs were identified. Left over cells were further subdivided into CD1c+ and CD141+ cells. NKs and ILCs were subsampled to include all 51.459 cells.
  • B cells were subsampled to include all 31.774 cells.
  • First B cells were subgrouped into Translational B cells (CD27+CD38-), plasmablasts (CD27+CD38+) and CD38- cells.
  • CD38- cells are subgrouped IgD- memory B cells (IgD-) and metaclusters best matching CD27- IgD+ cells were annotated as naive B cells. Metacluster were visually appointed to a cell type based on position in the general gates.
  • IgD- memory B cells (IgD-) were further subclustered based on switched IgD- memory B cells and IgD- non-switched cells (IgM+, also called IgM+ cells). Switched IgD- memory B cells were subannotated as IgG+ when showing a high expression of IgG.
  • Switched IgD- memory B cells combined with IgG+ and IgM+ cells are all memory B cells. A few cells were left unannotated. T cells were subsampled to include all 619.961 cells.
  • Metacluster were visually appointed to a cell type based on position in the general gates. Metaclusters positive for gdTCR were grouped as gd T cells (CD3+gdTCR+). Metaclusters negative for gdTCR were divided into CD56- and CD56+ cells, the latter group forms the NKT- Like cells. Metacluster negative for CD3- but positive for CD4+ and CD8+ were also annotated.
  • the left over metaclusters are appointed to CD8+, double positive (dp: CD4+CD8+), CD4+ and double negative (dn: CD4-CD8-) based on their position in the general gates.
  • CD4+ metaclusters were divided into Tregs (CD25hiCD127lo) based on their position in the general gates.
  • CD4+ non Treg cell metaclusters were fused and manually clustered based on markers CCR7 and CD45RA.
  • CD4+ TEMRA CD4+ Naive T cells
  • CD4+ Late TEM CD4+ Late TEM
  • CD4+ Translation TCM CD4+ TEM
  • CD4+ TEM CD4+ TEM
  • CD4+ TCM CD4+ CD45RA-
  • Effector memory cells were also fused and manually subclustered based on CD27 and CD28, resulting in CD4+ early like TEM (CD27- CD28+), CD4+ early TEM (CD27+CD28+), CD4+ intermediate TEM (CD27+CD28-), CD4+ terminal TEM (CD27-CD28-).
  • CD8+ cell metaclusters were fused and manually clustered based on markers CCR7 and CD45RA. Resulting in CD8+ TEMRA (CCR7-CD45RAb), CD8+ Naive 178 WBD (US) 4854-8046-9185v2 T cells (CCR7+CD45RAb), CD8+ Late TEM (CCR7-CD45RAd), CD8+ Translation TCM (CCR7+CD45RAd), CD8+ TEM (CCR7-CD45RA-) and CD8+ TCM (CCR7+CD45RA-).
  • Effector memory cells were also fused and manually subclustered based on CD27 and CD28, resulting in CD8+ early like TEM (CD27-CD28+), CD8+ early TEM (CD27+CD28+), CD8+ intermediate TEM (CD27+CD28-) and CD8+ terminal TEM (CD27-CD28-).
  • CD27-CD28+ CD8+ early like TEM
  • CD27+CD28+ CD8+ early TEM
  • CD8+CD28- CD8+ intermediate TEM
  • CD27-CD28- CD8+ terminal TEM
  • Compositional analysis reveals changes in cell abundances that take place in the mucosa and peripheral blood of VDZ-treated UC patients
  • the frequencies of cell types were compared between responders and non-responders both at pre- VDZ and at post-VDZ.
  • the analysis was executed in parallel for single-cell RNA-seq data and Cytek data to allow for the necessary comparisons.
  • Cell composition changes over treatment duration in responders (FIG.3)
  • analysis of cell abundances in scRNAseq data revealed a partial recovery of the epithelial and stromal cell mucosal compartments in responders after treatment.
  • enterocyte progenitors BEST4+ enterocytes, immature enterocytes, goblet cells, immature goblet cells, microfold (M) cells, cycling TA cells, secretory TA cells, TA 1 cells, TA 2 cells, stem cells, WNT5B+ 1 fibroblasts, WNT5B+ 2 fibroblasts, WNT2B+ Fos-lo 1 fibroblasts, RSPO3+ fibroblasts increased, while the abundance of inflammatory fibroblasts and Paneth-like cells decreased.
  • the Cytek analysis showed results similar to the scRNA-seq: in responders, CD4+ naive T cells, CD8 naive T cells, CD4+ Memory T cells, B naive cells, DCs, macrophages, ILCs, plasmablasts, and pDCs were decreased at post-VDZ compared to pre-VDZ (FIG.2).
  • both scRNA-seq analysis and Cytek data analysis showed an increase in the presence of certain cell types:
  • the scRNA-seq analysis revealed a significant increase in the percentage of CD4+ Cytotoxic T cells, NK cells, cDC2, and pDC in post-VDZ compared to pre-VDZ in responders.
  • Cytek data analysis showed an increased presence of NK cells, pDCs, and CD16+ monocytes, and a decrease of CD8+ Naive T cells and CD4-CD8- T cells.
  • Cytek analysis at post-VDZ compared to pre-VDZ showed an increase in mucosal CD8+ effector memory T cells (CD8 TEM), CD8+ memory T cells (CD8 CM), CD4+ memory T cells, and ⁇ -T cells, and a decrease in DC2s, naive B cells, and DCs in non- responders (FIG.2).
  • CD8 TEM mucosal CD8+ effector memory T cells
  • CD8 CM CD8+ memory T cells
  • CD4+ memory T cells CD4+ memory T cells
  • ⁇ -T cells a decrease in DC2s, naive B cells, and DCs in non- responders
  • CD4+ naive T cells included CD25– CD4+ naive T cells and CD45RA+CD25dim CD4+ naive T cells
  • CD4+ TEM included CD25dim CD4+ TEM and CD25int CD4+ TEM
  • Teregs included CD25high memory Tregs and CD25int naive Tregs.
  • PBMCs peripheral blood mononuclear 180 WBD (US) 4854-8046-9185v2 cells; VDZ, vedolizumab; pre-VDZ, 2 weeks prior to vedolizumab treatment; post-VDZ, 14 weeks after vedolizumab treatment. Table 7.
  • Tissue Compartment Cell Change Change Change CI P value technique Mucosa Stroma Glia Increase 95% 0.01 scRNA-seq Mucosa Stroma WNT2B+
  • Fos-lo 1 Increase 75% - scRNA-seq Mucosa Stroma RSPO3+ Increase 75% 0.026 scRNA-seq fibrbolasts Mucosa Stroma WNT5B+ 1 Increase 75% - scRNA-seq Mucosa Stroma
  • Microvascular Increase 75% - scRNA-seq Mucosa Stroma Myofibroblasts Increase 75% - scRNA-seq Mucosa Immune CD4+ activated Decrease 75% - scRNA-seq Fos-lo Mucosa Immune
  • scRNA-seq analysis of the colon mucosa at pre-VDZ non-responders had lower initial frequencies of tuft cells and glial cells and higher initial frequencies of enterocyte progenitors than responders.
  • scRNA-seq analysis of the colon mucosa at pre-VDZ non-responders had higher baseline abundances of NKs, ILCs, DC2s, inflammatory monocytes, and Ig-negative plasma cells, and lower baseline abundances of CD69- and CD69+ mast cells compared to responders.
  • PBMC samples mirrored those in the mucosa:
  • the scRNA-seq analysis revealed a higher level of peripheral blood NKs, NK proliferating cells, and ⁇ -T cells, and a decrease of CD8+ naive T cells and B memory cells in non-responders compared to responders at pre-treatment.
  • Statistical analysis was performed using two methods: the Bayesian multinomial logistic regression (pibble model) with the credible intervals (CI) 75%, 90% and 95%, and the Wilcoxon rank sum test (p value ⁇ 0.05). For each cell type, the direction of change post-VDZ is shown in column “change” and level of significance is recorded as CI (for pibble) and p value (for Wilcoxon test), while “–” represents no significant change.
  • Some cell types from the mucosal Cytek dataset were merged to match cell types identified in the mucosal scRNA-seq dataset.
  • CD4+ naive T cells'' included CD25– CD4+ naive T cells and CD45RA+CD25dim CD4+ naive T cells
  • CD4+ TEM included CD25dim CD4+ TEM and CD25int CD4+ TEM
  • Teregs included CD25high memory Tregs and CD25int naive Tregs.
  • PBMCs peripheral blood mononuclear cells
  • VDZ vedolizumab
  • pre-VDZ 2 weeks prior to vedolizumab treatment
  • post-VDZ 14 weeks after vedolizumab treatment.
  • Pre-VDZ changes in non-responders (compared to responders)
  • Pre-VDZ changes in non-responders (compared to responders)
  • Tissue Compartment Cell Change CI P value technique Change Mucosa Epithelium Enterocyte Increase 75% - scRNAseq progenitors Mucosa Epithelium Tuft Decrease 75% 0.034 scRNAseq Mucosa Stroma Glia Decrease 90% - scRNA-seq Mucosa Immune Cycling B Decrease 75% - scRNA-seq Mucosa Immune Ig negative Increase 75% - scRNA-seq Mucosa Immune NKs Increase 75% - scRNA-seq Mucosa Immune ILCs Increase - 0.040 scRNA-seq Mucosa Immune DC2 Increase 95% - scRNA-seq Mucosa Immune Inflammator Increase 75% - scRNA-
  • Post-VDZ changes in non-responders (compared to responders)
  • Post-VDZ changes in non-responders (compared to responders)
  • Tissue Compartment Cell Change Change Change CI P value technique Mucosa Epithelium Immature Decrease 75% - scRNA-seq enterocytes 2 Mucosa Epithelium BEST4+ Decrease 75% - scRNA-seq enterocytes Mucosa Epithelium Immature goblet Decrease 95% 0.012 scRNA-seq Mucosa Epithelium Enteroendocrine Decrease 90% - scRNA-seq Mucosa Epithelium M cells Decrease 95% - scRNA-seq Mucosa Epithelium Cycling TA Decrease 95% 0.006 scRNA-seq Mucosa Epithelium Secretory TA Decrease 95% 0.006 scRNA-seq Mucosa Epithelium TA
  • both scRNA-seq and Cytek analysis of colon mucosa revealed that non-responders still showed active mucosal inflammation, as evidenced by a larger proportion of infiltrating innate and adaptive immune cells compared to responders.
  • an increase in the abundance of mucosal NKs, DC1 cells, DC2 cells, inflammatory monocytes, macrophages, CD8+ IL17+ T cells, plasma cells in non-responders compared to responders at pre-VDZ was detected based on the single-cell RNA-seq analysis.
  • the results obtained from Cytek analysis in the mucosa were comparable with the scRNA-seq analysis (FIG.2).
  • PBMC scRNAseq a higher abundance of ⁇ -T cells and a lower abundance of pDC and cDC1 cells in non-responders vs responders post-VDZ was observed.
  • PBMC Cytek a higher abundance of Tregs, CD8+ na ⁇ ve T cells, NK cells and classical monocytes and a lower abundance of CD4+ T effector memory cells, CD8+ T central memory cells, CD123+ pDCs, plasmablasts in non- responders vs responders post-VDZ was observed.
  • non-responders the gene expression of ITGA4 and ITGB7 was decreased in IgG plasma (suggesting the effect of VDZ is in peripheral lymph nodes based on the interaction of plasma cells and effector T cells).
  • an increase in alpha 4 expressions was detected in CD4+ T cells, CD8+ T cells, and B memory cells, as evidenced by the results of Cytek analysis.
  • Non-responders displayed reduced beta 7 expressions on CD4+ T cells, ⁇ -T cells, and Plasmablast based on Cytek evaluation.
  • Non-responders vs. responders at post-treatment the ITGA4 gene was upregulated on Inflammatory Monocytes, CD69+ Mast, DCs, IgA, and IgG plasma in responders compared to non-responders, and the ITGB7 gene was upregulated on Tregs, Follicular, IgA, and IgG plasma (the compensatory mechanism).
  • Cytek analysis showed in responders an increase in alpha E on T cell subsets including CD4+ T cells and CD8+ T cells and a decrease in beta 2 on NKs and pDCs compared to non-responders.
  • Non-responders over VDZ treatment duration At post-VDZ compared to pre-VDZ, non-responders showed a higher gene expression of ITGAL, ITGAM, ITGAX, ITGB1, and ITGB2 on Follicular B cells and GC cells than responders.
  • 190 WBD (US) 4854-8046-9185v2 Furthermore, a significantly elevated ITGAX and ITGB1 gene expression among plasma in the same patients was observed.
  • Non-responders vs. responders at pre-treatment At pre-treatment, in non-responders, inflammatory monocytes expressed a higher level of ITGAE, ITGAM, and ITGB2 gene expression than responders.
  • Inflammatory monocytes in mucosa of non-responders expressed a set of alternative integrins that was different in responders.
  • the relative abundance of inflammatory monocytes was increased in non-responders before VDZ therapy both in PBMCs and mucosal biopsies compared to responders.
  • differential gene analysis identified 482 genes that distinguished these inflammatory monocytes: 205 genes were significantly upregulated in non- responders and 277 genes in responders (FIG. 1A).
  • Genes indicative of pro-inflammatory macrophage profile (IL1B, IL1RN, CCL3, CCL4, CXCL2 and CXCL3) were upregulated in inflammatory monocytes of responders, while in non-responders they highly expressed S10011A, S100A6, S100A4, LGALS1 and LGALS3.
  • the latter encodes galectin-3, a macrophage-secreted protein that is involved in cell adhesion and chemotaxis.
  • GSEA Gene set enrichment analysis
  • Neutrophil mediated immunity, cellular response to lipopolysaccharide, interferon- gamma-mediated signaling pathway, and cytokine-mediated signaling pathway were among the most significantly regulated pathways in responders, which were suggestive of the specific function of monocytes including presenting antigens, promoting inflammation, and wound repair.
  • many upregulated genes were involved in cellular protein translation and metabolism, like regulation of the T cell apoptotic process, ribosome assembly and biogenesis, and cellular protein metabolic process (FIG. 1A-B).
  • pathways such as inflammatory response, regulation of lymphocyte mediated immunity, activation of innate immune response and cellular response to cytokine stimulus were significantly upregulated (FIG. 1E).
  • Tregs were of particular interest because a recent study reported that responses to VDZ are associated with a distinct behavior of Tregs (Abreu, et al. Transcriptional Behavior of Regulatory T Cells Predicts IBD Patient Responses to Vedolizumab Therapy. Inflamm Bowel Dis 28, 1800–1812 (2022)). Furthermore, the overactivated monocyte phenotype has been described to be unable to induce an adequate Treg reaction (Cordes et al. Impaired IFN- ⁇ -dependent STAT3 Activation Is Associated With Dysregulation of Regulatory and Inflammatory Signaling in Monocytes of Ulcerative Colitis Patients.
  • Tregs in non-responders much like inflammatory monocytes, do not seem to participate in the local inflammatory environment, while in responders they upregulate a spectrum of immune-mediating pathways (FIG.1F).
  • FOG.1F immune-mediating pathways
  • the focus is on inflammatory fibroblasts since they have the highest anti-TNF ⁇ resistance score in UC among all mucosal cells (Smillie et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019)) and have been implicated in pathogenic cellular module that marks non-response to anti-TNF ⁇ in Crohn’s disease (Martin et al. Single- Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated 193 WBD (US) 4854-8046-9185v2 with Resistance to Anti-TNF Therapy. Cell 178, 1493–1508 (2019)).
  • inflammatory fibroblasts of non-responders highly express a broad spectrum of CXC and CC ligand chemokines, IL-6, CSF2 and CSF3 among others, which enables them to regulate migration and chemotaxis of leukocytes, mononuclear cells and granulocytes.
  • inflammatory fibroblasts highly express TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and WNT2B, which renders them to play less of the inflammation mediation role and more of the typical fibroblast role as illustrated by enriched pathways like wound healing and tissue repair (FIG.1G).
  • inflammatory fibroblasts may contribute to the VDZ non-response by actively promoting immune cell functions.
  • Monocyte activation is associated with worsening of colonic inflammation in non- responders
  • molecular signatures including cytokines gene signatures, transcription factors gene signatures, lipopolysaccharide (LPS) signatures, immune complexes (IC) signatures, and resident macrophage genes signatures were generated [Uzzan et al 2022, NatMed], and differential expression of cytokines gene signatures and transcript factors gene signatures in all mucosal cells, LPS signatures and IC signatures in mucosal Inflammatory Monocytes, and resident macrophage genes signatures in mucosal Macrophages between responders and non-responders were compared both before and at week 14 of VDZ therapy (FIG.3).
  • Pathogenic mucosal inflammatory module with a distinct cell cross-talk marks non- response to vedolizumab at baseline Functionally exhausted inflammatory monocytes, inactive Tregs and reactive inflammatory fibroblasts staging the pre-treatment mucosal inflammation was hypothesized to form a pathogenic inflammatory module with a distinct, rewired cross-talk in VDZ-unresponsive UC patients.
  • a cell-cell interaction analysis was thus conducted in four steps: (1) 10 mucosal cell types of immune, stromal and epithelial origin were nominated that are likely to engage in the cross-talk, (2) intercellular communications were quantitatively inferred using CellChat (Jin et al. Inference and analysis of cell-cell communication using CellChat.
  • the following cell types were selected: cells of the identified innate inflammatory signature of non-response – inflammatory monocytes, DCs, NKs and ILCs, adaptive immune cells – Tregs, Tc17 and IgG + plasma cells, stromal cells – inflammatory fibroblasts and activated endothelial cells, and lastly M cells. Most of these cell types comprise the GIMATS module described by Martin et al. (Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.
  • Table 11 Extended data on the number of ligand-receptor pairs detected by CellChat where a sender cell is a CD8+ IL17+ T cell, DC, IgG+ plasma cell, NK, ILC, activated endothelial cell or an M cell Number of L-R pairs Sender Receiver VDZ-R VDZ-NR CD8+IL17+ T cells CD8+IL17+ T cells 6 6 CD8+IL17+ T cells DCs 10 4 CD8+IL17+ T cells IgG+ plasma cells 2 1 CD8+IL17+ T cells ILCs 4 4 CD8+IL17+ T cells Inflammatory 7 2 fibroblasts CD8+IL17+ T cells Inflammatory 12 4 monocytes CD8+IL17+ T cells M cells 8 3 CD8+IL17+ T cells NKs 5 7 CD8+IL17+ T cells Activated endothelial 13 6 cells CD8
  • inflammatory fibroblasts and activated endothelial cells involved the highest number of ligand-receptor pairs, and IgG + plasma cells the lowest. Dissecting the networks further, inflammatory monocytes in the mucosa of responders appear in full function as they are predicted to express MHC-II receptors on their surface, self-regulate via autocrine IL-10 signaling, communicate to Tregs to ensure continuous cytokine production and promote proliferation and migration of inflammatory fibroblasts.
  • Tregs in the mucosa of responders are actively involved in resolving the inflammation: they engage in cell-cell adhesion, negatively regulate cytotoxicity of leukocytes including inflammatory monocytes, Tc17, NKs and DCs, as well as regulate B cell chemotaxis and leukocyte adhesion to vascular endothelial cells (FIG.4A).
  • Tregs which no longer receive inducing signals from inflammatory monocytes do not communicate back to them nor do they show autocrine signaling.
  • Tregs towards other cells in the network is reduced to negative regulation of NK-mediated cytotoxicity, regulation of response to oxidative stress by DCs and MCP-1 production by activated endothelial cells in an attempt to promote monocyte migration from the bloodstream into the tissue (FIG.4B).
  • a phenotype switch of inflammatory fibroblasts from immune-mediation in non-responders to restorative wound healing in responders was observed (FIG.1G).
  • responder inflammatory fibroblasts carried out most of their functions via IL-11, CXCL2 and CXCL14, while in non-responders they employed CXCL12, CXCL16 and CCL2. Therefore, responder inflammatory fibroblasts are able to promote Treg extravasation and negatively regulate apoptotic signaling in Tc17, IgG + plasma cells and NKs, suggesting their attempt for fast resolution of inflammation (FIG. 4A). In non-responders, inflammatory fibroblasts negatively regulate extravasation of Tregs, Tc17 and IgG + plasma cells, participate in regulation of NK-mediated cytotoxicity and stimulate proliferation of endothelial cells (FIG. 4B).
  • VDZ mucosal inflammatory monocytes of non-responders to VDZ seem to have aberrant phenotypes, which could be a causal factor for non-response to therapy.
  • Response rates for VDZ in anti-TNF ⁇ naive and anti-TNF ⁇ exposed patients Multiple researchers observed that IBD patients with no prior use of anti-TNF ⁇ agents were significantly more likely to respond to VDZ treatment compared to patients who had been previously exposed to anti-TNF ⁇ agents (Sands BE, et al., Inflamm Bowel Dis. (2017); Stallmach A, et al., Aliment Pharmacol Therapeut. (2016); Narula N, et al., Am J Gastroenterol.
  • Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut 68, 25–39 (2019)). Similarly, a study conducted by Schleier et al. demonstrated that impaired gut homing of non-classical monocytes was associated with the efficacy of VDZ. In responders, a partial recovery of the epithelial and stromal cell mucosal compartments at week 14 was observed. Specifically, BEST4+ enterocytes, goblet, immature goblet, RSPO3+ fibroblasts increased after treatment, whereas inflammatory fibroblasts depleted.
  • non-responders In non- responders a further decrease of enterocyte lines, among which BEST4+ enterocytes, is seen, as well as a further decrease of immature goblet cells and M cells, and an increase in inflammatory fibroblasts which shows progression of the inflammation during non-response.
  • Innate cellular signature of non-response to VDZ A higher presence of innate immune cells in the gut mucosa in non-responders vs responders at baseline was observed, namely NK cells, inflammatory monocytes, ILCs and DCs, showing a significant difference between the two groups already before the start of VDZ. This profile is also visible in peripheral blood in which NK cells, monocytes, ILCs and DCs are increased before treatment in non-responders.
  • NK cells in IBD have aberrant NK cell function, with reduced cytotoxicity, a dysregulated pattern of cytokine secretion with reduced IFN ⁇ production and increased TNF ⁇ and IL17a production (Zaiatz Bittencourt, V., Jones, F., Tosetto, M., Doherty, G. A. & Ryan, E. J. Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients.
  • Activation of NK cells is related to the NKG2D receptor expression in intestinal mucosa from UC patients, by its ligand MICA in the epithelial compartment, with lower frequency of lamina intestinal NKG2D+ NK cells in severe UC (Ge, L. Q. et al. Upregulated mRNA expression of major histocompatibility complex class I chain-related gene A in colon and activated natural killer cells of Chinese patients with ulcerative colitis. J Dig Dis 12, 82–89 (2011); Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling - PubMed.Wang et al.
  • inflammatory monocytes While more abundant in non-responders, appear to have little to no role in the local inflammatory process, whereas in responders these cells exert their expected functions such as activation of the adaptive and the innate immune response, but also regulation of said immune responses and of their own activity through IL10 self-signaling.
  • inflammatory fibroblasts While in responders these fibroblasts appear to be involved in restorative processes through wound healing and smooth muscle cell migration pathways, in non-responders inflammatory fibroblasts appear to play a role in inflammation regulation through response to interferon, migration of both innate and adaptive immune cells, and regulation of the inflammatory process pathways.
  • This inflammatory fibroblast phenotype does to an extent correspond to the activated fibroblast phenotype that plays a central role in non-response to anti-TNF ⁇ in CD as described by Martin et al. in the GIMATS module (Martin et al. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell 178, 1493–1508 (2019)).
  • the GIMATS module also includes inflammatory monocytes as an important player in non-response to anti-TNF ⁇
  • the non-response module that was observed for VDZ is notably different as there appears to be no significant role for the IgG plasma cells and activated T cells in non-response to VDZ as opposed to in non-response to anti- TNF ⁇ .
  • their dysfunctional role in non-responder mucosal inflammation pre-VDZ, and their primary role in response to VDZ it most likely that these dysfunctional inflammatory monocytes play a central role in non-response to VDZ.
  • Tofacitinib which at adequate dosage inhibits STAT1, but not STAT3, can correct this phenotype and shift UC inflammatory monocytes to a more regulatory phenotype (Cordes, F. et al. Tofacitinib Reprograms Human Monocytes of IBD Patients and Healthy Controls Toward a More Regulatory Phenotype. Inflamm Bowel Dis 26, 391–406 (2020)). This provides a rational basis for combination therapy for UC.
  • VDZ is an attractive choice for maintenance therapy because of its limited effect on the systemic immune system and therefore low long term risk of malignancy
  • the initial response rate of ⁇ 50% and ultimate maintenance rate of ⁇ 30% means that only a limited number of patients can reap these long term benefits.
  • induction remission with Tofacitinib during the start of treatment with VDZ can improve the inflammatory monocyte phenotype and radically improve response and maintenance rates. This is the largest prospective study using single cell transcriptomic profiling and the analyses of 206 WBD (US) 4854-8046-9185v2 surface markers in both the diseased intestinal tissue and peripheral blood to study the response to biological therapy in UC.
  • Optimal Treatment Target in Ulcerative Colitis Disease activity and response to therapy in ulcerative colitis (UC) can be assessed by a range of endpoints including symptoms, endoscopic mucosal activity, histological disease activity, and biomarkers.
  • This study (VERDICT: In actiVE Ulcerative Colitis, a RanDomIzed Controlled Trial for Determination of the Optimal Treatment Target) aims to determine the optimal treatment target, which is a research priority for the management of UC both to inform clinical practice and to help inform regulatory endpoints and targets for drug development. Participants with active UC will be randomized in a 2:3:5 ratio to 1 of 3 groups, each with a different treatment target.
  • Treatment targets will be defined as: Group 1: corticosteroid-free [CSF] symptomatic remission; Group 2: corticosteroid-free [CSF] endoscopic + symptomatic remission; Group 3: corticosteroid-free [CSF] histological + endoscopic + symptomatic remission, also termed disease clearance.
  • Treatment algorithms may include the use of vedolizumab.
  • a key premise is that vedolizumab has a favorable safety profile and can be used to treat subjects who are in symptomatic remission but who have not attained endoscopic or histopathologic remission. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy.
  • treatment and/or dose escalation will be administered according to the algorithm. Participants who are treatment-na ⁇ ve at randomization will follow treatment algorithm A. Participants, upon entry into the study, will require standard first-line therapy. Either oral 5-ASA and/or immunosuppressive (with optional oral corticosteroid in combination) will be initiated. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm. Participants who are taking non-biologic UC therapies at randomization will follow treatment algorithm B.
  • Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm. Participants who are taking anti-TNF, tofacitinib or ustekinumab therapy at randomization will follow treatment algorithm C. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy.
  • the primary outcome measure is Difference in Time to UC-related Complication Between Treatment Target Groups 1 and 3 [Time Frame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first] (i.e., time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 3).
  • VDZ 300 mg was administered intravenously following a treatment algorithm related to baseline UC treatment until assigned treatment target was reached at week 32, with an escalation step between week 16 and 32 as indicated.
  • CSF endoscopic remission was defined as Mayo Endoscopic Score [MES] ⁇ 1
  • CSF histologic remission was defined as Geboes score ⁇ 2B.0.
  • 612 patients were enrolled with 154, 198, and 260 patients assigned to target Groups 1, 2, and 3, respectively.
  • Group 1 is defined as CSF symptomatic remission
  • Group 2 is defined as CSF symptomatic remission + CSF endoscopic remission
  • Group 3 is defined as CSF symptomatic remission + CSF endoscopic remission + CSF histologic remission.
  • Remission target status missing includes patients who ended the study before the week 32 visit, those who had not reached the week 32 visit, and those who reached the week 32 visit but had no status, as of 29 FEB 2024.
  • CSF corticosteroid-free.

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Abstract

The invention provides methods and compositions related to methods for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin for treating ulcerative colitis. The invention provides response markers that can be used to identify responders of ulcerative colitis.

Description

METHODS AND COMPOSITIONS FOR TREATING ULCERATIVE COLITIS RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Appln. No.63/507,369, filed on June 9, 2023, and U.S. Provisional Appln. No.63/590,182, filed on October 13, 2023. The contents of the foregoing applications are hereby incorporated by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 7, 2024, is named T103022_1340WO_SL.xml and is 363,282 bytes in size. FIELD OF THE INVENTION The present invention relates to methods and compositions related to treating ulcerative colitis. BACKGROUND OF THE INVENTION Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of the colon characterized by the inflammation of colonic mucosa, with diarrhea and rectal bleeding as its main symptoms (Kaser, A., Zeissig, S. & Blumberg, R. S. Inflammatory bowel disease. Annu Rev Immunol 28, 573–621 (2010); Cui, G., Fan, Q., Li, Z., Goll, R. & Florholmen, J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers. EBioMedicine 66, 103329 (2021)). UC patients experience a significant decrease in their quality of life due to symptoms, endoscopies, and frequent hospital visits (Kappelman, M. D. et al. Utilization of healthcare resources by U.S. children and adults with inflammatory bowel disease. Inflamm Bowel Dis 17, 62–68 (2011)). In an effort to improve clinical care for UC patients, the number of pharmacological treatment options has been rising over the past years. Today, physicians can opt for several biologic agents such as anti-tumor necrosis factor alpha (TNF-α) monoclonal antibodies (e.g. Infliximab), Janus kinase (JAK) inhibitors (e.g. Tofacitinib), and integrin receptor antagonists like Vedolizumab (VDZ) (Ferretti, F., Cannatelli, R., Monico, 1 WBD (US) 4854-8046-9185v2 M. C., Maconi, G. & Ardizzone, S. An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis. J Clin Med 11, 2302 (2022)). One of the major problems in the treatment of IBD is that medical therapy often leads to a sustained remission in less than 50% of patients (Jairath, V. & Feagan, B. G. Global burden of inflammatory bowel disease. Lancet Gastroenterol Hepatol 5, 2–3 (2020)). Non-response to therapy not only comes as a significant expense for healthcare system, but it also places a major socioeconomic burden on patients (Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol 12, 720–727 (2015)). Anti-TNFα agents are often the first-line biologic treatment for moderate-to-severe ulcerative colitis (UC), with a response rate of ~60%, but sustained remission rate of 30% (Cui, G., Fan, Q., Li, Z., Goll, R. & Florholmen, J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers. EBioMedicine 66, 103329 (2021)). In cases of loss of response to anti-TNFα medication or intolerance, patients are often switched to vedolizumab (VDZ). The growing evidence for VDZ to be equally effective and safer than anti-TNFα agents advocates for a shift in clinical practice towards using VDZ as a first-line biologic (Bohm, M. et al. Comparative safety and effectiveness of vedolizumab to tumour necrosis factor antagonist therapy for Crohn’s disease. Aliment Pharmacol Ther 52, 669– 681 (2020)). The ability to predict which patients will respond to vedolizumab will spare the patients from enduring unsuccessful treatment and provide confidence in treatment plans or highlight the need for early modification of the treatment options. Expedient and accurate treatment based on analytical results for patients likely to have favorable therapeutic outcomes lead to effective management of the UC. SUMMARY OF THE INVENTION Vedolizumab (VDZ), an anti-α4β7 integrin antibody that inhibits leukocyte trafficking to the inflamed gut mucosa, has emerged as an effective treatment for patients with moderate-to- severe ulcerative colitis (UC) who have failed conventional therapy. Approximately half of patients achieve remission with VDZ; leaving response rates in many patients unpredictable. The present disclosure is based, at least in part, on the discovery of an association between certain cellular and molecular signatures (e.g., mRNA and/or protein biomarkers) and 2 WBD (US) 4854-8046-9185v2 response or non-response to VDZ in patients with UC. Using single-cell RNA sequencing, the transcriptome profiles of 159,188 mucosal high-quality single cells and 95,057 high-quality PBMCs of 25 UC patients treated with VDZ, in addition to the immunophenotyping of 797,670 mucosal CD45+ cells and 900,000 PBMC CD45+ cells based on multidimensional flow cytometry data, were used to identify cellular and molecular signatures (markers) of response and non-response to VDZ in UC patients. Accordingly, the present disclosure provides that certain factors disclosed herein can be used, e.g., as biomarkers, to predict whether a human subject having ulcerative colitis will respond or not respond to treatment with VDZ. Disclosed herein are methods and compositions for predicting a UC patient’s response to treatment with an anti-α4β7 integrin antibody. The methods and compositions provided herein are also useful for improving clinical care for a UC patient by enabling informed decisions regarding treatment options in a UC patient that is predicted to respond or not respond to treatment with VDZ. Accordingly, in one aspect, the disclosure provides a method for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin, said method comprising determining an expression level of at least one response marker in a biological sample from the human subject, wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, wherein the human subject will respond to treatment if the level of the at least one response marker correlates with a reference level for a human subject who has responded to treatment with the humanized antibody, or wherein the human subject will not respond to treatment if the level of the at least one response marker correlates with a reference level for a human subject who has not responded to treatment with the humanized antibody, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human α4β7 integrin comprises the CDRs: light chain: CDR1 SEQ ID NO: 4, CDR2 SEQ ID NO: 5, CDR3 SEQ ID NO: 6; heavy chain: CDR1 SEQ ID NO: 1; CDR2 SEQ ID NO: 2; and CDR3 SEQ ID NO: 3. In another aspect, the disclosure provides method for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin, said method comprising comparing the expression 3 WBD (US) 4854-8046-9185v2 level of at least one response marker in a biological sample from the human subject to a non- response control level of the at least one response marker; wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, and determining whether the level of the at least one response marker from the biological sample is equal to or higher than the level of the at least one response marker of a non- response control, wherein a higher level of the at least one response marker from the biological sample from the human subject relative to the level of the at least one response marker from the non-response control indicates that the human subject will respond to treatment, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human α4β7 integrin comprises the CDRs: light chain: CDR1 SEQ ID NO: 4, CDR2 SEQ ID NO: 5, CDR3 SEQ ID NO: 6; heavy chain: CDR1 SEQ ID NO: 1; CDR2 SEQ ID NO: 2; and CDR3 SEQ ID NO: 3. In another aspect, the disclosure provides a method of treating ulcerative colitis in a human subject, said method comprising determining an expression level of at least one response marker in a biological sample from the human subject, wherein the human subject will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin if the level of the at least one response marker correlates with a reference level for a human subject who has responded to treatment, wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, further comprising administering to the human subject the humanized antibody, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human α4β7 integrin comprises the CDRs: light chain: CDR1 SEQ ID NO: 4, CDR2 SEQ ID NO: 5, CDR3 SEQ ID NO: 6; heavy chain: CDR1 SEQ ID NO: 1; CDR2 SEQ ID NO: 2; and CDR3 SEQ ID NO: 3. In some embodiments of the methods of the invention, the biological sample is a peripheral blood sample or a gut mucosal biopsy sample from the human subject. In some embodiments, the sample comprises colonic inflammatory monocytes that express galectin-3 and CD68 at immunofluorescence staining. In some embodiments, the sample is collected within two weeks prior to treatment. 4 WBD (US) 4854-8046-9185v2 In some embodiments, the expression level of the at least one response marker is determined by single-cell RNAseq. In some embodiments, the ulcerative colitis is moderately to severely active ulcerative colitis. In some embodiments, the human subject had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof. In some embodiments, the human subject previously received treatment with at least one corticosteroid. In some embodiments, response to treatment is assessed by Physician Global Assessment (PGA) score at 14 weeks after the start of treatment. In some embodiments, the methods of the invention further comprises measuring the level of dendritic cells (DCs), innate lymphoid cells (ILCs), natural killer (NK) cells, and/or inflammatory monocytes in the sample from the human subject, wherein an increased level relative to a response control level of DCs, ILCs, NK cells, and/or inflammatory monocytes indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is selected from a gene expressed in colonic inflammatory monocytes and involved in neutrophil mediated immunity, cellular response to lipopolysaccharide, the interferon-gamma-mediated signaling pathway, and/or the cytokine-mediated signaling pathway. In some embodiments, increased expression of the at least one response marker selected from a gene expressed in colonic inflammatory monocytes and involved in neutrophil mediated immunity, cellular response to lipopolysaccharide, the interferon-gamma-mediated signaling pathway, and/or the cytokine-mediated signaling pathway indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is selected from a gene expressed in colonic inflammatory monocytes and involved in the regulation of T cell apoptotic process, ribosome assembly and biogenesis, and/or cellular metabolic process. In some embodiments, increased expression of at least one response marker selected from a gene expressed in colonic inflammatory monocytes and involved in the regulation of T cell 5 WBD (US) 4854-8046-9185v2 apoptotic process, ribosome assembly and biogenesis, and/or cellular metabolic process indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN indicates that the human subject will respond to treatment. In some embodiments the at least one response marker is expressed in colonic inflammatory monocytes and selected from HIF1A, SOCS3, and/or IL1RN. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from HIF1A, SOCS3, and/or IL1RN indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 and/or IL1RN. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 and/or IL1RN indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic mucosal macrophages and selected from RGS2 and/or MAFB. In another embodiment, increased expression of the at least one response marker expressed in colonic mucosal macrophages and selected from RGS2 and/or MAFB indicates that the human subject will respond to treatment. 6 WBD (US) 4854-8046-9185v2 In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and selected from TREM1 and/or TGM2. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from TREM1 and/or TGM2 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and is selected from IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and is selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and selected from ADAM17 and/or TNF. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from ADAM17 and/or TNF indicates the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B. 7 WBD (US) 4854-8046-9185v2 In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and is selected from CCL5, CEBPB, IL23A, and/or DCHS2. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from CCL5, CEBPB, IL23A, and/or DCHS2 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and is selected from SELE, LTB, OSM, and/or CXCL10. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and selected from SELE, LTB, OSM, and/or CXCL10 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in IgG plasma cells and is SEC63. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells, wherein the at least one response marker is SEC63 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in IgG plasma cells and is selected from TNFRSF17, TNFRSF13C, and/or SDC1. In another embodiment, the at least one response marker is expressed in IgG plasma cells and is SDC1. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells and selected from TNFRSF17, TNFRSF13C, and/or SDC1 indicates that the human subject will not respond to treatment. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells, wherein the at least one response marker is SDC1 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2. 8 WBD (US) 4854-8046-9185v2 In another embodiment, the at least one response marker is expressed in colonic inflammatory monocytes and is ITGB1 and/or IL10RA. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2 indicates that the human subject will respond to treatment. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and wherein the at least one response marker is ITGB1 and/or IL10RA indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in colonic inflammatory monocytes and is IL1R1 and/or IL1RAP. In another embodiment, increased expression of the at least one response marker expressed in colonic inflammatory monocytes and wherein the at least one response marker is IL1R1 and/or IL1RAP indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF. In another embodiment, the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CD40LG, IL18R1, IL10RA, IL7R, and/or TNFRSF14. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF indicates that the human subject will respond to treatment. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from CD40LG, IL18R1, IL10RA, IL7R, and/or TNFRSF14 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and is IL12RB, IL2RG, and/or TNFRSF1B. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) selected from IL12RB, IL2RG, and/or TNFRSF1B indicates that the human subject will not respond to treatment. 9 WBD (US) 4854-8046-9185v2 In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from IL-11, CXCL2, and/or CXCL14. In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from IL-11, CXCL2, and/or CXCL14 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from CXCL12, CXCL16, and/or CCL2. In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from CXCL12, CXCL16, and/or CCL2 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in IgG plasma cells and is selected from ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells and selected from ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory monocytes and is selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD36, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, and/or FLT1. In another embodiment, increased expression of the at least one response marker expressed in inflammatory monocytes and selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD36, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, and/or FLT1 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25 indicates that the human subject will respond to treatment. 10 WBD (US) 4854-8046-9185v2 In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74. In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in IgG plasma cells and is selected from CD44/SDC1, CD40, GLG1, and/or ITGA6. In another embodiment, increased expression of the at least one response marker expressed in IgG plasma cells and selected from CD44/SDC1, CD40, GLG1, and/or ITGA6 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory monocytes and is selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST. In another embodiment, increased expression of the at least one response marker expressed in inflammatory monocytes and selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6 indicates that the human subject will not respond to treatment. 11 WBD (US) 4854-8046-9185v2 In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR. In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory monocytes and is selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CXCR4, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1. In another embodiment, increased expression of the at least one response marker expressed in inflammatory monocytes and selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CXCR4, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV. In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1. 12 WBD (US) 4854-8046-9185v2 In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1 indicates that the human subject will respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory monocytes and is selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5. In another embodiment, increased expression of the at least one response marker expressed in inflammatory monocytes and selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5 indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in inflammatory fibroblasts and is selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK. In another embodiment, increased expression of the at least one response marker expressed in inflammatory fibroblasts and selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK indicates that the human subject will not respond to treatment. In some embodiments, the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4. In another embodiment, increased expression of the at least one response marker expressed in regulatory T cells (Tregs) and selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4 indicates that the human subject will not respond to treatment. In some embodiments, the mRNA expression level and/or protein expression level of the at least one response marker is determined. In some embodiments, the mRNA expression level is determined by in situ hybridization or RNA sequencing. In some embodiments, the protein expression level is determined by flow cytometry, mass cytometry, or immunohistochemistry. In some embodiments, a human subject that is determined to respond to treatment is administered the humanized antibody. 13 WBD (US) 4854-8046-9185v2 In some embodiments, a human subject that is determined not to respond to treatment is further treated with a higher dose and/or more frequent administration of the humanized antibody. In some embodiments, a human subject that is determined not to respond to treatment is further treated with a combination therapy that includes the humanized antibody and a second agent. In some embodiments, the second agent is a JAK inhibitor, an anti-TNFα inhibitor, or an IL-23 inhibitor. In some embodiments, the second agent is infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, risankizumab, guselkumab, mirikizumab, or tofacitinib. In some embodiments, a response with reference to ulcerative colitis subjects refers to at least one response selected from the group consisting of a clinical response of a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding, endoscopic response, and mucosal healing. In some embodiments, a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission. In some embodiments, a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission and CSF endoscopic remission. In some embodiments, a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission, CSF endoscopic remission, and CSF histologic remission. In some embodiments, the humanized antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the humanized antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the humanized antibody is vedolizumab. Other features and advantages of the invention will be apparent from the following detailed description, drawings and from the claims. 14 WBD (US) 4854-8046-9185v2 BRIEF DESCRIPTION OF DRAWINGS FIGS.1A-H show that inflammatory monocytes, Tregs and inflammatory fibroblasts display dysregulated functional state in pre-treatment inflamed mucosa in ulcerative colitis (UC) patients that did not respond to vedolizumab therapy. FIG.1A depicts reclustering of inflammatory monocytes captured in the mucosa of UC patients before the start of VDZ treatment (pre-VDZ). Shown is a UMAP representation of 1355 single-cell inflammatory monocytes (transcriptomes) shaded by the response status according to the PGA score. FIG.1B depicts a Volcano plot showing the differential genes expressed by inflammatory monocytes derived from responders (left side of the plot) and non-responders (right side of the plot) prior to VDZ treatment. A gene was considered differentially expressed if the negative log10 FDR (adjusted p value) was greater than 0.05, and log2 fold change was either less than –0.25 or greater than 0.25. FIG.1C shows overrepresented GO terms in the inflammatory monocytes based on 205 differentially expressed genes in responders and 277 genes in non-responders at baseline (pre-VDZ). Circle size corresponds to the proportion of tested genes annotated to a given term, while the shading indicates the level of significance from low (blue) to high (magenta) according to the -log10 of the adjusted p value. FIG.1D depicts CellChat analysis of the intercellular communication network between 10 distinct cell types in the mucosa of the responders (on the left) and non-responders (on the right) at baseline (pre-VDZ). In the circle plots, lines represent predicted interaction between two cell types, and the thickness of each line is proportional to the number of interactions (i.e. how many ligand-receptor pairs contribute to the communication between two cell types). The round loops represent autocrine circuits, while the dot size is proportional to the number of cells in each cell group. Inflammatory monocytes in the mucosa of non-responders do not receive signals from Tregs in contrast to responders. In non-responders, IgG cells do not send signals to CD8+IL17+ T cells and inflammatory fibroblasts (while receiving signals from these two cell types), and do not communicate at all with Tregs. FIGS.1E-G depicts enriched pathways (in GO terms) that reflect functional state of the mucosal inflammatory monocytes, Tregs, and inflammatory fibroblasts. Circle size corresponds to the proportion of tested genes annotated to a given term, while the shading indicates the level of significance from low (light shading) to high (darker shading) according to the -log10 of the adjusted p value. FIG.1H depicts proportion of IgG+ (on the left) or IgA+ (on the right) plasma cells of the total number of captured plasma cells in each sample. UC, 15 WBD (US) 4854-8046-9185v2 ulcerative colitis; VDZ, vedolizumab; UMAP, Uniform Manifold Approximation and Projection; PGA, Physician Global Assessment; FDR, false discovery rate; GO, Gene Ontology; VDZ-R, responders to vedolizumab; VDZ-NR, non-responders to vedolizumab; FC, fold change. FIG.2A and FIG.2B show changes in immune cell composition of the mucosa in responders and non-responders to vedolizumab therapy. In particular, FIG.2A depicts cell proportions within adaptive and innate immune cells (Cytek immunoprofiles) in the mucosa in responders and non-responders pre-VDZ and post-VDZ. Shown are stacked fractions of each cell subtype (y axis) divided by the total number of cells in each of the four sample groups (VDZ-R pre- and post-treatment, VDZ-NR pre- and post-treatment). FIG.2B depicts identification of the innate cellular signature that distinguishes non-responders to VDZ prior to treatment. Shown are significant changes in cell frequency (y axis) for innate cell subsets in mucosal Cytek immunoprofiles in responders and non-responders pre-VDZ. Each dot represents a single sample, cell frequency of each cell type divided by the total number of cells in a sample. Statistical analysis was performed using Bayesian Multinomial Logistic Regression (the Pibble model) with 75% Credible Interval (# indicates significance detected at 75%, 90% or 95% CI). VDZ, vedolizumab; VDZ-R, responders to vedolizumab; VDZ-NR, non-responders to vedolizumab; CI, Credible Interval. FIG.3A and FIG.3B show mucosal expression of selected genes associated with cytokine signaling, monocyte-specific LPS and immune complex (IC) signatures, and genes that mark resident macrophages. FIG.3A depicts heatmaps showing the average log2 fold change in cytokine expression in responders and non-responders over the course of 14 weeks of vedolizumab treatment (top panel), as well as average log2 fold change in cytokine expression between these two groups of patients at pre-VDZ and post-VDZ (bottom panel). The single-cell RNAseq mucosal cells dataset was converted to a pseudo-bulk dataset to interrogate the expression of the cytokines across all cells together (left panels) or across only epithelial cells (right panels). The dotted (“concrete”) pattern in the top panel represents a significant increase in gene expression of a cytokine post-VDZ compared to pre-VDZ, the diagonal line pattern in the top panel represents a significant decrease. The crosshatch pattern in the bottom panel represents a significant increase in gene expression of a cytokine in responders, while the dotted (“sand”) pattern in the bottom panel represents a significant increase in non-responders. No pattern indicates no significant change. A gene appears on the x axis if at least one of the tested 16 WBD (US) 4854-8046-9185v2 cytokines shows a significant change. Statistical differential gene expression analysis was performed using the “MAST” method (“Seurat” R package) (adjusted p < 0.05 after Benjamini- Hochberg multiple test correction). FIG.3B depicts heatmaps showing the average log2 fold change in the expression of selected genes in inflammatory monocytes and macrophages in the mucosa in responders and non-responders over the course of 14 weeks of vedolizumab treatment (top panel), as well as average log2 fold change in the expression between these two groups of patients at pre-VDZ and post-VDZ (bottom panel). The diagonal patterns in the top panel represent a significant increase in gene expression of a cytokine post-VDZ compared to pre-VDZ, the hexagon pattern and dotted (“concrete”) pattern in the top panel represent a significant decrease. The large-dotted pattern and crosshatch pattern in the bottom panel represents a significant increase in gene expression of a cytokine in responders, while the small-dotted (“sand”) pattern, diagonal line pattern, and dashed diagonal line pattern in the bottom panel represents a significant increase in non-responders. No pattern indicates no significant change. A gene appears on the x axis if at least one of the tested cytokines shows a significant change. Statistical differential gene expression analysis was performed using the “MAST” method (“Seurat” R package) (adjusted p < 0.05 after Benjamini-Hochberg multiple test correction). LPS, lipopolysaccharide; IC, immune complex; VDZ, vedolizumab; VDZ-R, responder to vedolizumab treatment; VDZ-NR, non-responder to vedolizumab treatment; pre-VDZ, a study time point of 2 weeks before the start of the vedolizumab treatment; post-VDZ, a study time point of 14 weeks after the start of the vedolizumab treatment. FIG.4A and FIG.4B show a schematic illustration of the cell-cell interactions within the mucosal inflammatory module that underlie fundamentally different inflammatory mechanisms in responders and non-responders to vedolizumab. The cell interaction networks were built for responders (FIG.4A) and non-responders (FIG.4B) based on genes differentially expressed by selected mucosal cell types at baseline which were analyzed using CellChat and NicheNet. Detailed information on the number of ligand-receptor pairs, identity of these pairs as well as predicted biological functions that the ligand-receptor pairs represent are shown in FIG.7. FIG.5 depicts heatmaps showing the average log2 fold change in the expression of the genes previously reported to have the potential to distinguish non-responders to VDZ from responders. The top panel shows changes over the course of 14 weeks of vedolizumab treatment, and the bottom panel shows changes in gene expression between responders and non-responders 17 WBD (US) 4854-8046-9185v2 at pre-VDZ and post-VDZ. The single-cell RNAseq mucosal cells dataset was converted to a pseudo-bulk dataset to interrogate the expression of the cytokines across all cells together. With respect to the top panel, the bottom five fill patterns in the left log2FC legend represent a significant increase in gene expression post-VDZ compared to pre-VDZ, the top five fill patterns in the left avg log2FC legend represents a significant decrease. With respect to the bottom panel, the top three fill patterns in the right avg log2FC legend represent a significant increase in gene expression in responders, while the bottom eight fill patterns in the right log2FC legend represent a significant increase in non-responders. No pattern indicates no significant change. Statistical differential gene expression analysis was performed using the “MAST” method (“Seurat” R package) (adjusted p < 0.05 after Benjamini-Hochberg multiple test correction). FIG.6A and FIG.6B , and FIG.6C depict a characterization of the functional state of circulating monocytes in responders and non-responders prior to vedolizumab treatment. FIG. 6A shows a reclustering of the monocytes captured in the peripheral blood of UC patients before the start of VDZ treatment (pre-VDZ). Shown is the UMAP representation of 21,031 single-cell monocytes (transcriptomes, CD14+ and CD16+ monocytes combined) shaded by the PGA response. FIG.6B is a Volcano plot showing the differential genes expressed by monocytes derived from responders (left side of the plot) and non-responders (right side of the plot) prior to VDZ treatment. A gene was considered differentially expressed if the negative log10 FDR (adjusted p value) was greater than 0.05, and log2 fold change was either less than –0.25 or greater than 0.25. FIG.6C shows enriched pathways (in GO terms) that reflect the functional state of the circulating monocytes. Circle size corresponds to the proportion of tested genes annotated to a given term, while the shading indicates the level of significance from low to high according to the -log10 of the adjusted p value. FIG.7 depicts differences in the mucosal cell-cell crosstalk of responders and non- responders prior to VDZ treatment. In particular, FIG.7 is an overview of the changes in ligand- receptor interactions between a sender cell (inflammatory monocyte, Treg or inflammatory fibroblast) and a receiver cell in the mucosa in two groups of UC patients – responders (top row) and non-responders (bottom row). Numbers indicate the quantity of ligand-receptor pairs for each intercellular link. The loops indicate autocrine circuits. Analysis was done using CellChat. VDZ, vedolizumab; VDZ-R, responder to vedolizumab treatment; VDZ-NR, non-responder to vedolizumab treatment. 18 WBD (US) 4854-8046-9185v2 DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are methods and compositions for predicting an ulcerative colitis patient’s response to an anti-α4β7 integrin antibody, such as vedolizumab. Not all patients with ulcerative colitis (UC) who receive treatment with an anti-α4β7 antibody, such as vedolizumab, respond to the treatment and some do not respond fully to treatment. To improve clinical care for the treatment of UC, there is a need to identify UC patients before treatment who will respond to anti-α4β7 antibody therapy and those who will not respond. Predicted responders can then be treated with standard treatment options, and the treatment options of predicted non-responders can be modified (e.g., increased dosing, increased dosing frequency, combination therapy). Methods disclosed herein relate to the surprising discovery that there is an association between certain cellular and molecular signatures (e.g., mRNA and/or protein biomarkers) and response or non-response to vedolizumab in patients with ulcerative colitis. Vedolizumab, a humanized monoclonal antibody that binds specifically to the α4β7 integrin, is indicated for the treatment of patients with moderately to severely active ulcerative colitis and Crohn’s disease. Vedolizumab has a novel gut-selective mechanism of action that differs from that of other currently marketed biologic agents for the treatment for inflammatory bowel disease (IBD), including natalizumab and tumor necrosis factor-α (TNF-α) antagonists. By binding to cell surface–expressed α4β7 integrin, vedolizumab blocks the interaction of a subset of memory gut-homing T lymphocytes with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on endothelial cells. Consequently, migration of these cells into inflamed intestinal tissue is inhibited. The efficacy and safety of vedolizumab was demonstrated in patients with UC in the GEMINI 1 trial (ClinicalTrials.gov number, NCT00783718) and in patients with CD in the GEMINI 2 (ClinicalTrials.gov number, NCT00783692) and GEMINI 3 (ClinicalTrials.gov number, NCT01224171) trials. The exposure-response (efficacy) relationships of vedolizumab in patients with UC and CD for induction and maintenance therapy have been presented elsewhere. I. Definitions In order that the present invention may be more readily understood, certain terms are first defined. Unless otherwise defined herein, scientific and technical terms used in connection with 19 WBD (US) 4854-8046-9185v2 the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise. The cell surface molecule, "α4β7 integrin," or "α4β7" (used interchangeably throughout) is a heterodimer of an α4 chain (CD49D, ITGA4) and a β7 chain (ITGB7). Human α4-integrin and β7-integrin genes GenBank (National Center for Biotechnology Information, Bethesda, Md.) RefSeq Accession numbers NM_000885 and NM_000889, respectively) are expressed by B and T lymphocytes, particularly memory CD4+ lymphocytes. Typical of many integrins, α4β7 can exist in either a resting or activated state. Ligands for α4β7 include vascular cell adhesion molecule (VCAM), fibronectin and mucosal addressin (MAdCAM (e.g., MAdCAM-1)). An antibody that binds to α4β7 integrin is referred to herein as an “anti-α4β7 antibody”. As used herein, an antibody, or antigen-binding fragment thereof, that has "binding specificity for the α4β7 complex" binds to α4β7, but not to α4β1 or αEB7. Vedolizumab is an example of an antibody that has binding specificity for the α4β7 complex. The term "about" denotes that the thereafter following value is no exact value but is the center point of a range that is +/-5% of the value of the value. If the value is a relative value given in percentages the term "about" also denotes that the thereafter following value is no exact value but is the center point of a range that is +/-5% of the value, whereby the upper limit of the range cannot exceed a value of 100%. The term "antibody" as used herein, is intended to refer to an immunoglobulin molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter- connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region (CH). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain 20 WBD (US) 4854-8046-9185v2 constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the antibody has a fragment crystallizable (Fc) region. In certain embodiments, the antibody is an IgG1 isotype and has a kappa light chain. A "CDR" or “complementarity determining region” is a region of hypervariability interspersed within regions that are more conserved, termed "framework regions" (FR). As used herein, the term "antigen binding fragment" or “antigen binding portion” of an antibody refers to Fab, Fab', F(ab')2, and Fv fragments, single chain antibodies, functional heavy chain antibodies (nanobodies), as well as any portion of an antibody having specificity toward at least one desired epitope, that competes with the intact antibody for specific binding (e.g., an isolated portion of a complementarity determining or variable region having sufficient framework sequences so as to bind specifically to an epitope). Antigen binding fragments can be produced by recombinant techniques, or by enzymatic or chemical cleavage of an antibody. For instance, papain or pepsin cleavage can be used to generate Fab or F(ab')2 fragments, respectively. Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a recombinant construct encoding the heavy chain of an F(ab')2 fragment can be designed to include DNA sequences encoding the CHI domain and hinge region of the heavy chain. “Antigen binding fragments” of a humanized anti-α4β7 antibody comprise at least the variable regions of the heavy and/or light chains of an anti-α4β7 antibody (e.g., SEQ ID NOs: 9 and 10). Examples of such antigen binding fragments include Fab fragments, Fab′ fragments, scFv and F(ab′)2 fragments of a humanized immunoglobulin known in the art. In one aspect, antigen binding fragments of an anti-α4β7 antibody inhibit binding of α4β7 integrin to one or more of its ligands (e.g., the mucosal addressin MAdCAM (e.g., MAdCAM-1), fibronectin). “Treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disease as well as those in which the disease or its recurrence is to be prevented. Hence, the patient to be treated herein 21 WBD (US) 4854-8046-9185v2 may have been diagnosed as having the disease or may be predisposed or susceptible to the disease. The terms “patient” and “subject” are used interchangeably herein. Preferably a patient is a human. “Baseline” as used herein describes a value of a parameter which is measured prior to the initial dose of a therapeutic agent or initiation of a treatment. It can refer to a measurement on a sample obtained the same day, the day before, during the week before initial treatment, i.e., at a time period before the first dose when little change is expected until after the first dose and values of the measurement obtained after the first dose can be compared to this baseline value to represent the change caused by the dose. The term “determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin”, as used herein, is intended to refer to an ability to assess the likelihood that treatment of a subject with a humanized antibody having binding specificity for human α4β7 integrin will or will not be effective in (e.g., provide a measurable benefit to) the subject. In particular, such an ability to assess the likelihood that treatment will or will not be effective typically is exercised before treatment with the humanized antibody having binding specificity for human α4β7 integrin is begun in the subject. As used herein, the term “expression” when used in connection with detecting the expression of a biomarker of the present disclosure, can refer to detecting transcription of the gene encoding a biomarker protein and/or detecting translation of the biomarker protein. To detect expression of a biomarker refers to the act of actively determining whether a biomarker is expressed or not. To quantitate expression refers to the act of determining the level of the given biomarker, e.g., ng/ml. Detecting and/or quantitating expression can include determining whether the biomarker expression is upregulated as compared to a known standard level, downregulated as compared to a known standard level, or substantially unchanged as compared to a known standard level. Therefore, the step of quantitating and/or detecting expression does not require that expression of the biomarker actually is upregulated or downregulated, but rather, can also include detecting no expression of the biomarker or detecting that the expression of the biomarker has not changed or is not different (i.e., detecting no significant expression of the biomarker or no significant change in expression of the biomarker as compared to a control). 22 WBD (US) 4854-8046-9185v2 The term "level" or "amount" of a biomarker, as used herein, refers to the measurable quantity of a biomarker, e.g., a transcript, a peptide, a protein (or polypeptide). The amount may be either (a) an absolute amount as measured in molecules, moles or weight per unit volume or cells or (b) a relative amount. The term "marker" or "biomarker," as used herein, refers generally to a molecule, e.g., mRNA (and a nucleotide sequence of such mRNA), a gene (and a nucleotide sequence of such gene), a peptide and a protein (and an amino acid sequence of such), the expression of which in or on a sample derived from a mammalian tissue or cell can be detected, for example, by standard methods in the art such as in situ hybridization (as well as methods disclosed herein, e.g., single cell RNAseq), and is predictive or denotes a condition of the subject from which it was obtained. As used herein, the term “reference level” or "control level", refers to an accepted or pre- determined level of a biomarker which is used to compare the biomarker level derived from the sample of a subject. The level of the biomarker may also be compared to a baseline level which is not accepted or pre-determined. The term "sample" or "biological sample" as used herein refers to cells or tissue obtained from a subject. The source of the tissue or cell sample may be solid tissue (as from a fresh, frozen and/or preserved organ or tissue sample or biopsy (e.g., mucosal biopsy) or aspirate); whole blood or any blood constituents (e.g., peripheral blood mononuclear cells (PBMCs)); or bodily fluids, such as serum, plasma, urine, feces, saliva, sweat or synovial fluid. As used herein, “inflammatory monocytes” are cells that are characterized by cell type annotations set forth in Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019). Inflammatory monocytes as used herein may reside in the colonic mucosa. The term “Physician Global Assessment” or “PGA” as used herein refers to a scoring system used to assess disease severity and incorporates “clinical response” defined as a decrease in Simple Clinical Colitis Activity Index (SCCAI) by at least 3 points post-VDZ with no reported rectal bleeding, “endoscopic response” defined as a decrease in total Mayo score by at least 3 points post-VDZ in the last three segments of the intestinal tract, and serological and fecal markers such as C-Reactive Protein, hemoglobin, and calprotectin. The term “Composite Outcome Score” or “COS” may also be used to refer to PGA. 23 WBD (US) 4854-8046-9185v2 II. Response Markers The present disclosure is based, at least in part, on the discovery that certain cellular and molecular signatures (e.g., mRNA and/or protein biomarkers) are associated with response or non-response to vedolizumab in patients with ulcerative colitis. In particular, the markers described herein are mRNA markers and/or protein markers. As described in the Examples below, the disclosure provides biomarkers whose expression levels can be used to predict whether a subject with UC will respond or not respond to treatment with vedolizumab. Thus, in one embodiment, the disclosure relates to the use of differential expression of mRNA and/or protein response markers in a biological sample from a UC patient to predict/determine whether said patient will respond or not respond to treatment with vedolizumab. The response markers that can be used in the compositions and methods disclosed herein include nucleic acid sequences (e.g., mRNA transcripts) that encode the following proteins, alone or in combination: CYP27A1: CYP27A1 (also known as Cytochrome P450 Family 27 Subfamily A Member 1; CYP27; CP27; CTX; Sterol 26-Hydroxylase, Mitochondrial; Vitamin D(3) 25-Hydroxylase; Cytochrome P-450C27/25; Sterol 27-Hydroxylase; Cytochrome P45027; 5-Beta-Cholestane-3- Alpha, 7-Alpha, 12-Alpha-Triol 26-Hydroxylase) encodes a member of the cytochrome P450 superfamily of enzymes that catalyzes regio- and stereospecific hydroxylation of cholesterol and its derivatives. The enzyme is known to catalyze the first step in the oxidation of the side chain of sterol intermediates in the bile acid synthesis pathway (Cali et al. J Biol Chem.1991 Apr 25;266(12):7774-8). The amino acid sequence of CYP27A1 is SEQ ID NO: 11 and can be found under UniProt Accession No. Q02318. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 11 and/or the protein level thereof. C4orf3: C4orf3 (also known as chromosome 4 open reading frame 3; ALN; HCVFTP1; uncharacterized protein C4orf3; HCV F-transactivated protein 1; another-regulin; hepatitis C virus F protein-transactivated protein 1) encodes a protein predicted to be located in the endoplasmic reticulum membrane and predicted to act upstream of or within negative regulation 24 WBD (US) 4854-8046-9185v2 of ATPase-coupled calcium transmembrane transporter activity and negative regulation of calcium ion binding activity. The amino acid sequence of C4orf3 is SEQ ID NO: 12 and can be found under UniProt Accession No. Q8WVX3. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 12 and/or the protein level thereof. IRAK3: IRAK3 (also known as Interleukin-1 Receptor-Associated Kinase 3; IRAK-M; Inactive IL-1 Receptor-Associated Kinase 3; IL-1 Receptor-Associated Kinase M; ASRT5; IRAKM) encodes a member of the interleukin-1 receptor-associated kinase protein family that regulates signaling downstream of immune receptors including IL1R and Toll-like receptors and is found mainly in cells of monomyeloic origin (Wesche et al. J Biol Chem.1999 Jul 2;274(27):19403-10). The amino acid sequence of IRAK3 is SEQ ID NO: 13 and can be found under UniProt Accession No. Q9Y616. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 13 and/or the protein level thereof. CXCL9: CXCL9 (also known as C-X-C Motif Chemokine Ligand 9; SCYB9; Crg-10; Humig; CMK; MIG; Monokine Induced By Gamma Interferon; Gamma-Interferon-Induced Monokine; Chemokine (C-X-C Motif) Ligand 9; Small-Inducible Cytokine B9) encodes a cytokine involved in immunoregulatory and inflammatory processes. CXCL9 is known to be induced in THP-1 cells and in peripheral blood mononuclear cells by interferon-gamma but not by interferon-alpha or by lipopolysaccharide (Farber JM. Biochem Biophys Res Commun.1993 Apr 15;192(1):223-30. doi: 10.1006/bbrc.1993.1403). The amino acid sequence of CXCL9 is SEQ ID NO: 14 and can be found under UniProt Accession No. Q07325. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 14 and/or the protein level thereof. 25 WBD (US) 4854-8046-9185v2 SLCO4A1: SLCO4A1 (also known as Solute Carrier Organic Anion Transporter Family Member 4A1; OATP4A1; OATP-E; SLC21A12; Solute Carrier Family 21 (Organic Anion Transporter), Member 12; Organic Anion Transporter Polypeptide-Related Protein 1; Sodium- Independent Organic Anion Transporter E; Solute Carrier Family 21 Member 12; Colon Organic Anion Transporter; OATPRP1; OATP1; POAT; Solute Carrier Organic Anion Transporter Family, Member 4A1; Organic Anion Transporting Polypeptide E) encodes a member of the solute carrier family and is predicted to enable sodium-independent organic anion transmembrane transporter activity and thyroid hormone transmembrane transporter activity. It is involved in the transport of various compounds, including sugars, bile salts, organic acids, metal ions, amine compounds, and estrogen (Ban et al. J Cancer Res Clin Oncol.2017 Aug;143(8):1437-1447. doi: 10.1007/s00432-017-2393-7). The amino acid sequence of SLCO4A1 is SEQ ID NO: 15 and can be found under UniProt Accession No. Q96BD0. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 15 and/or the protein level thereof. CLEC4E: CLEC4E (also known as C-Type Lectin Domain Family 4 Member E; MINCLE; Macrophage-Inducible C-Type Lectin; CLECSF9; C-Type (Calcium Dependent, Carbohydrate-Recognition Domain) Lectin, Superfamily Member 9; C-Type Lectin Superfamily Member 9) encodes a C-type lectin receptor that acts as a pattern recognition receptor (PRR) of the innate immune system. CLEC4E is thought to sense nonhomeostatic cell death and thereby induces the production of inflammatory cytokines to drive the infiltration of neutrophils into damaged tissue (Yamasaki et al. Nat Immunol.2008 Oct;9(10):1179-88. doi: 10.1038/ni.1651). The amino acid sequence of CLEC4E is SEQ ID NO: 16 and can be found under UniProt Accession No. Q9ULY5. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 16 and/or the protein level thereof. TREM1: TREM1 (also known as Triggering Receptor Expressed On Myeloid Cells 1; TREM-1; CD354; CD354 Antigen) encodes a cell surface receptor expressed on neutrophils and 26 WBD (US) 4854-8046-9185v2 monocytes that amplifies inflammation induced by stimulation of pattern-recognition receptors (Arts et al. Eur Cytokine Netw.2011 Mar;22(1):11-4. doi: 10.1684/ecn.2011.0274). The amino acid sequence of TREM1 is SEQ ID NO: 17 and can be found under UniProt Accession No. Q9NP99. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 17 and/or the protein level thereof. IL1B: IL1B (also known as Interleukin 1 Beta; IL1F2; IL1-BETA; IL-1 Beta; Catabolin; Pro-Interleukin-1-Beta; Preinterleukin 1 Beta; Interleukin 1beta) encodes a key innate cytokine that is essential for immune activation and promoting the inflammatory process (Yaseen et al. Rev Med Virol.2023 Jan;33(1):e2400. doi: 10.1002/rmv.2400). The amino acid sequence of IL1B is SEQ ID NO: 18 and can be found under UniProt Accession No. P01584. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 18 and/or the protein level thereof. FLT1: FLT1 (also known as Fms Related Receptor Tyrosine Kinase 1; VEGFR1; Vascular Endothelial Growth Factor Receptor 1; Vascular Permeability Factor Receptor; FLT; Fms-Related Tyrosine Kinase 1 (Vascular Endothelial Growth Factor/Vascular Permeability Factor Receptor); Tyrosine-Protein Kinase Receptor FLT; Fms Related Tyrosine Kinase 1) encodes a tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion (Lesslie et al. Br J Cancer.2006 Jun 5;94(11):1710-7. doi: 10.1038/sj.bjc.6603143). The amino acid sequence of FLT1 is SEQ ID NO: 19 and can be found under UniProt Accession No. P17948. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 19 and/or the protein level thereof. 27 WBD (US) 4854-8046-9185v2 SOD2: SOD2 (also known as Superoxide Dismutase 2; GClnc1; IPOB; GC1; Superoxide Dismutase 2, Mitochondrial; MnSOD) encodes a protein that binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. As such, SOD2 has antiapoptotic functions against inflammatory cytokines, oxidative stress, and ionizing radiation (Becuwe et al. Free Radic Biol Med.2014 Dec;77:139-51. doi: 10.1016/j.freeradbiomed.2014.08.026). The amino acid sequence of SOD2 is SEQ ID NO: 20 and can be found under UniProt Accession No. P04179. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 20 and/or the protein level thereof. HIF1A: HIF1A (also known as Hypoxia-inducible factor 1-alpha; HIF-1-alpha; HIF-1A; HIF-1alpha; HIF1; HIF1-ALPHA; MOP1; PASD8; bHLHe78; hypoxia inducible factor 1 alpha subunit; hypoxia inducible factor 1 subunit alpha; HIF-1α) encodes a basic helix-loop-helix PAS domain containing protein that functions as a master transcriptional regulator of the adaptive response to hypoxia. It is known to induce expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons in monocytes (Codo et al. Cell Metab.2020 Sep 1;32(3):437-446.e5). The amino acid sequence of HIF1A is SEQ ID NO: 21 and can be found under UniProt Accession No. Q16665. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 21 and/or the protein level thereof. GBP2: GBP2 (also known as Guanylate Binding Protein 2; Interferon-Induced Guanylate-Binding Protein 2; Guanylate Binding Protein 2, Interferon-Inducible; Guanine Nucleotide-Binding Protein 2; Guanylate-Binding Protein 2) encodes an interferon-induced protein that can bind to guanine nucleotides. Murine GBP2 is also known to be expressed in innate and adaptive immune cells (Praefcke GJK. Regulation of innate immune functions by guanylate-binding proteins. Int J Med Microbiol.2018 Jan;308(1):237-245). The amino acid sequence of GBP2 is SEQ ID NO: 22 and can be found under UniProt Accession No. P32456. 28 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 22 and/or the protein level thereof. SLAMF1: SLAMF1 (also known as Signaling Lymphocytic Activation Molecule Family Member 1; Signaling Lymphocytic Activation Molecule; CD150; SLAM; SLAM Family Member 1; CDw150; IPO-3; CD150 Antigen) encodes a self-ligand receptor on the surface of activated T- and B-lymphocytes, macrophages, and dendritic cells (DCs) and is thought to inhibit CD40-induced signal transduction in monocyte-derived dendritic cells (Réthi et al. Blood.2006 Apr 1;107(7):2821-9. doi: 10.1182/blood-2005-06-2265). The amino acid sequence of SLAMF1 is SEQ ID NO: 23 and can be found under UniProt Accession No. Q13291. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 23 and/or the protein level thereof. IL1A: IL1A (also known as Interleukin 1 Alpha; IL1F1; Hematopoietin-1; IL1-ALPHA; IL-1A; Pro-Interleukin-1-Alpha; Preinterleukin 1 Alpha; Interleukin-1 Alpha) encodes a member of the interleukin 1 cytokine family that functions as a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity (Cohen et al. Sci Rep.2015 Oct 6;5:14756. doi: 10.1038/srep14756). The amino acid sequence of IL1A is SEQ ID NO: 24 and can be found under UniProt Accession No. P01583. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 24 and/or the protein level thereof. PTGS2: PTGS2 (also known as Prostaglandin-endoperoxide synthase 2; cyclooxygenase- 2; COX-2; COX2; GRIPGHS; PGG/HS; PGHS-2; PHS-2; hCox-2) encodes one of two cyclooxygenases in humans involved in the conversion of arachidonic acid to prostaglandin H2. PTSG2 transcripts are highly induced in mesenchymal-derived inflammatory cells (Hla et al. Proc Natl Acad Sci U S A.1992 Aug 15;89(16):7384-8). The amino acid sequence of PTGS2 is SEQ ID NO: 25 and can be found under UniProt Accession No. P35354. 29 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 25 and/or the protein level thereof. BCL2L1: BCL2L1 (also known as Bcl-2-like protein 1; Bcl2l1; Bcl(X)L; Bcl-XL; Bcl2l; BclX; bcl-x; bcl2-L-1; BCL-XL/S; BCLXL; BCLXS; PPP1R52; bcl-xS; BCL2L; BCLX; Bcl-X; bcl-xL; BCL2 like 1) encodes Bcl-xL and Bcl-xS through alternative splicing that function as a regulators of apoptotic cell death (Korsmeyer SJ. Regulators of cell death. Trends Genet.1995 Mar;11(3):101-5. doi: 10.1016/S0168-9525(00)89010-1). Bcl-xS mRNA is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes (Boise et al. Cell.1993 Aug 27;74(4):597-608. doi: 10.1016/0092-8674(93)90508-n). The amino acid sequence of BCL2L1 is SEQ ID NO: 26 and can be found under UniProt Accession No. Q07817. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 26 and/or the protein level thereof. SOCS3: SOCS3 (also known as ATOD4; CIS3; Cish3; SOCS-3; SSI-3; SSI3; suppressor of cytokine signaling 3) encodes a cytokine-inducible negative regulator of cytokine signaling. SOCS is thought to play a critical role in negative feedback control of JAK-STAT signaling pathway (Minamoto et al. Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochem Biophys Res Commun.1997 Aug 8;237(1):79-83. doi: 10.1006/bbrc.1997.7080). The amino acid sequence of SOCS3 is SEQ ID NO: 27 and can be found under UniProt Accession No. O14543. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 27 and/or the protein level thereof. DUSP7: DUSP7 (also known as MKPX; PYST2; dual specificity phosphatase 7) encodes a dual specificity protein phosphatase that shows high activity towards MAPK1/ERK2 and lower activity towards MAPK14 and MAPK8 (Dowd et al. J Cell Sci.1998 Nov;111 ( Pt 22):3389-99). 30 WBD (US) 4854-8046-9185v2 The amino acid sequence of DUSP7 is SEQ ID NO: 28 and can be found under UniProt Accession No. Q16829. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 28 and/or the protein level thereof. PLEK: PLEK (also known as Pleckstrin; P47; PLEK1; Platelet 47 KDa Protein) encodes the major protein kinase C (PKC) substrate of platelets and functions in mediating cellular responses evoked by agonist-induced phosphoinositide turnover (Tyers et al. J Cell Biochem. 1989 Jun;40(2):133-45). The amino acid sequence of PLEK is SEQ ID NO: 29 and can be found under UniProt Accession No. P08567. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 29 and/or the protein level thereof. SPP1: SPP1 (also known as secreted phosphoprotein 1; Osteopontin; OPN; bone /sialoprotein I; BSP-1; BNSP; early T-lymphocyte activation; ETA-1) encodes a cytokine involved in enhancing production of interferon-gamma and interleukin-12 and reducing production of interleukin-10 and is essential in the pathway that leads to type I immunity. It is known to enhance B lymphocyte immunoglobulin production and proliferation (Wang et al. Cytokine Growth Factor Rev.2008 Oct-Dec;19(5-6):333-45). The amino acid sequence of SPP1 is SEQ ID NO: 30 and can be found under UniProt Accession No. P10451. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 30 and/or the protein level thereof. TGM2: TGM2 (also known as Transglutaminase 2; Tissue transglutaminase; G-ALPHA- h; GNAH; HEL-S-45; TG2; TGC; TG(C); transglutaminase 2; G(h); hTG2; tTG) encodes a 78- kDa, calcium-dependent enzyme of the transglutaminase family. Intracellularly, TGM2 is thought to function in apoptosis (McConkey et al. Biochem Biophys Res Commun.1997 Oct 31 WBD (US) 4854-8046-9185v2 20;239(2):357-66. doi: 10.1006/bbrc.1997.7409). The amino acid sequence of TGM2 is SEQ ID NO: 31 and can be found under UniProt Accession No. P21980. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 31 and/or the protein level thereof. EGR2: EGR2 (also known as Early growth response protein 2; AT591; CMT1D; CMT4E; KROX20; early growth response 2; CHN1) encodes a transcription regulatory factor, containing three zinc finger DNA-binding sites. EGR2 functions in osteoprogenitor maintenance and new bone formation (Chandra et al. J Biol Chem.2013 Jul 12;288(28):20488-98. doi: 10.1074/jbc.M112.447250). The amino acid sequence of EGR2 is SEQ ID NO: 32 and can be found under UniProt Accession No. P11161. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 32 and/or the protein level thereof. INHBA: INHBA (also known as Inhibin, beta A; EDF; FRP; inhibin beta A; inhibin beta A subunit; inhibin subunit beta A) encodes a preproprotein that is proteolytically processed to generate a subunit of the dimeric activin and inhibin protein complexes. Activins and inhibins are structurally related members of the TGF-beta superfamily of growth and differentiation factors that regulate reproductive and other functions (Lewis et al. Nature.2000 Mar 23;404(6776):411-4). The amino acid sequence of INHBA is SEQ ID NO: 33 and can be found under UniProt Accession No. P08476. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 33 and/or the protein level thereof. IL1RN: IL1RN (also known as interleukin-1 receptor antagonist protein; DIRA; ICIL- 1RA; IL-1RN; IL-1ra; IL-1ra3; IL1F3; IL1RA; IRAP; MVCD4; interleukin 1 receptor antagonist) encodes a member of the interleukin 1 cytokine family that inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 32 WBD (US) 4854-8046-9185v2 1 related immune and inflammatory responses. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement (Aksentijevich et al. N Engl J Med.2009 Jun 4;360(23):2426-37. doi: 10.1056/NEJMoa0807865). The amino acid sequence of IL1RN is SEQ ID NO: 34 and can be found under UniProt Accession No. P18510. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 34 and/or the protein level thereof. PLAU: PLAU (also known as Urokinase; urokinase-type plasminogen activator; ATF; BDPLT5; QPD; UPA; URK; u-PA; plasminogen activator) encodes a secreted serine protease that converts plasminogen to plasmin. PLAU regulates extracellular matrix remodeling by activating ubiquitous protease plasmin in many important physiological processes and is active in tumors where misregulation has been associated with the development of metastatic phenotype (Madunić. The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role. Thromb Haemost.2018 Dec;118(12):2020-2036. doi: 10.1055/s-0038-1675399). The amino acid sequence of PLAU is SEQ ID NO: 35 and can be found under UniProt Accession No. P00749. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 35 and/or the protein level thereof. SMAD3: SMAD3 (also known as SMAD family member 3; Mothers against decapentaplegic homolog 3; HSPC193; HsT17436; JV15-2; LDS1C; LDS3; MADH3) encodes a member of the SMAD family of proteins that functions in mediating the signals initiated by the transforming growth factor beta (TGF-β) superfamily of cytokines, which regulate cell proliferation, differentiation and death (Moustakas et al. J Cell Sci.2001 Dec;114(Pt 24):4359- 69. doi: 10.1242/jcs.114.24.4359). The amino acid sequence of SMAD3 is SEQ ID NO: 36 and can be found under UniProt Accession No. P84022. 33 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 36 and/or the protein level thereof. REV3L: REV3L (also known as Protein reversionless 3-like; DNA polymerase zeta catalytic subunit; POLZ; REV3; REV3 like; DNA directed polymerase zeta catalytic subunit) encodes a catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (Murakumo et al. J Biol Chem.2001 Sep 21;276(38):35644-51. doi: 10.1074/jbc.M102051200). The amino acid sequence of REV3L is SEQ ID NO: 37 and can be found under UniProt Accession No. O60673. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 37 and/or the protein level thereof. HCAR3: HCAR3 (also known as Hydroxycarboxylic acid receptor 3; niacin receptor 2; NIACR2; GPR109B; HCA3; HM74; PUMAG; Puma-g) encodes a receptor for 3-OH-octanoid acid that mediates negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. HCAR3 is required for pertussis toxin-sensitive migration of primary human monocytes in response to lactic acid bacteria derived metabolites (Peters et al. PLoS Genet.2019 May 23;15(5):e1008145). The amino acid sequence of HCAR3 is SEQ ID NO: 38 and can be found under UniProt Accession No. P49019. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 38 and/or the protein level thereof. TLR8: TLR8 (also known as Toll-like receptor 8; CD288; cluster of differentiation 288; hIMD98) encodes an endosomal receptor that functions in innate and adaptive immunity. TLR8 is known to recognize viral ssRNA and endogenous RNA, such as microRNAs, resulting in the production of proinflammatory cytokines (Ishii et al. J Immunol.2014 Nov 15;193(10):5118-28. 34 WBD (US) 4854-8046-9185v2 doi: 10.4049/jimmunol.1401375). The amino acid sequence of TLR8 is SEQ ID NO: 39 and can be found under UniProt Accession No. Q9NR97. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 39 and/or the protein level thereof. BMF: BMF (also known as Bcl2 Modifying Factor; Bcl-2-Modifying Factor) encodes a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex. BMF is thought to function to sense intracellular damage by their localization to distinct cytoskeletal structures (Puthalakath et al. Science.2001 Sep 7;293(5536):1829-32. doi: 10.1126/science.1062257). The amino acid sequence of BMF is SEQ ID NO: 40 and can be found under UniProt Accession No. Q96LC9. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 40 and/or the protein level thereof. APOL3: APOL3 (also known as Apolipoprotein L3; APOLIII; CG121; CG12_1; apoL- III) encodes a potent bactericidal protein protecting multiple non-immune barrier cell types against infection when expressed in the gut (Gaudet et al. Science.2021 Jul 16;373(6552):eabf8113. doi: 10.1126/science.abf8113). The amino acid sequence of APOL3 is SEQ ID NO: 41 and can be found under UniProt Accession No. O95236. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 41 and/or the protein level thereof. ARHGEF10L: ARHGEF10L (also known as Rho Guanine Nucleotide Exchange Factor 10 Like; GrinchGEF; Rho Guanine Nucleotide Exchange Factor 10-Like Protein; Rho Guanine Nucleotide Exchange Factor (GEF) 10-Like) encodes a protein that acts as a guanine nucleotide exchange factor (GEF) for RHOA, RHOB and RHOC. Increased expression of ARHGEF10L is known to stimulate hepatocellular tumorigenesis by activating the RhoA-ROCK1- phospho ERM pathway and EMT (Tang et al. Exp Cell Res.2019 Jan 1;374(1):46-68. doi: 35 WBD (US) 4854-8046-9185v2 10.1016/j.yexcr.2018.11.007). The amino acid sequence of ARHGEF10L is SEQ ID NO: 42 and can be found under UniProt Accession No. Q9HCE6. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 42 and/or the protein level thereof. GSDMD: GSDMD (also known as Gasdermin D; DF5L, DFNA5L, GSDMDC1, FKSG10) encodes a precursor of a pore-forming protein that functions in host defense against pathogen infection and promotes pyroptosis in response to microbial infection and danger signals (Shi et al. Nature.2015 Oct 29;526(7575):660-5. doi: 10.1038/nature15514). The amino acid sequence of GSDMD is SEQ ID NO: 43 and can be found under UniProt Accession No. P57764. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 43 and/or the protein level thereof. PDPN: PDPN (also known as Podoplanin; AGGRUS; GP36; GP40; Gp38; HT1A-1; OTS8; PA2.26; T1A; T1A-2; T1A2; TI1A; D2-40) encodes a type-I, integral membrane, O- glycosylated glycoprotein with mucin-type characteristics. Expression of mouse PDPN and its human homolog induces platelet aggregation without requiring plasma components. The amino acid sequence of PDPN is SEQ ID NO: 44 and can be found under UniProt Accession No. Q86YL7. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 44 and/or the protein level thereof. RGS2: RGS2 (also known as Regulator of G-protein signaling 2; G0S8; Cell Growth- Inhibiting Gene 31 Protein; G0/G1 Switch Regulatory Protein 8) encodes a regulator of G protein-coupled receptor signaling cascades. RGS2 was found to bind to eIF2Bepsilon (eukaryotic initiation factor 2B epsilon subunit) and inhibit the translation of messenger RNA (mRNA) into new protein (Nguyen et al. J Cell Biol.2009 Sep 7;186(5):755-65. doi: 36 WBD (US) 4854-8046-9185v2 10.1083/jcb.200811058). The amino acid sequence of RGS2 is SEQ ID NO: 45 and can be found under UniProt Accession No. P41220. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 45 and/or the protein level thereof. MAFB: MAFB (also known as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B; KRML; MCTO; MAF bZIP transcription factor B; DURS3) encodes a basic leucine zipper transcription factor that functions in the regulation of lineage-specific hematopoiesis. MAFB is known to act as a transcriptional activator or repressor (Park et al. Am J Hum Genet. 2016 Jun 2;98(6):1220-1227. doi: 10.1016/j.ajhg.2016.03.023). The amino acid sequence of MAFB is SEQ ID NO: 46 and can be found under UniProt Accession No. Q9Y5Q3. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 46 and/or the protein level thereof. CCL2: CCL2 (also known as chemokine (C-C motif) ligand 2; monocyte chemoattractant protein 1; small inducible cytokine A2; GDCF-2; HC11; HSMCR30; MCAF; MCP-1; MCP1; SCYA2; SMC-CF) encodes a small cytokine primarily secreted by monocytes, macrophages, and dendritic cells. CCL2 acts a major chemoattractant for monocytes and memory T cells by binding to its specific cell-surface receptor, CC-chemokine receptor-2 (CCR2) (Xia et al. Expert Opin Ther Pat.2009 Mar;19(3):295-303. doi: 10.1517/13543770902755129). The amino acid sequence of CCL2 is SEQ ID NO: 47 and can be found under UniProt Accession No. P13500. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 47 and/or the protein level thereof. ANXA1: ANXA1 (also known as Annexin A1; lipocortin I; ANX1; LPC1; Phospholipase A2 Inhibitory Protein; Chromobindin-9) encodes a calcium-dependent phospholipid-binding protein. ANXA1 functions as an anti-inflammatory protein that plays an important homeostatic role in innate immunity and contributes to the adaptive immune response by enhancing signaling 37 WBD (US) 4854-8046-9185v2 cascades that are triggered by T-cell activation (D'Acquisto et al. Blood.2007 Feb 1;109(3):1095-102. doi: 10.1182/blood-2006-05-022798). The amino acid sequence of ANXA1 is SEQ ID NO: 48 and can be found under UniProt Accession No. P04083. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 48 and/or the protein level thereof. ADAM17: ADAM17 (also known as A disintegrin and metalloprotease 17; tumor necrosis factor-α-converting enzyme; ADAM18; CD156B; CSVP; NISBD; NISBD1; TACE; ADAM metallopeptidase domain 17) encodes a 70 kDA enzyme that functions in the cleavage of the membrane bound precursor of TNF-alpha to its mature soluble form (Moss et al. Nature. 1997 Feb 20;385(6618):733-6. doi: 10.1038/385733a0). The amino acid sequence of ADAM17 is SEQ ID NO: 49 and can be found under UniProt Accession No. P78536. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 49 and/or the protein level thereof. TNF: TNF (also known as Tumor necrosis factor; cachexin; cachectin; tumor necrosis factor alpha; TNF-α; DIF; TNF-alpha; TNFA; TNFSF2; TNLG1F) encodes a cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR and is involved in promoting inflammatory responses. TNF is known to function in the pathogenesis of several chronic inflammatory diseases (Szondy et al. Pharmacol Res.2017 Jan;115:124-132. doi: 10.1016/j.phrs.2016.11.025). The amino acid sequence of TNF is SEQ ID NO: 50 and can be found under UniProt Accession No. P01375. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 50 and/or the protein level thereof. CCL3: CCL3 (also known as Chemokine (C-C motif) ligand 3; macrophage inflammatory protein 1-alpha; MIP-1-alpha; G0S19-1; LD78ALPHA; MIP1A; SCYA3; C-C motif chemokine ligand 3) encodes a cytokine that binds to CCR1, CCR4 and CCR5. CCL3 is 38 WBD (US) 4854-8046-9185v2 thought to CCL3 negatively regulate the proliferation of hematopoietic stem/progenitor cells (HSPCs) in addition to its proinflammatory activities (Baba, T., & Mukaida, N. (2014). Role of macrophage inflammatory protein (MIP)-1α/CCL3 in leukemogenesis. Molecular & cellular oncology, 1(1), e29899). The amino acid sequence of CCL3 is SEQ ID NO: 51 and can be found under UniProt Accession No. P10147. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 51 and/or the protein level thereof. CCL4: CCL4 (also known as Chemokine (C-C motif) ligands 4; CCL4L1; AT744.2; CCL4L; LAG-1; LAG1; SCYA4L; SCYA4L1; MIP-1-beta; SCYA4L2; C-C motif chemokine ligand 4 like 1) encodes a small cytokine that binds to CCR5. CCL4 is thought to promote tumor development and progression by recruiting regulatory T cells and pro-tumorigenic macrophages (Mukaida, N., Sasaki, S. I., & Baba, T. (2020). CCL4 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology, 1231, 23–32). The amino acid sequence of CCL4 is SEQ ID NO: 52 and can be found under UniProt Accession No. P13236. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 52 and/or the protein level thereof. CXCL2: CXCL2 (also known as hemokine (C-X-C motif) ligand 2; CXCL2, CINC-2a, GRO2, GROb, MGSA-b, MIP-2a, MIP2, MIP2A, SCYB2, C-X-C motif chemokine ligand 2) encodes a small cytokine produced by activated monocytes and neutrophils and expressed at sites of inflammation. CXCL2 is thought to rapidly mobilized hematopoietic stem cells into the peripheral blood in combination with the CXCR4 inhibitor plerixafor (Hoggatt J, et al. (January 2018). "Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell". Cell.172 (1–2): 191–204.e10. doi:10.1016/j.cell.2017.11.003). The amino acid sequence of CXCL2 is SEQ ID NO: 53 and can be found under UniProt Accession No. P19875. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 53 and/or the protein level thereof. 39 WBD (US) 4854-8046-9185v2 CXCL3: CXCL3 (also known as Chemokine (C-X-C motif) ligand 3, CINC-2b, GRO3, GROg, MIP-2b, MIP2B, SCYB3, C-X-C motif chemokine ligand 3) encodes a small cytokine that signals through the G-protein coupled receptor, CXC receptor 2 and plays a role in inflammation and as a chemoattractant for neutrophils. CXCL3 is thought to act as an arrest chemokine for monocyte adhesion on vascular cell adhesion molecule (VCAM)-1 under flow in the presence of P-selection (Smith et al. (2005). GRO family chemokines are specialized for monocyte arrest from flow. American journal of physiology. Heart and circulatory physiology, 289(5), H1976–H1984). The amino acid sequence of CXCL3 is SEQ ID NO: 54 and can be found under UniProt Accession No. P19876. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 54 and/or the protein level thereof. S10011A: S10011A (also known as S100 calcium-binding protein A11, HEL-S-43, MLN70, S100C, S100 calcium binding protein A11) encodes a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs and is involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S10011A is also thought to function as a chemotactic agent in inflammatory disease (Zhang et al. (2021). The Calcium Binding Protein S100A11 and Its Roles in Diseases. Frontiers in cell and developmental biology, 9, 693262). The amino acid sequence of S10011A is SEQ ID NO: 55 and can be found under UniProt Accession No. P31949. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 55 and/or the protein level thereof. S100A6: S100A6 (also known as 2A9, 5B10, CABP, CACY, PRA, S100 calcium binding protein A6, S10A6) encodes a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors (Donato, R., Sorci, G., & Giambanco, I. (2017). S100A6 protein: 40 WBD (US) 4854-8046-9185v2 functional roles. Cellular and molecular life sciences: CMLS, 74(15), 2749–2760). The amino acid sequence of S100A6 is SEQ ID NO: 56 and can be found under UniProt Accession No. P06703. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 56 and/or the protein level thereof. S100A4: S100A4 (also known as) encodes a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs and is thought to be involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100A4 may function as a calcium sensor and modular thereby contributing to cellular calcium signaling (Yamaguchi et al. (2012). S100 proteins modulate protein phosphatase 5 function: a link between CA2+ signal transduction and protein dephosphorylation. The Journal of biological chemistry, 287(17), 13787–13798). The amino acid sequence of S100A4 is SEQ ID NO: 57 and can be found under UniProt Accession No. P26447. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 57 and/or the protein level thereof. LGALS1: LGALS1 (also known as GAL1, GBP, galectin 1) encodes a lectin that binds beta-galactoside and a wide array of complex carbohydrates. LGALS1 functions in regulating apoptosis, cell proliferation, and cell differentiation. Dendritic cells lacking LGALS1 have greater immunogenic potential and an impaired ability to halt inflammatory disease (Ilarregui et al. (2009). Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nature immunology, 10(9), 981–991). The amino acid sequence of LGALS1 is SEQ ID NO: 58 and can be found under UniProt Accession No. P09382. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 58 and/or the protein level thereof. 41 WBD (US) 4854-8046-9185v2 LGALS3: LGALS3 (also known as CBP35, GAL3, GALBP, GALIG, L31, LGALS2, MAC2, lectin, galactoside binding soluble 3, galectin 3) encodes a 30kDa lectin that contains a carbohydrate recognition binding domain and binding beta-galactosides. LGALS3 is known to be involved in cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis (Dumic, J. et al. (2006). Galectin-3: an open-ended story. Biochimica et biophysica acta, 1760(4), 616–635). The amino acid sequence of LGALS3 is SEQ ID NO: 59 and can be found under UniProt Accession No. P17931. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 59 and/or the protein level thereof. TIMP3: TIMP3 (also known as HSMRK222, K222, K222TA2, SFD, TIMP metallopeptidase inhibitor 3) encodes an inhibitor of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. TIMP3 is thought to block the binding of VEGF to VEGF receptor-2 and inhibit downstream signaling and angiogenesis (Qi et al. (2003). A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature medicine, 9(4), 407– 415). The amino acid sequence of TIMP3 is SEQ ID NO: 60 and can be found under UniProt Accession No. P35625. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 60 and/or the protein level thereof. ADAMDEC1: ADAMDEC1 (also known as ADAM-like, decysin 1; A Disintegrin And Metalloproteinase Domain-Like Protein Decysin-1) encodes a secreted protein belonging to the disintegrin metalloproteinase family. ADAMDEC1 is thought to function as a positive regulator of Epithelial Defense Against Cancer (EDAC) that promotes apical extrusion of RasV12- transformed cells (Yako et al. ADAM-like Decysin-1 (ADAMDEC1) is a positive regulator of Epithelial Defense Against Cancer (EDAC) that promotes apical extrusion of RasV12- transformed cells. Sci Rep.2018 Jun 25;8(1):9639. doi: 10.1038/s41598-018-27469-z). The 42 WBD (US) 4854-8046-9185v2 amino acid sequence of ADAMDEC1 is SEQ ID NO: 61 and can be found under UniProt Accession No. O15204. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 61 and/or the protein level thereof. CXCL14: CXCL14 (also known as SCYB14, BRAK, NJAC, bolekine, Kec, MIP-2g, BMAC, KS1, breast and kidney-expressed chemokine) encodes a non-ELR (glutamic acid- leucine-arginine) chemokine with a broad spectrum of biological activities and is thought to contribute to the regulation of immune cell migration and executing antimicrobial immunity (Lu et al. (2016). CXCL14 as an emerging immune and inflammatory modulator. Journal of inflammation (London, England), 13, 1). The amino acid sequence of CXCL14 is SEQ ID NO: 62 and can be found under UniProt Accession No. O95715. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 62 and/or the protein level thereof. AGT: AGT (also known as O6-alkylguanine DNA alkyltransferase, Mgmt, AI267024, Agat, O-6-methylguanine-DNA methyltransferase) encodes a protein important for genome stability as it repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. AGT is known to be inducible by glucocorticoids and genotoxins such as radiation and alkylating agents (Kaina, B., Christmann, M., Naumann, S., & Roos, W. P. (2007). MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA repair, 6(8), 1079–1099). The amino acid sequence of AGT is SEQ ID NO: 63 and can be found under UniProt Accession No. P16455. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 63 and/or the protein level thereof. 43 WBD (US) 4854-8046-9185v2 LAMA4: LAMA4 (also known as CMD1JJ, LAMA3, LAMA4*-1, Laminin, alpha 4, laminin subunit alpha 4) encodes a member of a family of extracellular matrix glycoproteins implicated in cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Deletion of LAMA4 in mice results in impaired hematopoiesis regeneration following irradiation-induced stress (Cai et al. (2022). Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression. Blood, 139(20), 3040–3057). The amino acid sequence of LAMA4 is SEQ ID NO: 64 and can be found under UniProt Accession No. Q16363. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 64 and/or the protein level thereof. WNT2B: WNT2B (also known as WNT13, Wnt family member 2B) encodes a ligand for members of the frizzled family of seven transmembrane receptors and functions in the canonical Wnt/beta-catenin signaling pathway. WNT2B is thought to act as a putative stem cell factor in the retina (Kubo, F., Takeichi, M., & Nakagawa, S. (2003). Wnt2b controls retinal cell differentiation at the ciliary marginal zone. Development (Cambridge, England), 130(3), 587– 598). The amino acid sequence of WNT2B is SEQ ID NO: 65 and can be found under UniProt Accession No. Q93097. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 65 and/or the protein level thereof. CCL5: CCL5 (also known as D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228, eoCP, C-C motif chemokine ligand 5) encodes a 8kDa protein acting as a chemotactic cytokine or chemokine. CCL5 is mostly expressed in T-cells and monocytes (Zeng, Z., Lan, T., Wei, Y., & Wei, X. (2022). CCL5/CCR5 axis in human diseases and related treatments. Genes & diseases, 9(1), 12–27). The amino acid sequence of CCL5 is SEQ ID NO: 66 and can be found under UniProt Accession No. P13501. 44 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 66 and/or the protein level thereof. CEBPB: CEBPB (also known as C/EBP-beta, IL6DBP, NF-IL6, TCF5, CCAAT/enhancer binding protein beta, CCAAT enhancer binding protein beta) encodes a bZIP transcription factor that can bind as a homodimer to certain DNA regulatory regions. CREB- mediated induction of Cebpb expression is thought to be required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration (Ruffell et al. (2009). A CREB- C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proceedings of the National Academy of Sciences of the United States of America, 106(41), 17475–17480). The amino acid sequence of CEBPB is SEQ ID NO: 67 and can be found under UniProt Accession No. P17676. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 67 and/or the protein level thereof. IL23A: IL23A (also known as IL-23, IL-23A, IL23P19, P19, SGRF, Interleukin 23, interleukin 23 subunit alpha) encodes one of the two subunits of the cytokine Interleukin-23 and is an important in inflammatory responses against infection. IL23 is thought to stimulate IFN- gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cell (Oppmann (2000). Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 13(5), 715–725). The amino acid sequence of IL23A is SEQ ID NO: 68 and can be found under UniProt Accession No. Q9NPF7. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 68 and/or the protein level thereof. DCHS2: DCHS2 (also known as CDH27, CDHJ, CDHR7, PCDH23, PCDHJ, dachsous cadherin-related 2) encodes a Calcium-dependent cell-adhesion protein. There is an association 45 WBD (US) 4854-8046-9185v2 between DCHS2 and amnestic mild cognitive impairment and Alzheimer's disease (Vieira et al. (2016). Association between DCHS2 gene and mild cognitive impairment and Alzheimer's disease in an elderly Brazilian sample. International journal of geriatric psychiatry, 31(12), 1337–1344). The amino acid sequence of DCHS2 is SEQ ID NO: 69 and can be found under UniProt Accession No. Q6V1P9. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 69 and/or the protein level thereof. SELE: SELE (also known as E-selectin, CD62E, ELAM, ELAM1, ESEL, LECAM2, selectin E, selectin-e) encodes a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. SELE recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes (Jubeli, E., Moine, L., Vergnaud-Gauduchon, J., & Barratt, G. (2012). E-selectin as a target for drug delivery and molecular imaging. Journal of controlled release : official journal of the Controlled Release Society, 158(2), 194–206). The amino acid sequence of SELE is SEQ ID NO: 70 and can be found under UniProt Accession No. P16581. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 70 and/or the protein level thereof. LTB: LTB (also known as TNFC, TNFSF3, p33, Lymphotoxin beta, TNLG1C) encodes a type II membrane protein of the TNF family that anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. It is thought to have a role in immune regulation distinct from the functions ascribed to TNF (Browning et al. (1993). Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell, 72(6), 847–856). The amino acid sequence of LTB is SEQ ID NO: 71 and can be found under UniProt Accession No. Q06643. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 71 and/or the protein level thereof. 46 WBD (US) 4854-8046-9185v2 OSM: OSM (also known as OncoM, oncostatin M) encodes a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. OSM exhibits many unique biological activities in inflammation, hematopoiesis, and development (Tanaka, M., & Miyajima, A. (2003). Oncostatin M, a multifunctional cytokine. Reviews of physiology, biochemistry and pharmacology, 149, 39–52). The amino acid sequence of OSM is SEQ ID NO: 72 and can be found under UniProt Accession No. P13725. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 72 and/or the protein level thereof. CXCL10: CXCL10 (also known as C7, IFI10, INP10, IP-10, SCYB10, crg-2, gIP-10, mob-1, C-X-C motif chemokine ligand 10, C-X-C motif chemokine 10) encodes a small cytokine belonging to the CXC chemokine family and is secreted by several cell types in response to IFN-γ. CXCL10 is thought to have a role in effector T cell generation and trafficking in vivo (Dufour, J. H., Dziejman, M., Liu, M. T., Leung, J. H., Lane, T. E., & Luster, A. D. (2002). IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. Journal of immunology (Baltimore, Md. : 1950), 168(7), 3195–3204). The amino acid sequence of CXCL10 is SEQ ID NO: 73 and can be found under UniProt Accession No. P02778. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 73 and/or the protein level thereof. SEC63: SEC63 (also known as DNAJC23, ERdj2, PRO2507, SEC63L, SEC63 homolog, protein translocation regulator, PCLD2) encodes a protein associate with the ribosome-free SEC61 complex and involved in protein translocation of the endoplasmic reticulum membrane (Jung, S. J., & Kim, H. (2021). Emerging View on the Molecular Functions of Sec62 and Sec63 in Protein Translocation. International journal of molecular sciences, 22(23), 12757). The amino acid sequence of SEC63 is SEQ ID NO: 74 and can be found under UniProt Accession No. Q9UGP8. 47 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 74 and/or the protein level thereof. TNFRSF17: TNFRSF17 (also known as B-cell maturation antigen, BCM, BCMA, CD269, TNFRSF13A, tumor necrosis factor receptor superfamily member 17, TNF receptor superfamily member 17) encodes a cell surface receptor of the TNF receptor superfamily which recognizes B-cell activating factor that is expressed in mature B lymphocytes and may be important for B-cell development and autoimmune response. TNFRSF17 is a receptor for the tumor necrosis factor family member TALL-1 (Shu, H. B., & Johnson, H. (2000). B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1. Proceedings of the National Academy of Sciences of the United States of America, 97(16), 9156–9161). The amino acid sequence of TNFRSF17 is SEQ ID NO: 75 and can be found under UniProt Accession No. Q02223. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 75 and/or the protein level thereof. TNFRSF13C: TNFRSF13C (also known as BAFF receptor, B-cell activating factor receptor, BLyS receptor 3, BAFF-R, BAFFR, BROMIX, CD268, CVID4, prolixin, tumor necrosis factor receptor superfamily member 13C, TNF receptor superfamily member 13C) encodes a membrane protein of the TNF receptor superfamily which recognizes BAFF, an essential factor for B cell maturation and survival. TNFRSF13C is thought to down regulate cell apoptosis (Rauch, M., Tussiwand, R., Bosco, N., & Rolink, A. G. (2009). Crucial role for BAFF- BAFF-R signaling in the survival and maintenance of mature B cells. PloS one, 4(5), e5456). The amino acid sequence of TNFRSF13C is SEQ ID NO: 76 and can found under UniProt Accession No. Q96RJ3. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 76 and/or the protein level thereof. 48 WBD (US) 4854-8046-9185v2 SDC1: SDC1 (also known as CD138, SDC, SYND1, syndecan, syndecan 1) encodes a transmembrane (type I) heparan sulfate proteoglycan and functions as an integral membrane protein to participate in cell proliferation, cell migration and cell-matrix interactions. SDC1 is thought to negatively regulate dendritic cell migration (Averbeck, M., Kuhn, S., Bühligen, J., Götte, M., Simon, J. C., & Polte, T. (2017). Syndecan-1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens. Experimental dermatology, 26(11), 1060–1067). The amino acid sequence of SDC1 is SEQ ID NO: 77 and can be found under UniProt Accession No. P18827. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 77 and/or the protein level thereof. ITGB1: ITGB1 (also known as Integrin beta-1, CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA, VLAB, integrin subunit beta 1) encodes a cell surface receptor that associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen receptors. ITGB1 is involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metastatic diffusion of tumor cells (Hynes R. O. (1992). Integrins: versatility, modulation, and signaling in cell adhesion. Cell, 69(1), 11–25). The amino acid sequence of ITGB1 is SEQ ID NO: 78 and can be found under UniProt Accession No. P05556. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 78 and/or the protein level thereof. IL17RA: IL17RA (also known as Interleukin 17 receptor A, CANDF5, CD217, CDw217, IL-17RA, IL17R, hIL-17R, IMD51) encodes a proinflammatory cytokine secreted by activated T-lymphocytes. IL17RA is known to play a role in the development of asthma, and allergy (Nejman-Gryz, P., Paplińska-Goryca, M., Proboszcz, M., Grabczak, M., Hermanowicz-Salamon, J., & Krenke, R. (2021). The expression of IL17RA on sputum macrophages in asthma patients. Cytokine, 143, 155518). The amino acid sequence of IL17RA is SEQ ID NO: 79 and can be found under UniProt Accession No. Q96F46. 49 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 79 and/or the protein level thereof. IL10RA: IL10RA (also known as CD210, CD210a, CDW210A, HIL-10R, IL-10R1, IL10R, Interleukin 10 receptor, alpha subunit, interleukin 10 receptor subunit alpha) encodes a recetor for interleukin 10 and is thought to promote survival of progenitor myeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKT pathway. IL10RA is frequently reported as a monogenic inflammatory bowel disease gene (Nambu et al. (2022). A Systematic Review of Monogenic Inflammatory Bowel Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 20(4), e653–e663). The amino acid sequence of IL10RA is SEQ ID NO: 80 and can be found under UniProt Accession No. Q13651. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 80 and/or the protein level thereof. IFNGR1: IFNGR1 (also known as CD119, IFNGR, IMD27A, IMD27B, interferon gamma receptor 1) encodes IFN-γR1, which is the ligand-binding chain (alpha) of the heterodimeric gamma interferon receptor, and is expressed on macrophages. Germline mutations in the gene IFNGR1 encoding the IFN-γR1 cause a primary immunodeficiency that mainly leads to mycobacterial infections (van de Vosse, E., & van Dissel, J. T. (2017). IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database. Human mutation, 38(10), 1286–1296). The amino acid sequence of IFNGR1 is SEQ ID NO: 81 and can be found under UniProt Accession No. P15260. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 81 and/or the protein level thereof. IFNGR2: IFNGR2 (also known as Interferon gamma receptor 2 or IFN-γR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. IFNGR2 is required for 50 WBD (US) 4854-8046-9185v2 interferon-γ signalling and therefore plays a critical immunoregulatory role in innate and adaptive immunity against viral and also bacterial and protozoal infections (Mikulecký et al. (2016). Crystal structure of human interferon-γ receptor 2 reveals the structural basis for receptor specificity. Acta crystallographica. Section D, Structural biology, 72(Pt 9), 1017–1025). The amino acid sequence of IFNGR2 is SEQ ID NO: 82 and can be found under UniProt Accession No. P38484. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 82 and/or the protein level thereof. IL1R1: IL1R1 (also known as CD121A, D2S1473, IL-1R-alpha, IL1R, IL1RA, P80, Interleukin 1 receptor, type I, interleukin 1 receptor type 1) encodes a cytokine receptor for interleukin 1 alpha (IL1A), interleukin 1 beta (IL1B), and interleukin 1 receptor antagonist (IL1RA) and has a role in cytokine induced immune and inflammatory responses. Common IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients (Latiano et al. (2013). Associations between genetic polymorphisms in IL-33, IL1R1 and risk for inflammatory bowel disease. PloS one, 8(4), e62144). The amino acid sequence of IL1R1 is SEQ ID NO: 83 and can be found under UniProt Accession No. P14778. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 83 and/or the protein level thereof. IL1RAP: IL1RAP (also known as C3orf13, IL-1RAcP, IL1R3, interleukin 1 receptor accessory protein) encodes an accessory protein that forms a complex at the cell membrane with an interleukin 1 receptor and interleukin 1 to induce synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress. IL1RAP is reported to be upregulated in Acute Myeloid Leukemia (AML) (De Boer, B., Sheveleva, S., Apelt, K., Vellenga, E., Mulder, A. B., Huls, G., & Jacob Schuringa, J. (2021). The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis. Haematologica, 106(12), 3067–3078). The amino acid 51 WBD (US) 4854-8046-9185v2 sequence of IL1RAP is SEQ ID NO: 84 and can be found under UniProt Accession No. Q9NPH3. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 84 and/or the protein level thereof. TNFRSF1: TNFRSF1 (also known as TNFRSF1A, CD120a, FPF, MS5, TBP1, TNF-R, TNF-R-I, TNF-R55, TNFAR, TNFR1, TNFR1-d2, TNFR55, TNFR60, p55, p55-R, p60, tumor necrosis factor receptor superfamily member 1A, TNF receptor superfamily member 1A) encodes one of the major receptors for the tumor necrosis factor-alpha and can activate the transcription factor NF-κB, mediate apoptosis, and function as a regulator of inflammation. The R92Q variant of the TNFRSF1A gene was identified as a new susceptibility locus for multiple sclerosis (Kümpfel, T., & Hohlfeld, R. (2009). Multiple sclerosis. TNFRSF1A, TRAPS and multiple sclerosis. Nature reviews. Neurology, 5(10), 528–529). The amino acid sequence of TNFRSF1 is SEQ ID NO: 85 and can be found under UniProt Accession No. P19438. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 85 and/or the protein level thereof. CCR6: CCR6 (also known as BN-1, C-C CKR-6, CC-CKR-6, CCR-6, CD196, CKR-L3, CKRL3, CMKBR6, DCR2, DRY6, GPR29, GPRCY4, STRL22, C-C motif chemokine receptor 6, CD196) encodes a protein belonging to family A of G protein-coupled receptor superfamily and is expressed on B-cells, immature dendritic cells (DC), T-cells (Th1, Th2, Th17, Treg), natural killer T cells (NKT cells) and neutrophils. CCR6 is thought to recruit immature dendritic cells to sites of injury (Dieu et al.1998). Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. The Journal of experimental medicine, 188(2), 373–386). The amino acid sequence of CCR6 is SEQ ID NO: 86 and can be found under UniProt Accession No. P51684. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 86 and/or the protein level thereof. 52 WBD (US) 4854-8046-9185v2 CD80: CD80 (also known as Cluster of differentiation 80, B7, B7-1, B7.1, BB1, CD28LG, CD28LG1, LAB7) encodes a B7, type I membrane protein and is expressed specifically on DC, activated B-cells, and macrophages, but also T-cells. Expression levels of CD80 on dendritic cells are modulated during progression from an immature to a mature state (Zheng, Y., Manzotti, C. N., Liu, M., Burke, F., Mead, K. I., & Sansom, D. M. (2004). CD86 and CD80 differentially modulate the suppressive function of human regulatory T cells. Journal of immunology (Baltimore, Md. : 1950), 172(5), 2778–2784). The amino acid sequence of CD80 is SEQ ID NO: 87 and can be found under UniProt Accession No. P33681. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 87 and/or the protein level thereof. CD40LG: CD40LG (also known as CD154, CD40L, HIGM1, IGM, IMD3, T-BAM, TNFSF5, TRAP, gp39, hCD40L, CD40 ligand) encodes a member of the TNF superfamily of molecules and is primarily expressed on activated T cells. CD40L has a central role in costimulation and regulation of the immune response via T cell priming and activation of CD40- expressing immune cells (Grewal, I. S., & Flavell, R. A. (1998). CD40 and CD154 in cell- mediated immunity. Annual review of immunology, 16, 111–135). The amino acid sequence of CD40LG is SEQ ID NO: 88 and can be found under UniProt Accession No. P29965. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 88 and/or the protein level thereof. IL2RG: IL2RG (also known as CD132, CIDX, IL-2RG, IMD4, P64, SCIDX, SCIDX1, interleukin 2 receptor subunit gamma) encodes a cytokine receptor subunit that is common to the receptor complexes for at least IL-2, IL-4, IL-7, IL-9, IL-15. An increased circulating level of IL2RG is found in inflammatory bowel disease (Nielsen, O. H., Kirman, I., Johnson, K., Giedlin, M., & Ciardelli, T. (1998). The circulating common gamma chain (CD132) in inflammatory bowel disease. The American journal of gastroenterology, 93(3), 323–328). The amino acid sequence of IL2RG is SEQ ID NO: 89 and can be found under UniProt Accession No. P31785. 53 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 89 and/or the protein level thereof. CD40: CD40 (also known as Bp50, CDW40, TNFRSF5, p50, Cluster of differentiation 40) encodes a type I transmembrane protein found on antigen-presenting cells that is required for their activation. CD40 interacts with its binding partner CD40L to play a role in promoting germinal center formation and the production of class-switched antibodies (Karnell, J. L., Rieder, S. A., Ettinger, R., & Kolbeck, R. (2019). Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Advanced drug delivery reviews, 141, 92–103). The amino acid sequence of CD40 is SEQ ID NO: 90 and can be found under UniProt Accession No. P25942. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 90 and/or the protein level thereof. IL2RB: IL2RB (also known as CD122, IL15RB, P70-75, interleukin 2 receptor subunit beta, IMD63) encodes a type I membrane protein subunit of the interleukin 2 receptor and has a role in T cell-mediated immune responses. IL2RB is thought to play a role in tumorigenesis, tumor metabolism, and immunity (Li, G., Wang, Y., & Cheng, Y. (2022). IL2RB Is a Prognostic Biomarker Associated with Immune Infiltrates in Pan-Cancer. Journal of oncology, 2022, 2043880). The amino acid sequence of IL2RB is SEQ ID NO: 91 and can be found under UniProt Accession No. P14784. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 91 and/or the protein level thereof. IL18R1: IL18R1 (also known as CD218a, CDw218a, IL-1Rrp, IL18RA, IL1RRP, interleukin 18 receptor 1, IL-18R-alpha, IL18Ralpha2, IL-18Ralpha) encodes a cytokine receptor that belongs to the interleukin 1 receptor family and is essential for IL18 mediated signal transduction. IL18R1 is repressed during Th2 development (Yu, Q., Chang, H. C., Ahyi, A. N., 54 WBD (US) 4854-8046-9185v2 & Kaplan, M. H. (2008). Transcription factor-dependent chromatin remodeling of Il18r1 during Th1 and Th2 differentiation. Journal of immunology (Baltimore, Md.: 1950), 181(5), 3346– 3352). The amino acid sequence of IL18R1 is SEQ ID NO: 92 and can be found under UniProt Accession No. Q13478. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 92 and/or the protein level thereof. IL7R: IL7R (also known as interleukin-7 receptor, CD127, IL7RA, Soluble Interleukin-7 Receptor, IL7RA) encodes a heterodimer consisting of interleukin-7 receptor-α (CD127) and common-γ chain receptor (CD132). The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase (Schlissel, M. S., Durum, S. D., & Muegge, K. (2000). The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase. The Journal of experimental medicine, 191(6), 1045–1050). The amino acid sequence of IL7R is SEQ ID NO: 93 and can be found under UniProt Accession No. P16871. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 93 and/or the protein level thereof. TNFRSF14: TNFRSF14 (also known as Herpesvirus entry mediator, ATAR, CD270, HVEA, HVEM, LIGHTR, TR2, tumor necrosis factor receptor superfamily member 14, TNF receptor superfamily member 14) encodes a member of the TNF-receptor superfamily. TNFRSF14 is thought to regulate the persistence of T helper memory cell populations (Soroosh et al. (2011). Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations. The Journal of experimental medicine, 208(4), 797–809). The amino acid sequence of TNFRSF14 is SEQ ID NO: 94 and can be found under UniProt Accession No. Q92956. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 94 and/or the protein level thereof. 55 WBD (US) 4854-8046-9185v2 IL12RB: IL12RB (also known as IL12RB1, CD212, IL-12R-BETA1, IMD30, Interleukin 12 receptor beta 1 subunit, IL12 receptor beta 1 subunit, interleukin 12 receptor subunit beta 1) encodes a subunit of the interleukin 12 receptor and the interleukin 23 receptor. IL12RB is essential for mycobacterial disease resistance and T cell differentiation (Reeme, A. E., Claeys, T. A., Aggarwal, P., Turner, A. J., Routes, J. M., Broeckel, U., & Robinson, R. T. (2019). Human IL12RB1 expression is allele-biased and produces a novel IL12 response regulator. Genes and immunity, 20(3), 181–197). The amino acid sequence of IL12RB is SEQ ID NO: 95 and can be found under UniProt Accession No. P42701. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 95 and/or the protein level thereof. TNFRSF1B: TNFRSF1B (also known as CD120b, TBPII, TNF-R-II, TNF-R75, TNFBR, TNFR1B, TNFR2, TNFR80, p75, p75TNFR, tumor necrosis factor receptor superfamily member 1B, TNF receptor superfamily member 1B) encodes one of two membrane receptors that binds tumor necrosis factor-alpha (TNFα). TNFRSF1B is associated with antineutrophil cytoplasmic antibody, an important biomarker in inflammatory bowel disease (Li, D., Silverberg, M. S., Haritunians, T., Dubinsky, M. C., Landers, C., Stempak, J. M., Milgrom, R., Guo, X., Chen, Y. D., Rotter, J. I., Taylor, K. D., McGovern, D. P., & Targan, S. R. (2016). TNFRSF1B Is Associated with ANCA in IBD. Inflammatory bowel diseases, 22(6), 1346–1352). The amino acid sequence of TNFRSF1B is SEQ ID NO: 96 and can be found under UniProt Accession No. P20333. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 96 and/or the protein level thereof. IL-11: IL-11 (also known as AGIF, IL-11, interleukin 11, adipogenesis inhibitory factor) encodes a cytokine thought to regulate adipogenesis, osteoclastogenesis, neurogenesis and platelet maturation. IL-11 is thought to contribute to the pathogenesis of autoimmune inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory conditions such as periodontitis, asthma, chronic 56 WBD (US) 4854-8046-9185v2 obstructive pulmonary disease, psoriasis and colitis (Fung, K. Y., Louis, C., Metcalfe, R. D., Kosasih, C. C., Wicks, I. P., Griffin, M. D. W., & Putoczki, T. L. (2022). Emerging roles for IL- 11 in inflammatory diseases. Cytokine, 149, 155750). The amino acid sequence of IL-11 is SEQ ID NO: 97 and can be found under UniProt Accession No. P20809. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 97 and/or the protein level thereof. CXCL12: CXCL12 (also known as Stromal cell-derived factor 1, IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1, C-X-C motif chemokine ligand 12) encodes a chemokine protein that is strongly chemotactic for lymphocytes and ubiquitously expressed. CXCL12 plays an important role in embryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration of hematopoietic progenitor and stem cells, endothelial cells and most leukocytes (Janssens, R., Struyf, S., & Proost, P. (2018). The unique structural and functional features of CXCL12. Cellular & molecular immunology, 15(4), 299–311). The amino acid sequence of CXCL12 is SEQ ID NO: 98 and can be found under UniProt Accession No. P48061. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 98 and/or the protein level thereof. CXCL16: CXCL16 (also known as Chemokine (C-X-C motif) ligand 16, SCYB16, SR- PSOX, CXCLG16) encodes a small cytokine that is induced by IFN-gamma and TNF-alpha. CXCL16 is linked to the development of numerous autoimmune diseases (Bao et al. (2023). Role of the CXCR6/CXCL16 axis in autoimmune diseases. International immunopharmacology, 121, 110530). The amino acid sequence of CXCL16 is SEQ ID NO: 99 and can be found under UniProt Accession No. Q9H2A7. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 99 and/or the protein level thereof. 57 WBD (US) 4854-8046-9185v2 ICAM1: ICAM1 (also known as BB2, CD54, P3.58, intercellular adhesion molecule 1) encodes a surface glycoprotein expressed on endothelial cells and cells of the immune system. ICAM1 has been proposed to be a ligant in many LFA-1-dependent adhesion reactions (Rothlein, R., Dustin, M. L., Marlin, S. D., & Springer, T. A. (1986). A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. Journal of immunology (Baltimore, Md. : 1950), 137(4), 1270–1274). The amino acid sequence of ICAM1 is SEQ ID NO: 100 and can be found under UniProt Accession No. P05362. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 100 and/or the protein level thereof. PECAM1: PECAM1 (also known as CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM- 1, endoCAM, platelet and endothelial cell adhesion molecule 1, PCAM-1) encodes a cell-cell adhesion protein that plays a role in removing aged neutrophils from the body. Myocyte- enhancer factor 2 has been shown to transcriptionally activate PECAM1 and CXCR4 to activate the B-cell and NF-κB signaling pathways, leading to inflammatory cell infiltration and pulpitis progression (Liu, Y., Zhang, Z., Li, W., & Tian, S. (2020). PECAM1 Combines With CXCR4 to Trigger Inflammatory Cell Infiltration and Pulpitis Progression Through Activating the NF-κB Signaling Pathway. Frontiers in cell and developmental biology, 8, 593653). The amino acid sequence of PECAM1 is SEQ ID NO: 101 and can be found under UniProt Accession No. P16284. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 101 and/or the protein level thereof. CXCR4: CXCR4 (also known as CD184, D2S201E, FB22, HM89, HSY3RR, LAP-3, LAP3, LCR1, LESTR, NPY3R, NPYR, NPYRL, NPYY3R, WHIM, WHIMS, C-X-C motif chemokine receptor 4, WHIMS1) encodes an alpha-chemokine receptor specific for stromal- derived-factor-1. Cancer cell CXCR4 overexpression has been shown to contribute to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance (Chatterjee, S., Behnam Azad, B., & Nimmagadda, S. (2014). The intricate role of CXCR4 in cancer. Advances 58 WBD (US) 4854-8046-9185v2 in cancer research, 124, 31–82). The amino acid sequence of CXCR4 is SEQ ID NO: 102 and can be found under UniProt Accession No. P61073. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 102 and/or the protein level thereof. CD44: CD44 (also known as CDW44, CSPG8, ECMR-III, HCELL, HUTCH-I, IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp) encodes a cell-surface glycoprotein that is known to have a role in lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. CD44 isoforms are also known to be functionally involved in immune responses (Wittig, B. M., Stallmach, A., Zeitz, M., & Günthert, U. (2002). Functional involvement of CD44 variant 7 in gut immune response. Pathobiology : journal of immunopathology, molecular and cellular biology, 70(3), 184–189). The amino acid sequence of CD44 is SEQ ID NO: 103 and can be found under UniProt Accession No. P16070. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 103 and/or the protein level thereof. PTPRC: PTPRC (also known as B220, CD45, CD45R, GP180, L-CA, LCA, LY5, T200, protein tyrosine phosphatase, receptor type C) encodes a type I transmembrane protein that is a member of the protein tyrosine phosphatase (PTP) family. PTPRC is thought to be essential for the innate immune system, is expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation (Al Barashdi, M. A., Ali, A., McMullin, M. F., & Mills, K. (2021). Protein tyrosine phosphatase receptor type C (PTPRC or CD45). Journal of clinical pathology, 74(9), 548–552). The amino acid sequence of PTPRC is SEQ ID NO: 104 and can be found under UniProt Accession No. P08575. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 104 and/or the protein level thereof. 59 WBD (US) 4854-8046-9185v2 ITGAE: ITGAE (also known as CD103, HUMINAE, integrin subunit alpha E) encodes an integrin protein that binds integrin beta 7 to form the heterodimeric integrin molecule αEβ7. ITGAE has been shown to have a role in the development of autoimmune diabetes in non-obese diabetic mice (Barrie, E. S., Lodder, M., Weinreb, P. H., Buss, J., Rajab, A., Adin, C., Mi, Q. S., & Hadley, G. A. (2015). Role of ITGAE in the development of autoimmune diabetes in non- obese diabetic mice. The Journal of endocrinology, 224(3), 235–243). The amino acid sequence of ITGAE is SEQ ID NO: 105 and can be found under UniProt Accession No. P38570. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 105 and/or the protein level thereof. ITGA5: ITGA5 (also known as CD49e, FNRA, VLA5A, VLA-5, integrin subunit alpha 5) encodes a member of the integrin adhesion molecule family and is implicated in cancer metastasis and oncogenesis. ITGA5 has been found to engage in remolding glioma immune infiltration and immune microenvironment, manifested by higher immune cell infiltration when ITGA5 is highly expressed (Li, S., Zhang, N., Liu, S., Zhang, H., Liu, J., Qi, Y., Zhang, Q., & Li, X. (2022). ITGA5 Is a Novel Oncogenic Biomarker and Correlates With Tumor Immune Microenvironment in Gliomas. Frontiers in oncology, 12, 844144). ITGA5 has also been shown to be correlated with immune infiltration in gastrointestinal tumors (Zhu, H., Wang, G., Zhu, H., & Xu, A. (2021). ITGA5 is a prognostic biomarker and correlated with immune infiltration in gastrointestinal tumors. BMC cancer, 21(1), 269). The amino acid sequence of ITGA5 is SEQ ID NO: 106 and can be found under UniProt Accession No. P08648. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 106 and/or the protein level thereof. HAVCR2: HAVCR2 (also known as HAVcr-2, KIM-3, TIM3, TIMD-3, TIMD3, Tim-3, CD366, hepatitis A virus cellular receptor 2, SPTCL) encodes a member of TIM immunoregulatory proteins family and is known to be a regulator of the immune response. Experimental data suggests that TIM-3 acts as an immune checkpoint and plays an aimportant role in autoimmune disease, chronic viral infections, and tumors (Zhao, L., Cheng, S., Fan, L., 60 WBD (US) 4854-8046-9185v2 Zhang, B., & Xu, S. (2021). TIM-3: An update on immunotherapy. International immunopharmacology, 99, 107933). The amino acid sequence of HAVCR2 is SEQ ID NO: 107 and can be found under UniProt Accession No. Q8TDQ0. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 107 and/or the protein level thereof. CD36: CD36 (also known as BDPLT10, CHDS7, FAT, GP3B, GP4, GPIV, PASIV, SCARB3) encodes an integral membrane protein that imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. It functions in both innate and adaptive immune cells to contribute to pathogenesis of common diseases, including atherosclerosis and tumor progression (Chen, Y., Zhang, J., Cui, W., & Silverstein, R. L. (2022). CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate. The Journal of experimental medicine, 219(6), e20211314). The amino acid sequence of CD36 is SEQ ID NO: 108 and can be found under UniProt Accession No. P16671. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 108. PILRA: PILRA (also known as FDF03 or paired immunoglobin like type 2 receptor alpha) encodes an inhibitory receptor that is mainly expressed on myeloid cells and negatively regulates neutrophil infiltration during inflammation. PILRA is thought to control monocyte mobility through regulating integrin signaling and inhibiting CD99-CD99 binding (Kohyama, M., Matsuoka, S., Shida, K., Sugihara, F., Aoshi, T., Kishida, K., Ishii, K. J., & Arase, H. (2016). Monocyte infiltration into obese and fibrilized tissues is regulated by PILRα. European journal of immunology, 46(5), 1214–1223). The amino acid sequence of PILRA is SEQ ID NO: 109 and can be found under UniProt Accession No. Q9UKJ1. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 109 and/or the protein level thereof. 61 WBD (US) 4854-8046-9185v2 LILRB1: LILRB1 (also known as CD85J, ILT-2, ILT2, LIR-1, LIR1, MIR-7, MIR7, PIR- B, PIRB, leukocyte immunoglobulin like receptor B1) encodes a receptor that is a member of the leukocyte immunoglobulin-like receptor (LIR) family and is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. LILRB1 is thought to engage major histocompatibility complex (MHC) class I to regulate the effector function of innate immune cells (Barkal et al. (2018). Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nature immunology, 19(1), 76–84). The amino acid sequence of LILRB1 is SEQ ID NO: 110 and can be found under UniProt Accession No. Q8NHL6. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 110 and/or the protein level thereof. NECTIN2: NECTIN2 (also known as Poliovirus receptor-related 2, CD112, HVEB, PRR2, PVRR2, PVRL2, nectin cell adhesion molecule 2) encodes a single-pass type I membrane glycoprotein that is is one of the plasma membrane components of adherens junctions. NECTIN2 is thought to influence cell apoptosis by regulating ANXA2 expression in neuroblastoma (Zhang, S., Jiang, C., Su, Y., Gui, J., Yue, Z., Jian, B., He, S., & Ma, X. (2023). Nectin2 is thought to influence cell apoptosis by regulating ANXA2 expression in neuroblastoma. Acta biochimica et biophysica Sinica, 55(3), 356–366). The amino acid sequence of NECTIN2 is SEQ ID NO: 111 and can be found under UniProt Accession No. Q92692. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 111 and/or the protein level thereof. PLXNB2: PLXNB2 (also known as MM1, Nbla00445, PLEXB2, dJ402G11.3, plexin B2) encodes a transmembrane protein that acts as a receptor for angiogenin in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells (Yu et al. (2017). Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin. Cell, 171(4), 849– 864.e25). PXNB2 is thought to orchestrate cytoskeletal tension and cell-cell/cell-matrix adhesion 62 WBD (US) 4854-8046-9185v2 (Alves et al. (2021). Plexin-B2 orchestrates collective stem cell dynamics via actomyosin contractility, cytoskeletal tension and adhesion. Nature communications, 12(1), 6019). The amino acid sequence of PLXNB2 is SEQ ID NO: 112 and can be found under UniProt Accession No. O15031. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 112 and/or the protein level thereof. TLR4: TLR4 (also known as ARMD10, CD284, TLR-4, TOLL, toll like receptor 4) encodes a transmembrane protein whose activation leads to intracellular signaling pathway NF- κB and inflammatory cytokine production. Prolonged activation of TLR4 is thought to be linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer (Ciesielska, A., Matyjek, M., & Kwiatkowska, K. (2021). TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cellular and molecular life sciences : CMLS, 78(4), 1233–126). The amino acid sequence of TLR4 is SEQ ID NO: 113 and can be found under UniProt Accession No. O00206. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 113 and/or the protein level thereof. ITGA4: ITGA4 (also known as CD49D, IA4, integrin subunit alpha 4) encodes an integrin alpha subunit that makes up half of α4β1 lymphocyte homing receptor. ITGA4 is thought to play an essential role in mediating both cell-cell and cell-matrix interactions in Chronic lymphocytic leukemia (CLL)-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. The amino acid sequence of ITGA4 is SEQ ID NO: 114 and can be found under UniProt Accession No. P13612. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 114 and/or the protein level thereof. 63 WBD (US) 4854-8046-9185v2 CD47: CD47 (also known as integrin associated protein, IAP, MER6, OA3) encodes a transmembrane protein belonging to the immunoglobulin superfamily and plays important roles in immune and angiogenic responses. In particular, CD47 is known to be upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis (Jaiwal et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138(2), 271–285). The amino acid sequence of CD47 is SEQ ID NO: 115 and can be found under UniProt Accession No. Q08722. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 115 and/or the protein level thereof. NOTCH2: NOTCH2 (also known as Neurogenic locus notch homolog protein 2, AGS2, HJCYS, hN2, Notch-2, notch 2, notch receptor 2) encodes a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. NOTCH2 is thought to be involved in intestinal immunity, given that the fate of mast cells and a subset of DCs is regulated by Notch2 in the intestine (Sakata-Yanagimoto, M., & Chiba, S. (2012). Notch2 and immune function. Current topics in microbiology and immunology, 360, 151–161). The amino acid sequence of NOTCH2 is SEQ ID NO: 116 and can be found under UniProt Accession No. Q04721. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 116 and/or the protein level thereof. TGFBR2: TGFBR2 (also known as Transforming growth factor, beta receptor II (70/80kDa), AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2, RIIC, TAAD2, TGFR-2, TGFbeta- RII, transforming growth factor beta receptor 2, TBR-ii, TBRII) encodes a transmembrane protein that is a member of the serine/threonine protein kinase family and the TGFB receptor subfamily. Depletion of transforming growth factor-β receptor 2 (TGFBR2) in CD4+ T cells, but not CD8+ T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions (Liu et al. (2020). TGF-β suppresses type 2 immunity to cancer. Nature, 587(7832), 115–120). The amino 64 WBD (US) 4854-8046-9185v2 acid sequence of TGFBR2 is SEQ ID NO: 117 and can be found under UniProt Accession No. P37173. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 117 and/or the protein level thereof. NRP2: NRP2 (also known as Neuropilin 2, NP2, NPN2, PRO2714, VEGF165R2) encodes a family member of neuropilins, cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. NRP2 has been proposed to be a novel angiogenic player by promoting ITGA5-mediated endothelial cell adhesion and migration on fibronectin. The amino acid sequence of NRP2 is SEQ ID NO: 118 and can be found under UniProt Accession No. O60462. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 118 and/or the protein level thereof. CD99: CD99 (also known as single-chain type-1 glycoprotein, HBA71, MIC2, MIC2X, MIC2Y, MSK5X) encodes an O-glycosylated transmembrane protein that is believed to be involved in T-cell adhesion and apoptosis of double positive T-cells. Activation of CD99 is thought to inhibit cell-extracellular matrix adhesion by suppressing β(1) integrin affinity (Lee et al. (2012). The activation of CD99 inhibits cell-extracellular matrix adhesion by suppressing β(1) integrin affinity. BMB reports, 45(3), 159–164). The amino acid sequence of CD99 is SEQ ID NO: 119 and can be found under UniProt Accession No. P14209. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 119 and/or the protein level thereof. TIGIT: TIGIT (also known as T cell immunoreceptor with Ig and ITIM domains, VSIG9, VSTM3, WUCAM) encodes an immune receptor expressed on T cells and natural killer cells. TIGIT is known to interact with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions (Harjunpää, H., & Guillerey, C. 65 WBD (US) 4854-8046-9185v2 (2020). TIGIT as an emerging immune checkpoint. Clinical and experimental immunology, 200(2), 108–119). The amino acid sequence of TIGIT is SEQ ID NO: 120 and can be found under UniProt Accession No. Q495A1. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 120 and/or the protein level thereof. IL6ST: IL6ST (also known as Glycoprotein 130, CD130, CDW130, GP130, IL-6RB, interleukin 6 signal transducer) encodes a transmembrane protein that acts as a signal transducing molecule following cytokine engagement. IL6ST is thought to be a predictive biomarker in breast cancer (Martínez-Pérez, C., Leung, J., Kay, C., Meehan, J., Gray, M., Dixon, J. M., & Turnbull, A. K. (2021). The Signal Transducer IL6ST (gp130) as a Predictive and Prognostic Biomarker in Breast Cancer. Journal of personalized medicine, 11(7), 618). The amino acid sequence of IL6ST is SEQ ID NO: 121 and can be found under UniProt Accession No. P40189. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 121 and/or the protein level thereof. TGFB2: TGFB2 (also known as LDS4, TGF-beta2, transforming growth factor beta 2, G- TSF, Glioblastoma-derived T-cell suppressor factor, Polyergin, Cetermin) encodes a secreted ligand of the TGF-beta family of proteins. In mice, TGFB2 is known to be secreted from adipose issue in response to exercise and improves glucose tolerance (Takahashi et al. (2019). TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nature metabolism, 1(2), 291–303). The amino acid sequence of TGFB2 is SEQ ID NO: 122 and can be found under UniProt Accession No. P61812. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 122 and/or the protein level thereof. 66 WBD (US) 4854-8046-9185v2 CD74: CD74 (also known as HLA class II histocompatibility antigen gamma chain, HLA-DR antigens-associated invariant chain, DHLAG, HLADG, II, Ia-GAMMA, CD74 molecule, p33, CLIP) encodes a non-polymorphic type II transmembrane glycoprotein that plays important roles in many inflammatory diseases, such as liver fibrosis, type I diabetes, systemic lupus erythematosus, and Alzheimer disease (Su, H., Na, N., Zhang, X., & Zhao, Y. (2017). The biological function and significance of CD74 in immune diseases. Inflammation research : official journal of the European Histamine Research Society ... [et al.], 66(3), 209–216). The amino acid sequence of CD74 is SEQ ID NO: 123 and can be found under UniProt Accession No. P04233. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 123 and/or the protein level thereof. TNFRSF25: TNFRSF25 (also known as APO-3, DDR3, DR3, LARD, TNFRSF12, TR3, TRAMP, WSL-1, WSL-LR, tumor necrosis factor receptor superfamily member 25, TNF receptor superfamily member 25, GEF720, PLEKHG5) encodes a cell surface receptor of the tumor necrosis factor receptor superfamily which mediates apoptotic signalling and differentiation. In humans, Tregs are known to express DR2 and demonstrate DR3-mediated activation of p38, ERK, and NFκB (Bittner, S., Knoll, G., & Ehrenschwender, M. (2017). Death receptor 3 signaling enhances proliferation of human regulatory T cells. FEBS letters, 591(8), 1187–1195). The amino acid sequence of TNFRSF25 is SEQ ID NO: 124 and can be found under UniProt Accession No. Q93038. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 124 and/or the protein level thereof. CD55: CD55 (also known as Complement decay-accelerating factor, CR, CROM, DAF, TC, CD55 molecule (Cromer blood group), CHAPLE) encodes a glycoprotein involved in the regulation of the complement cascade. CD55 is a major regulator of the alternative and classical pathways of complement activation and is expressed on all serum-exposed cells (Lea S. (2002). Interactions of CD55 with non-complement ligands. Biochemical Society transactions, 30(Pt 6), 67 WBD (US) 4854-8046-9185v2 1014–1019). The amino acid sequence of CD55 is SEQ ID NO: 125 and can be found under UniProt Accession No. P08174. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 125 and/or the protein level thereof. NRP1: NRP1 (also known as BDCA4, CD304, NP1, NRP, VEGF165R, Neuropilin 1) encodes a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor and semaphoring family members. NRP1 is thought to restrict CD8+ T cell reinvigoration in response to checkpoint inhibitors and act as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance (Chuckran, C. A., Liu, C., Bruno, T. C., Workman, C. J., & Vignali, D. A. (2020). Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy. Journal for immunotherapy of cancer, 8(2), e000967). The amino acid sequence of NRP1 is SEQ ID NO: 126 and can be found under UniProt Accession No. O14786. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 126 and/or the protein level thereof. FGFR1: FGFR1 (also known as BFGFR, CD331, CEK, FGFBR, FGFR-1, FLG, FLT-2, FLT2, HBGFR, HH2, HRTFDS, KAL2, N-SAM, OGD, bFGF-R-1, ECCL, fibroblast growth factor receptor 1) encodes a member of the fibroblast growth factor receptor (FGFR) family that possesses tyrosine kinase activity. FGFR-1 is known to be expressed during wound healing (Takenaka, H., Kishimoto, S., Tooyama, I., Kimura, H., & Yasuno, H. (1997). Protein expression of fibroblast growth factor receptor-1 in keratinocytes during wound healing in rat skin. The Journal of investigative dermatology, 109(1), 108–112). The amino acid sequence of FGFR1 is SEQ ID NO: 127 and can be found under UniProt Accession No. P11362. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 127 and/or the protein level thereof. 68 WBD (US) 4854-8046-9185v2 ITGAV: ITGAV (also known as CD51, MSK8, VNRA, VTNR, integrin subunit alpha V) encodes a member of integrin family of extracellular matrix receptors. ITGAV is overexpressed in gastric cancer and is associated with poorer prognostic outcomes (Wang, H., Chen, H., Jiang, Z., Lin, Y., Wang, X., Xiang, J., & Peng, J. (2019). Integrin subunit alpha V promotes growth, migration, and invasion of gastric cancer cells. Pathology, research and practice, 215(9), 152531 ). The amino acid sequence of ITGAV is SEQ ID NO: 128 and can be found under UniProt Accession No. P06756. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 128 and/or the protein level thereof. JAM3: JAM3 (also known as JAM-2, JAM-3, JAM-C, JAMC, junctional adhesion molecule 3, Junctional adhesion molecule C) encodes a member of the junctional adhesion molecule family, which has been linked to epithelial and cancer cell proliferation. JAM3 has been found to promote migration and suppresses apoptosis of renal carcinoma cell lines (Li, X., Yin, A., Zhang, W., Zhao, F., Lv, J., Lv, J., & Sun, J. (2018). Jam3 promotes migration and suppresses apoptosis of renal carcinoma cell lines. International journal of molecular medicine, 42(5), 2923–2929). The amino acid sequence of JAM3 is SEQ ID NO: 129 and can be found under UniProt Accession No. Q9BX67. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 129 and/or the protein level thereof. JAM2: JAM2 (also known as C21orf43, CD322, JAM-B, JAMB, PRO245, VE-JAM, VEJAM, junctional adhesion molecule 2, IBGC8, Junctional adhesion molecule B) encodes a receptor that mediates JAM2 adhesion to T-cells. Upregulation of JAM3 protein on peripheral blood lymphocytes has been observed following activation (Arrate, M. P., Rodriguez, J. M., Tran, T. M., Brock, T. A., & Cunningham, S. A. (2001). Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. The Journal of biological chemistry, 276(49), 45826–45832). The amino acid sequence of JAM2 is SEQ ID NO: 130 and can be found under UniProt Accession No. P57087. 69 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 130 and/or the protein level thereof. F11R: F11R (also known as Junctional adhesion molecule A, 9130004G24, AA638916, ESTM33, JAM, JAM-1, JAM-A, Jcam, Jcam1, Ly106, CD321, JAM1, JAMA, KAT, PAM-1, F11 receptor) encodes a transmembrane glycoprotein of the immunoglobulin superfamily, which is mainly located in epithelial and endothelial cell tight junctions and also expressed on circulating platelets and leukocytes. F11R has a role in the regulation of various biological processes, as diverse as paracellular permeability, tight junction formation and maintenance, leukocyte transendothelial migration, epithelial-to-mesenchymal transition, angiogenesis, reovirus binding, and platelet activation (Czubak-Prowizor, K., Babinska, A., & Swiatkowska, M. (2022). The F11 Receptor (F11R)/Junctional Adhesion Molecule-A (JAM-A) (F11R/JAM-A) in cancer progression. Molecular and cellular biochemistry, 477(1), 79–98). The amino acid sequence of F11R is SEQ ID NO: 131 and can be found under UniProt Accession No. Q9Y624. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 131 and/or the protein level thereof. PTPRM: PTPRM (also known as Receptor-type tyrosine-protein phosphatase mu, PTPRL1, R-PTP-MU, RPTPM, RPTPU, hR-PTPu, protein tyrosine phosphatase, receptor type M, protein tyrosine phosphatase receptor type M) encodes a transmembrane receptor type tyrosine phosphatase. PTPRM is thought to be a dysregulated candidate tumor suppressor gene in small intestinal neuroendocrine tumors (Barazeghi, E., Hellman, P., Westin, G., & Stålberg, P. (2019). PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors. Endocrine connections, 8(8), 1126–1135). The amino acid sequence of PTPRM is SEQ ID NO: 132 and can be found under UniProt Accession No. P28827. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 132 and/or the protein level thereof. 70 WBD (US) 4854-8046-9185v2 ITGA8: ITGA8 (also known as Integrin alpha-8 or integrin subunit alpha 8) encodes a single-pass type 1 membrane protein that plays an important role in wound-healing and organogenesis. ITGA8 signalling is thought to attenuate chronic renal interstitial fibrosis by reducing fibroblast activation (Marek, I., Lichtneger, T., Cordasic, N., Hilgers, K. F., Volkert, G., Fahlbusch, F., Rascher, W., Hartner, A., & Menendez-Castro, C. (2016). Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover. PloS one, 11(3), e0150471). The amino acid sequence of ITGA8 is SEQ ID NO: 133 and can be found under UniProt Accession No. P53708. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 133 and/or the protein level thereof. ACVR1: ACVR1 (also known as Activin A receptor type I, ACTRI, ACVR1A, ACVRLK2, ALK2, FOP, SKR1, TSRI, activin A receptor type 1) encodes a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. ACVR1 overactivity has been found to result in increased macrophage inflammatory responses (Matsuo, K., Lepinski, A., Chavez, R. D., Barruet, E., Pereira, A., Moody, T. A., Ton, A. N., Sharma, A., Hellman, J., Tomoda, K., Nakamura, M. C., & Hsiao, E. C. (2021). ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone, 153, 116129). The amino acid sequence of ACVR1 is SEQ ID NO: 134 and can be found under UniProt Accession No. Q04771. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 134 and/or the protein level thereof. BMPR2: BMPR2 (also known as Bone morphogenetic protein receptor type II, BMPR-II, BMPR3, BMR2, BRK-3, POVD1, PPH1, T-ALK, bone morphogenetic protein receptor type 2) encodes a a serine/threonine receptor kinase that binds binds bone morphogenetic proteins. Loss of function mutations in BMPR2 have been found to be the most common genetic factor in Pulmonary Arterial Hypertension (Dannewitz Prosseda, S., Ali, M. K., & Spiekerkoetter, E. (2020). Novel Advances in Modifying BMPR2 Signaling in PAH. Genes, 12(1), 8). The amino 71 WBD (US) 4854-8046-9185v2 acid sequence of BMPR2 is SEQ ID NO: 135 and can be found under UniProt Accession No. Q13873. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 135 and/or the protein level thereof. F2R: F2R (also known as Proteinase-activated receptor 1, protease-activated receptor 1, CHTR, PAR-1, PAR1, TR, Coagulation factor II receptor, coagulation factor II thrombin receptor) encodes a transmembrane G-protein-coupled receptor (GPCR) expressed in platelets and endothelial cells and plays a key role in mediating the interplay between coagulation and inflammation. F2R has been observed to respond to RANKL stimulation to attenuate osteoclastogenesis through inhibiting the both F2r-Akt and F2r-NFκB signaling pathways (Zhang, Y., Wang, H., Zhu, G., Qian, A., & Chen, W. (2020). F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NFκB signaling pathways. International journal of biological sciences, 16(9), 1629–1639 ). The amino acid sequence of F2R is SEQ ID NO: 136 and can be found under UniProt Accession No. P25116. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 136 and/or the protein level thereof. TGFBR1: TGFBR1 (also known as Transforming growth factor beta receptor I (activin A receptor type II-like kinase, 53kDa), AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1, LDS1A, LDS2A, MSSE, SKR4, TGFR-1, tbetaR-I, transforming growth factor beta receptor 1, TBRI, TBR-i) encodes a transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines. Endothelial cells angiogenesis has been found to be suppressed by miR-210-3p through the suppression of TGFBR1 mRNA translation (Tang, H., Zhu, W., Cao, L., Zhang, J., Li, J., Ma, D., & Guo, C. (2022). miR-210-3p protects against osteoarthritis through inhibiting subchondral angiogenesis by targeting the expression of TGFBR1 and ID4. Frontiers in immunology, 13, 982278). The amino acid sequence of TGFBR1 is SEQ ID NO: 137 and can be found under UniProt Accession No. P36897. 72 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 137 and/or the protein level thereof. LRP1: LRP1 (also known as alpha-2-macroglobulin receptor, apolipoprotein E receptor, cluster of differentiation 91, A2MR, APOER, APR, CD91, IGFBP3R, LRP, LRP1A, TGFBR5, low density lipoprotein receptor-related protein 1, LDL receptor related protein 1, KPA, IGFBP3R1, IGFBP-3R) encodes an endocytic/signaling cell surface receptor which controls cellular and molecular mechanisms driving the physiological and pathological inflammatory reactions and tissue remodeling in several organs (Wujak, L., Schnieder, J., Schaefer, L., & Wygrecka, M. (2018). LRP1: A chameleon receptor of lung inflammation and repair. Matrix biology : journal of the International Society for Matrix Biology, 68-69, 366–381). The amino acid sequence of LRP1 is SEQ ID NO: 138 and can be found under UniProt Accession No. Q07954. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 138 and/or the protein level thereof. EDNRB: EDNRB (also known as Endothelin receptor type B, ABCDS, ET-B, ET-BR, ETB, ETBR, ETRB, HSCR, HSCR2, WS4A, ETB1) encodes a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. EDNRB signaling has been found to promote proliferation and differentiation of melanocyte stem cells (Takeo, M., Lee, W., Rabbani, P., Sun, Q., Hu, H., Lim, C. H., Manga, P., & Ito, M. (2016). EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling. Cell reports, 15(6), 1291–1302). The amino acid sequence of EDNRB is SEQ ID NO: 139 and can be found under UniProt Accession No. P24530. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 139 and/or the protein level thereof. 73 WBD (US) 4854-8046-9185v2 ITGB5: ITGB5 (also known as Integrin beta-5 or Integrin, beta 5, integrin subunit beta 5) encodes a subunit of integrin that can interact with several alpha chains to form a variety of integrin heterodimers. ITGB5 is known to promote tumor development in several carcinomas (Wen, X., Chen, S., Chen, X., Qiu, H., Wang, W., Zhang, N., Liu, W., Wang, T., Ding, X., & Zhang, L. (2022). ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway. Frontiers in oncology, 12, 887068). The amino acid sequence of ITGB5 is SEQ ID NO: 140 and can be found under UniProt Accession No. P18084. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 140 and/or the protein level thereof. ITGB8: ITGB8 (also known as Integrin beta-8 or integrin subunit beta 8) encodes a single-pass type I membrane protein with a VWFA domain and four cysteine-rich repeats that is a member of the integrin beta chain family. ITGB8 is thought to mediate release of active TGF- β1 from the latent TGF-β1/GARP complex on T regulatory cells (Edwards, J. P., Thornton, A. M., & Shevach, E. M. (2014). Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8. Journal of immunology (Baltimore, Md. : 1950), 193(6), 2843–2849). The amino acid sequence of ITGB8 is SEQ ID NO: 141 and can be found under UniProt Accession No. P26012. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 141 and/or the protein level thereof. ACVRL1: ACVRL1 (also known as Serine/threonine-protein kinase receptor R3, ACVRLK1, ALK-1, ALK1, HHT, HHT2, ORW2, SKR3, TSR-I, activin A receptor like type 1) encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. ACVRL1 is thought to suppress plasmacytoid DC development while enhancing that of CD8α(+) DCs (Verma, R., Jaiswal, H., Chauhan, K. S., Kaushik, M., & Tailor, P. (2016). Cutting Edge: ACVRL1 Signaling Augments CD8α+ Dendritic Cell Development. Journal of immunology 74 WBD (US) 4854-8046-9185v2 (Baltimore, Md. : 1950), 197(4), 1029–1034). The amino acid sequence of ACVRL1 is SEQ ID NO: 142 and can be found under UniProt Accession No. P37023. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 142 and/or the protein level thereof. GLG1: GLG1 (also known as Golgi apparatus protein 1, CFR-1, ESL-1, MG-160, MG160, golgi glycoprotein 1) encodes an intracellular fibroblast growth factor receptor. GLG1 mRNA expression has been found to be upregulated by memantine, an NMDA antagonist, in a concentration dependent manner. The amino acid sequence of GLG1 is SEQ ID NO: 143 and can be found under UniProt Accession No. Q92896. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 143 and/or the protein level thereof. ITGA6: ITGA6 (also known as Integrin alpha-6, CD49f, ITGA6B, VLA-6, integrin subunit alpha 6, JEB6) encodes a member of the integrin alpha chain family of proteins. Down regulation of ITGA6 gene in the human thymic epithelium has been found to trigger a complex cascade of effects upon the expression levels of several other cell migration-related genes, including extracellular matrix and chemokine ligands and receptors (Golbert, D. C., Correa-de- Santana, E., Ribeiro-Alves, M., de Vasconcelos, A. T., & Savino, W. (2013). ITGA6 gene silencing by RNA interference modulates the expression of a large number of cell migration- related genes in human thymic epithelial cells. BMC genomics, 14 Suppl 6(Suppl 6), S3). The amino acid sequence of ITGA6 is SEQ ID NO: 144 and can be found under UniProt Accession No. P23229. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 144 and/or the protein level thereof. ALOX5: ALOX5 (also known as Arachidonate 5-lipoxygenase, 5-lipoxygenase, 5-LOX, 5-LO) encodes a member of the lipoxygenase family of enzymes. Elevated levels of ALOX5 75 WBD (US) 4854-8046-9185v2 have been found to contribute to autophagy and ferroptosis in vitro and in vivo (Wang, M., Zeng, G., Xiong, B., Zhu, X., Guo, J., Chen, D., Zhang, S., Luo, M., Guo, L., & Cai, L. (2023). ALOX5 promotes autophagy-dependent ferroptosis by activating the AMPK/mTOR pathway in melanoma. Biochemical pharmacology, 212, 115554). The amino acid sequence of ALOX5 is SEQ ID NO: 145 and can be found under UniProt Accession No. P09917. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 145 and/or the protein level thereof. CD4: CD4 (also known as cluster of differentiation 4, OKT4D, IMD79) encodes a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 has a key role in the development of CD4+T lymphocytes (Ravichandran, K. S., Collins, T. L., & Burakoff, S. J. (1996). CD4 and signal transduction. Current topics in microbiology and immunology, 205, 47– 62). The amino acid sequence of CD4 is SEQ ID NO: 146 and can be found under UniProt Accession No. P01730. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 146 and/or the protein level thereof. CEACAM5: CEACAM5 (also known as Carcinoembryonic antigen-related cell adhesion molecule 5, Cluster of Differentiation 66e, CD66e, CEA, carcinoembryonic antigen related cell adhesion molecule 5, CEA cell adhesion molecule 5) encodes a member of the carcinoembryonic antigen (CEA) gene family and has a role in adhesion between epithelial cells in the embryonic intestine and colon tumors (Benchimol, S., Fuks, A., Jothy, S., Beauchemin, N., Shirota, K., & Stanners, C. P. (1989). Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell, 57(2), 327–334). The amino acid sequence of CEACAM5 is SEQ ID NO: 147 and can be found under UniProt Accession No. P06731. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 147 and/or the protein level thereof. 76 WBD (US) 4854-8046-9185v2 ITGAX: ITGAX (also known as Integrin, alpha X (complement component 3 receptor 4 subunit), CD11C, SLEB6, integrin subunit alpha X) encodes a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst. ITGAX has been found to regulate late stage T cell development in the thymus (Hou, L., & Yuki, K. (2022). CD11c regulates late-stage T cell development in the thymus. Frontiers in immunology, 13, 1040818). The amino acid sequence of ITGAX is SEQ ID NO: 148 and can be found under UniProt Accession No. P20702. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 148 and/or the protein level thereof. TNFRSF10B: TNFRSF10B (also known as TRAIL receptor 2, CD262, DR5, KILLER, KILLER/DR5, TRAIL-R2, TRAILR2, TRICK2, TRICK2A, TRICK2B, TRICKB, ZTNFR9, tumor necrosis factor receptor superfamily member 10b, TNF receptor superfamily member 10b) encodes a receptor for the cytotoxic ligand TNFSF10/TRAIL and transduces an apoptosis signal. TNFRSF10B has been shown to promote neuronal injury and motor dysfunction in Parkinson's disease (Dai, M., Yan, L., Yu, H., Chen, C., & Xie, Y. (2023). TNFRSF10B is involved in motor dysfunction in Parkinson's disease by regulating exosomal α-synuclein secretion from microglia. Journal of chemical neuroanatomy, 129, 102249). The amino acid sequence of TNFRSF10B is SEQ ID NO: 149 and can be found under UniProt Accession No. O14763. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 149 and/or the protein level thereof. CSF3R: CSF3R (also known as granulocyte colony-stimulating factor receptor, Cluster of Differentiation 114, CD114, GCSFR, colony stimulating factor 3 receptor, SCN7) encodes a a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF). CSF3R signaling involves the recruitment of non-receptor protein tyrosine kinases and their dependent signaling pathways of serine/threonine kinases, tyrosine phosphatases, and lipid second messengers (Mehta, H. M., & Corey, S. J. (2021). G-CSF, the guardian of granulopoiesis. Seminars in 77 WBD (US) 4854-8046-9185v2 immunology, 54, 101515). The amino acid sequence of CSF3R is SEQ ID NO: 150 and can be found under UniProt Accession No. Q99062. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 150 and/or the protein level thereof. CSF1R: CSF1R (also known as Colony stimulating factor 1 receptor, C-FMS, CD115, CSF-1R, CSFR, FIM2, FMS, HDLS, M-CSF-R, BANDDOS, HDLS1) encodes. CSF1R encodes a receptor that is highy expressed in myeloid cells and can be activated by colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R has important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia (Stanley, E. R., & Chitu, V. (2014). CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor perspectives in biology, 6(6), a021857). The amino acid sequence of CSF1R is SEQ ID NO: 151 and can be found under UniProt Accession No. P07333. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 151 and/or the protein level thereof. LILRB3: LILRB3 (also known as Leukocyte immunoglobulin-like receptor subfamily B member 3, CD85A, HL9, ILT-5, ILT5, LILRA6, LIR-3, LIR3, PIRB, PIR-B, leukocyte immunoglobulin like receptor B3) encodes a receptor expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. LILRB3 has been proposed as a putative immune cell surface receptor for APOE (Zhou, J., Wang, Y., Huang, G., Yang, M., Zhu, Y., Jin, C., Jing, D., Ji, K., & Shi, Y. (2023). LilrB3 is a putative cell surface receptor of APOE4. Cell research, 33(2), 116–130). The amino acid sequence of LILRB3 is SEQ ID NO: 152 and can be found under UniProt Accession No. Q6PI73. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 152 and/or the protein level thereof. 78 WBD (US) 4854-8046-9185v2 FPR3: FPR3 (also known as N-formyl peptide receptor 3, FML2_HUMAN, FMLPY, FPRH1, FPRH2, FPRL2, RMLP-R-I, FMLP-R-II, formyl peptide receptor 3) encodes a G protein-coupled receptor essential for neutrophil activation. FPR3 has been identified as an important immune-related biomarker for predicting poor prognosis for breast cancer (Qi, J., Liu, Y., Hu, J., Lu, L., Dou, Z., Dai, H., Wang, H., & Yang, W. (2021). Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer. Frontiers in pharmacology, 11, 593247). The amino acid sequence of FPR3 is SEQ ID NO: 153 and can be found under UniProt Accession No. P25089. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 153 and/or the protein level thereof. CD28: CD28 (also known as Cluster of Differentiation 28, Tp44) encodes a B7 receptor that has a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation (Esensten, J. H., Helou, Y. A., Chopra, G., Weiss, A., & Bluestone, J. A. (2016). CD28 Costimulation: From Mechanism to Therapy. Immunity, 44(5), 973–988). The amino acid sequence of CD28 is SEQ ID NO: 154 and can be found under UniProt Accession No. P10747. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 154 and/or the protein level thereof. CTLA4: CTLA4 (also known as cytotoxic T-lymphocyte-associated protein 4, ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4, GSE, IDDM12, cytotoxic T-lymphocyte associated protein 4) encodes a protein receptor constitutively expressed in regulatory T cells and functions as an immune checkpoint to downregulate immune responses. CTLA4 has been found to inhibit CD28-dependent IL-2 production (Walunas, T. L., Bakker, C. Y., & Bluestone, J. A. (1996). CTLA-4 ligation blocks CD28-dependent T cell activation. The Journal of experimental medicine, 183(6), 2541–2550). The amino acid sequence of CTLA4 is SEQ ID NO: 155 and can be found under UniProt Accession No. P16410. 79 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 155 and/or the protein level thereof. IGF2R: IGF2R (also known as Insulin-like growth factor 2 receptor, cation-independent mannose-6-phosphate receptor, CD222, CIMPR, M6P-R, MPR1, MPRI, M6P/MPR 300, CI- M6PR, MPR300, insulin like growth factor 2 receptor) encodes a type I transmembrane protein. Activation of IGF2R is known to have a role in dictating anti-inflammatory macrophages (Wang, X., Lin, L., Lan, B., Wang, Y., Du, L., Chen, X., Li, Q., Liu, K., Hu, M., Xue, Y., Roberts, A. I., Shao, C., Melino, G., Shi, Y., & Wang, Y. (2020). IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages. Science advances, 6(48), eabb7389). The amino acid sequence of IGF2R is SEQ ID NO: 156 and can be found under UniProt Accession No. P11717. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 156 and/or the protein level thereof. ITGAL: ITGAL (also known as Integrin alpha L, antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide, CD11A, LFA-1, LFA1A) encodes the integrin alpha L chain and functions in cellular adhesion and costimulatory signaling. ITGAL has been found to be positively associated with most immune checkpoint genes and cytokines (Li, R., Wu, X., Xue, K., & Li, J. (2022). ITGAL infers adverse prognosis and correlates with immunity in acute myeloid leukemia. Cancer cell international, 22(1), 268). The amino acid sequence of ITGAL is SEQ ID NO: 157 and can be found under UniProt Accession No. P20701. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 157 and/or the protein level thereof. RPSA: RPSA (also known as 40S ribosomal protein SA, 37LRP, 67LR, ICAS, LAMBR, LAMR1, LBP, LBP/p40, LRP, LRP/LR, NEM/1CHD4, SA, lamR, p40, Ribosomal protein SA) encodes a protein component of the small ribosomal subunit and acts as a cell surface receptor 80 WBD (US) 4854-8046-9185v2 for laminin. RPSA governs critical cellular processes including growth, survival, migration, protein synthesis, development, and differentiation (DiGiacomo, V., & Meruelo, D. (2016). Looking into laminin receptor: critical discussion regarding the non-integrin 37/67-kDa laminin receptor/RPSA protein. Biological reviews of the Cambridge Philosophical Society, 91(2), 288– 310). The amino acid sequence of RPSA is SEQ ID NO: 158 and can be found under UniProt Accession No. P08865. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 158 and/or the protein level thereof. MYLK: MYLK (also known as kinase-related protein, AAT7, KRP, MLCK, MLCK1, MLCK108, MLCK210, MSTP083, MYLK1, smMLCK, myosin light chain kinase, MMIHS, MMIHS1, MYLK-L, telokin) encodes a myosin light-chain kinase, which is a calcium- /calmodulin-dependent enzyme. MYLK promotes hepatocellular carcinoma progression by altering the cytoskeleton to enhance epithelial-mesenchymal transition (Lin, J., He, Y., Chen, L., Chen, X., Zang, S., & Lin, W. (2018). MYLK promotes hepatocellular carcinoma progression through regulating cytoskeleton to enhance epithelial-mesenchymal transition. Clinical and experimental medicine, 18(4), 523–533). The amino acid sequence of MYLK is SEQ ID NO: 159 and can be found under UniProt Accession No. Q15746. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 159 and/or the protein level thereof. ITGA1: ITGA1 (also known as CD49a, VLA1, integrin subunit alpha 1) encodes an integrin alpha subunit that makes up half of the α1β1 integrin duplex. ITGA1 has a role in matrix remodeling such as is seen during morphogenesis and wound healing (Carver, W., Molano, I., Reaves, T. A., Borg, T. K., & Terracio, L. (1995). Role of the alpha 1 beta 1 integrin complex in collagen gel contraction in vitro by fibroblasts. Journal of cellular physiology, 165(2), 425–437). The amino acid sequence of ITGA1 is SEQ ID NO: 160 and can be found under UniProt Accession No. P56199. 81 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 160 and/or the protein level thereof. SDC4: SDC4 (also known as SYND4, syndecan 4) encodes a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. SDC4 functions as an independent receptor for heparin-binding growth factors, such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs) (Elfenbein, A., & Simons, M. (2013). Syndecan-4 signaling at a glance. Journal of cell science, 126(Pt 17), 3799–3804). The amino acid sequence of SDC4 is SEQ ID NO: 161 and can be found under UniProt Accession No. P31431. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 161. ITGB2: ITGB2 (also known as CD18, LAD, LCAMB, LFA-1, MAC-1, MF17, MFI7, integrin subunit beta 2) encodes an integrin beta chain protein that has roles in cellular adhesion, cell surface signaling, and immune responses. ITGB2 has been found to influence immune cell infiltration into the tumor microenviroment of acute myeloid leukemia (Wei, J., Huang, X. J., Huang, Y., Xiong, M. Y., Yao, X. Y., Huang, Z. N., Li, S. N., Zhou, W. J., Fang, D. L., Deng, D. H., & Cheng, P. (2021). Key immune-related gene ITGB2 as a prognostic signature for acute myeloid leukemia. Annals of translational medicine, 9(17), 1386). The amino acid sequence of ITGB2 is SEQ ID NO: 162 and can be found under UniProt Accession No. P05107. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 162 and/or the protein level thereof. TNFRSF10D: TNFRSF10D (also known as Decoy receptor 2, TRAIL receptor 4, CD264, DCR2, TRAIL-R4, TRAILR4, TRUNDD, tumor necrosis factor receptor superfamily member 10d, TNF receptor superfamily member 10d) encodes a member of the TNF-receptor superfamily that has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. TNFRSF10D has been found to promote the anti-tumoral cytotoxic activity of γδ T cells (Tawfik, 82 WBD (US) 4854-8046-9185v2 D., Groth, C., Gundlach, J. P., Peipp, M., Kabelitz, D., Becker, T., Oberg, H. H., Trauzold, A., & Wesch, D. (2019). TRAIL-Receptor 4 Modulates γδ T Cell-Cytotoxicity Toward Cancer Cells. Frontiers in immunology, 10, 2044). The amino acid sequence of TNFRSF10D is SEQ ID NO: 163 and can be found under UniProt Accession No. Q9UBN6. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 163 and/or the protein level thereof. FPR2: FPR2 (also known as N-formyl peptide receptor 2, ALXR, FMLP-R-II, FMLPX, FPR2A, FPRH1, FPRH2, FPRL1, HM63, LXA4R, formyl peptide receptor 2, ALX) encodes a G-protein coupled receptor expressed on phagocytic leukocytes and involved in host defense and inflammation. FPR2 has been proposed as a promising target for the treatment of influenza (Alessi, M. C., Cenac, N., Si-Tahar, M., & Riteau, B. (2017). FPR2: A Novel Promising Target for the Treatment of Influenza. Frontiers in microbiology, 8, 1719). The amino acid sequence of FPR2 is SEQ ID NO: 164 and can be found under UniProt Accession No. P25090. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 164 and/or the protein level thereof. LIFR: LIFR (also known as Cluster of Differentiation 118, CD118, LIF-R, SJS2, STWS, SWS, leukemia inhibitory factor receptor alpha, LIF receptor alpha, LIF receptor subunit alpha) encodes a subunit of a receptor for leukemia inhibitory factor. LIFR is known to be down regulated in hepatocellular carcinoma (Yao et al. (2021). A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature communications, 12(1), 7333). The amino acid sequence of LIFR is SEQ ID NO: 165 and can be found under UniProt Accession No. P42702. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 165 and/or the protein level thereof. 83 WBD (US) 4854-8046-9185v2 AREG: AREG (also known as AR, AREGB, CRDGF, SDGF, amphiregulin) encodes a ligand of the epidermal growth factor (EGF) receptor that acts as an autocrine growth factor as well as a mitogen for a broad range of target cells including astrocytes, Schwann cells and fibroblasts. AREG gene expression and release is induced by a plethora of stimuli including inflammatory lipids, cytokines, hormones, growth factors and xenobiotics (Berasain, C., & Avila, M. A. (2014). Amphiregulin. Seminars in cell & developmental biology, 28, 31–41). The amino acid sequence of AREG is SEQ ID NO: 166 and can be found under UniProt Accession No. P15514. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 166 and/or the protein level thereof. CD46: CD46 (also known as membrane cofactor protein, AHUS2, MCP, MIC10, TLX, TRA2.10) encodes a ubiquitously expressed complement regulatory protein, serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells and plays roles in human reproduction, autophagy, modulating T cell activation and effector functions. CD46 deficiencies are thought to contribute to inflammatory disorders (Liszewski, M. K., & Atkinson, J. P. (2021). Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections. Current opinion in immunology, 72, 126–134). The amino acid sequence of CD46 is SEQ ID NO: 167 and can be found under UniProt Accession No. P15529. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 167 and/or the protein level thereof. HBEGF: HBEGF (also known as DTR, DTS, DTSF, HEGFL, heparin binding EGF like growth factor) encodes a heparin-binding member of the EGF family that was initially identified in the conditioned medium of human macrophages. HB-EGF has been implicated as a participant in a variety of normal physiological processes such as blastocyst implantation and wound healing, and in pathological processes such as tumor growth, SMC hyperplasia and atherosclerosis (Raab, G., & Klagsbrun, M. (1997). Heparin-binding EGF-like growth factor. Biochimica et biophysica 84 WBD (US) 4854-8046-9185v2 acta, 1333(3), F179–F199). The amino acid sequence of HBEGF is SEQ ID NO: 168 and can be found under UniProt Accession No. Q99075. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 168 and/or the protein level thereof. HLA-DRB1: HLA-DRB1 (also known as DRB1, DRw10, HLA-DR1B, HLA-DRB, SS1, major histocompatibility complex, class II, DR beta 1) encodes a beta chain of antigen- presenting major histocompatibility complex class II (MHCII) molecule. DRB1 allese are associated with increased risk of rheumatoid arthritis (Gregersen PK, Silver J, Winchester RJ (November 1987). "The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis". Arthritis and Rheumatism.30 (11): 1205–13). The amino acid sequence of HLA-DRB1 is SEQ ID NO: 169 and can be found under UniProt Accession No. P01911. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 169 and/or the protein level thereof. IL10: IL10 (also known as human cytokine synthesis inhibitory factor, CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10) encodes an anti-inflammatory cytokine. IL-10 is known to play important roles in sterile wound healing, autoimmunity, cancer, and homeostasis (Saraiva, M., Vieira, P., & O'Garra, A. (2020). Biology and therapeutic potential of interleukin-10. The Journal of experimental medicine, 217(1), e20190418). The amino acid sequence of IL10 is SEQ ID NO: 170 and can be found under UniProt Accession No. P22301. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 170 and/or the protein level thereof. SELL: SELL (also known as L-selectin, CD62L, LAM1, LECAM1, LEU8, LNHR, LSEL, LYAM1, PLNHR, TQ1, selectin L) encodes a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. The leukocytic cell adhesion receptor L-selectin is thought to 85 WBD (US) 4854-8046-9185v2 mediate the initial step of the adhesion cascade, the capture and rolling of leukocytes on endothelial cells, which enables leukocytes to migrate out of the vasculature into surrounding tissues during inflammation and immune surveillance (Wedepohl, S., Beceren-Braun, F., Riese, S., Buscher, K., Enders, S., Bernhard, G., Kilian, K., Blanchard, V., Dernedde, J., & Tauber, R. (2012). L-selectin--a dynamic regulator of leukocyte migration. European journal of cell biology, 91(4), 257–264). The amino acid sequence of SELL is SEQ ID NO: 171 and can be found under UniProt Accession No. P14151. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 171 and/or the protein level thereof. TNFSF13B: TNFSF13B (also known as B-cell activating factor, BAFF, BLYS, CD257, DTL, TALL-1, TALL1, THANK, TNFSF20, ZTNF4, TNLG7A, tumor necrosis factor superfamily member 13b, TNF superfamily member 13b) encodes a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. TNFSF13B has been shown to be required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells (Schweighoffer, E., & Tybulewicz, V. L. (2021). BAFF signaling in health and disease. Current opinion in immunology, 71, 124–131). The amino acid sequence of TNFSF13B is SEQ ID NO: 172 and can be found under UniProt Accession No. Q9Y275. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 172 and/or the protein level thereof. BMP7: BMP7 (also known as osteogenic protein-1, OP-1, bone morphogenetic protein 7) encodes a member of the TGF-β superfamily that plays roles in embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis. BMP7 as been shown to counteract transforming growth factor-beta-mediated fibrosis (Patel, S. R., & Dressler, G. R. (2005). BMP7 signaling in renal development and disease. Trends in molecular medicine, 11(11), 512–518). The amino acid sequence of BMP7 is SEQ ID NO: 173 and can be found under UniProt Accession No. P18075. 86 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 173 and/or the protein level thereof. COL18A1: COL18A1 (also known as KNO, KNO1, KS, Collagen, type XVIII, alpha 1, collagen type XVIII alpha 1, collagen type XVIII alpha 1 chain, GLCC) encodes the alpha chain of type XVIII collagen. COL18A1 has been identified as a candidate eye iridocorneal angle- closure gene in humans (Suri, F., Yazdani, S., Chapi, M., Safari, I., Rasooli, P., Daftarian, N., Jafarinasab, M. R., Ghasemi Firouzabadi, S., Alehabib, E., Darvish, H., Klotzle, B., Fan, J. B., Turk, C., & Elahi, E. (2018). COL18A1 is a candidate eye iridocorneal angle-closure gene in humans. Human molecular genetics, 27(21), 3772–3786). The amino acid sequence of COL18A1 is SEQ ID NO: 174 and can be found under UniProt Accession No. P39060. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 174 and/or the protein level thereof. CSF1: CSF1 (also known as macrophage colony-stimulating factor, CSF-1, MCSF, colony stimulating factor 1) encodes secreted a cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types. Administration of recombinant CSF1 to humans or animals has been shown to lead to monocytosis and expansion of tissue macrophage populations and growth of the liver and spleen (Sehgal, A., Irvine, K. M., & Hume, D. A. (2021). Functions of macrophage colony-stimulating factor (CSF1) in development, homeostasis, and tissue repair. Seminars in immunology, 54, 101509). The amino acid sequence of CSF1 is SEQ ID NO: 175 and can be found under UniProt Accession No. P09603. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 175 and/or the protein level thereof. CSF3: CSF3 (also known as Granulocyte colony-stimulating factor, C17orf33, CSF3OS, GCSF, colony stimulating factor 3) encodes a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. CSF3 has been 87 WBD (US) 4854-8046-9185v2 shown to be involved in lipid metabolism and nonalcoholic fatty liver disease (NAFLD) (Zhang, Y., Zhou, X., Liu, P., Chen, X., Zhang, J., Zhang, H., Li, S., Chen, Y., Song, X., Wang, J., Zeng, H., Zhang, X., Tang, C., Yu, C., Li, Y., & Xu, C. (2021). GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration. American journal of physiology. Gastrointestinal and liver physiology, 320(4), G531–G542). The amino acid sequence of CSF3 is SEQ ID NO: 176 and can be found under UniProt Accession No. P09919. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 176 and/or the protein level thereof. CTGF: CTGF (also known as CCN2, HCS24, IGFBP8, NOV2, connective tissue growth factor, cellular communication network factor 2) encodes a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins and plays important roles in cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair. CTGF expression has been shown to be associated with tumor development and progression (Chu, C. Y., Chang, C. C., Prakash, E., & Kuo, M. L. (2008). Connective tissue growth factor (CTGF) and cancer progression. Journal of biomedical science, 15(6), 675–685). The amino acid sequence of CTGF is SEQ ID NO: 177 and can be found under UniProt Accession No. P29279. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 177 and/or the protein level thereof. FGF2: FGF2 (also known as basic fibroblast growth factor, BFGF, FGF-2, FGFB, HBGF-2, fibroblast growth factor 2) encodes a ligand that plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration. FGF2 is known to play crucial roles in the growth and development of several tissues, including osteoclastogenesis (Wen, X., Hu, G., Xiao, X., Zhang, X., Zhang, Q., Guo, H., Li, X., Liu, Q., & Li, H. (2022). FGF2 positively regulates osteoclastogenesis via activating the ERK-CREB pathway. Archives 88 WBD (US) 4854-8046-9185v2 of biochemistry and biophysics, 727, 109348). The amino acid sequence of FGF2 is SEQ ID NO: 178 and can be found under UniProt Accession No. P09038. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 178 and/or the protein level thereof. HSPG2: HSPG2 (also known as Perlecan, basement membrane-specific heparan sulfate proteoglycan core protein, HSPG, PLC, PRCAN, SJA, SJS, SJS1, heparan sulfate proteoglycan 2) encodes a multifunctional proteoglycan that preserves the integrity of extracellular matrices, patrols tissue borders, and controls various signaling pathways affecting cellular phenotype. Because of the role of HSPG2 in several fundamental processes, mutations to the gene in organisms are relatively rare (Martinez, J. R., Dhawan, A., & Farach-Carson, M. C. (2018). Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions. Genes, 9(11), 556). The amino acid sequence of HSPG2 is SEQ ID NO: 179 and can be found under UniProt Accession No. P98160. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 179 and/or the protein level thereof. LAMA2: LAMA2 (also known as Laminin subunit alpha-2, LAMM, Laminin, alpha 2, MDC1A) encodes the α2 subunit of laminins. LAMA2 has been found to regulate osteogenesis and adipogenesis of MSCs by modulating the hedgehog signaling pathway (Zhu, Y., Zhang, X., Gu, R., Liu, X., Wang, S., Xia, D., Li, Z., Lian, X., Zhang, P., Liu, Y., & Zhou, Y. (2020). LAMA2 regulates the fate commitment of mesenchymal stem cells via hedgehog signaling. Stem cell research & therapy, 11(1), 135). The amino acid sequence of LAMA2 is SEQ ID NO: 180 and can be found under UniProt Accession No. P24043. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 180 and/or the protein level thereof. 89 WBD (US) 4854-8046-9185v2 LAMB2: LAMB2 (also known as LAMS, NPHS5, Laminin, beta 2, laminin subunit beta 2, PIERS) encodes the β2 subunit of laminins. High concentrations of glucose have been found to reduce expression of this laminin subunit at the translational level (Schaeffer, V., Hansen, K. M., Morris, D. R., LeBoeuf, R. C., & Abrass, C. K. (2012). RNA-binding protein IGF2BP2/IMP2 is required for laminin-β2 mRNA translation and is modulated by glucose concentration. American journal of physiology. Renal physiology, 303(1), F75–F82). The amino acid sequence of LAMB2 is SEQ ID NO: 181 and can be found under UniProt Accession No. P55268. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 181 and/or the protein level thereof. MIF: MIF (also known as GIF, GLIF, Macrophage migration inhibitory factor (glycosylation-inhibiting factor), macrophage migration inhibitory factor, L-dopachrome isomerase, phenylpyruvate tautomerase) encodes an inflammatory cytokine that participates in innate and adaptive immune responses and contributes to the resistance against infection agents, but also to the cellular and tissue damage in infectious, autoimmune, and allergic diseases. MIF is known to regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signaling (Kang, I., & Bucala, R. (2019). The immunobiology of MIF: function, genetics and prospects for precision medicine. Nature reviews. Rheumatology, 15(7), 427–437). The amino acid sequence of MIF is SEQ ID NO: 182 and can be found under UniProt Accession No. P14174. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 182 and/or the protein level thereof. NAMPT: NAMPT (also known as 1110035O14Rik, PBEF, PBEF1, VF, VISFATIN, nicotinamide phosphoribosyltransferase, pre-B-cell colony-enhancing factor 1) encodes a protein that catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. NAMPT is thought to influence oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation 90 WBD (US) 4854-8046-9185v2 and insulin resistance (Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., & Kiess, W. (2015). Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nature reviews. Endocrinology, 11(9), 535–546). The amino acid sequence of NAMPT is SEQ ID NO: 183 and can be found under UniProt Accession No. P43490. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 183 and/or the protein level thereof. NRG1: NRG1 (also known as ARIA, GGF, GGF2, HGL, HRG, HRG1, HRGA, MST131, MSTP131, NDF, NRG1-IT2, SMDF, neuregulin 1) encodes a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. NRG1 is known to be secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury (Dugaucquier, L., Feyen, E., Mateiu, L., Bruyns, T. A. M., De Keulenaer, G. W., & Segers, V. F. M. (2020). The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling. American journal of physiology. Heart and circulatory physiology, 319(2), H443–H455). The amino acid sequence of NRG1 is SEQ ID NO: 184 and can be found under UniProt Accession No. Q02297. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 184 and/or the protein level thereof. TNC: TNC (also known as Tenascin C, 150-225, DFNA56, GMEM, GP, HXB, JI, TN, TN-C) encodes a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is known to have a role in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy (Imanaka-Yoshida K. (2021). Tenascin- C in Heart Diseases-The Role of Inflammation. International journal of molecular sciences, 22(11), 5828). The amino acid sequence of TNC is SEQ ID NO: 185 and can be found under UniProt Accession No. P24821. 91 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 185 and/or the protein level thereof. TSLP: TSLP (also known as thymic stromal lymphopoietin) encodes a cytokine that has been shown to be a key factor in maintaining immune homeostasis and regulating inflammatory responses at mucosal barriers. Anti-TSLP agents have been proposed for the treatment of a variety of inflammatory conditions (Corren, J., & Ziegler, S. F. (2019). TSLP: from allergy to cancer. Nature immunology, 20(12), 1603–1609). The amino acid sequence of TSLP is SEQ ID NO: 186 and can be found under UniProt Accession No. Q969D9. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 186 and/or the protein level thereof. VEGFA: VEGFA (also known as MVCD1, VEGF, VPF, vascular endothelial growth factor A) encodes a growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. VEGFA induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. VEGFA is a therapeutic target in ovarian cancer (OVCA) (Jang, K., Kim, M., Gilbert, C. A., Simpkins, F., Ince, T. A., & Slingerland, J. M. (2017). VEGFA activates an epigenetic pathway upregulating ovarian cancer- initiating cells. EMBO molecular medicine, 9(3), 304–318). The amino acid sequence of VEGFA is SEQ ID NO: 187 and can be found under UniProt Accession No. P15692. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 187 and/or the protein level thereof. WNT5A: WNT5A (also known as Wingless-Type MMTV Integration Site Family, Member 5A and hWnt family member 5A) encodes a signaling molecule expressed embryonically during gastrulation in various developing body regions including the caudal mesoderm of the primitive streak, lateral mesoderm, cranial neural crest cells, midbrain, frontal face region, limb buds, mammary gland mesenchyme, caudal region, genital primordia and 92 WBD (US) 4854-8046-9185v2 tailbud (Chu, E. Y., Hens, J., Andl, T., Kairo, A., Yamaguchi, T. P., Brisken, C., Glick, A., Wysolmerski, J. J., & Millar, S. E. (2004). Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development (Cambridge, England), 131(19), 4819–4829). WNT5A has oncogenic and tumor suppressive activities (Wang, K., Ma, F., Arai, S., Wang, Y., Varkaris, A., Poluben, L., Voznesensky, O., Xie, F., Zhang, X., Yuan, X., & Balk, S. P. (2023). WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth. Cancer research, 83(7), 1016–1030). The amino acid sequence of WNT5A is SEQ ID NO: 188 and can be found under UniProt Accession No. P41221. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 188 and/or the protein level thereof. BTLA: BTLA (also known as B- and T-lymphocyte attenuator, CD272, BTLA1, B and T lymphocyte associated) encodes a cosignaling molecule that belongs to the CD28 superfamily and is similar to programmed cell death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) in terms of its structure and function. BTLA has been found to participate in numerous physiopathological processes, such as tumor, inflammatory diseases, autoimmune diseases, infectious diseases, and transplantation rejection (Ning, Z., Liu, K., & Xiong, H. (2021). Roles of BTLA in Immunity and Immune Disorders. Frontiers in immunology, 12, 654960). The amino acid sequence of BTLA is SEQ ID NO: 189 and can be found under UniProt Accession No. Q7Z6A9. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 189 and/or the protein level thereof. SEMA4D: SEMA4D (also known as C9orf164, CD100, M-sema-G, SEMAJ, coll-4, semaphorin 4D, COLL4, A8, GR3, BB18) encodes a homodimeric protein belonging to the semaphorin family of axonal guidance proteins. SEMA4D has been described to have immune functions and serves important roles in T cell priming, antibody production, and cell-to-cell adhesion (Maleki, K. T., Cornillet, M., & Björkström, N. K. (2016). Soluble SEMA4D/CD100: 93 WBD (US) 4854-8046-9185v2 A novel immunoregulator in infectious and inflammatory diseases. Clinical immunology (Orlando, Fla.), 163, 52–59). The amino acid sequence of SEMA4D is SEQ ID NO: 190 and can be found under UniProt Accession No. Q92854. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 190 and/or the protein level thereof. LRP6: LRP6 (also known as Low-density lipoprotein receptor-related protein 6, ADCAD2, STHAG7, LDL receptor related protein 6) encodes a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Clinical studies have implicated LRP6 in various kinds of cancer, including bladder and breast cancer (Alrefaei, A. F., & Abu-Elmagd, M. (2022). LRP6 Receptor Plays Essential Functions in Development and Human Diseases. Genes, 13(1), 120). The amino acid sequence of LRP6 is SEQ ID NO: 191 and can be found under UniProt Accession No. O75581. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 191 and/or the protein level thereof. ADGRE5: ADGRE5 (also known as Cluster of differentiation 97, BL-Ac[F2], TM7LN1, CD97, adhesion G protein-coupled receptor E5) encodes a member of the EGF-TM7 family of adhesion G protein-coupled receptors (GPCRs) broadly expressed on leukocytes. ADGRE5 has been found to promote spleen dendritic cell homeostasis through the mechanosensing of red blood cells (Liu, D., Duan, L., Rodda, L. B., Lu, E., Xu, Y., An, J., Qiu, L., Liu, F., Looney, M. R., Yang, Z., Allen, C. D. C., Li, Z., Marson, A., & Cyster, J. G. (2022). CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells. Science (New York, N.Y.), 375(6581), eabi5965). The amino acid sequence of ADGRE5 is SEQ ID NO: 192 and can be found under UniProt Accession No. P48960. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 192 and/or the protein level thereof. 94 WBD (US) 4854-8046-9185v2 APOE: APOE (also known as AD2, APO-E, LDLCQ5, LPG, apolipoprotein E, ApoE4) encodes a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids. Genome-wide association studies and meta-analyses have implicated APOE in several neurodegenerative disorders (Forero DA, López-León S, González-Giraldo Y, Dries DR, Pereira-Morales AJ, Jiménez KM, Franco- Restrepo JE. APOE gene and neuropsychiatric disorders and endophenotypes: A comprehensive review. Am J Med Genet B Neuropsychiatr Genet.2018 Mar;177(2):126-142.). The amino acid sequence of APOE is SEQ ID NO: 193 and can be found under UniProt Accession No. P02649. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 193 and/or the protein level thereof. COL1A2: COL1A2 (also known as Collagen alpha-2(I) chain, OI4, collagen type I alpha 2, collagen type I alpha 2 chain, EDSCV, EDSARTH2) encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues. COL1A2 has been found to mediate the pro- and anti-migratory effects of TBX3 in chondrosarcoma and fibrosarcoma cells respectively (Omar R, Cooper A, Maranyane HM, Zerbini L, Prince S. COL1A2 is a TBX3 target that mediates its impact on fibrosarcoma and chondrosarcoma cell migration. Cancer Lett. 2019 Sep 10;459:227-239). The amino acid sequence of COL1A2 is SEQ ID NO: 194 and can be found under UniProt Accession No. P08123. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 194 and/or the protein level thereof. COL4A2: COL4A2 (also known as Collagen alpha-2(IV) chain, ICH, POREN2, collagen type IV alpha 2, collagen type IV alpha 2 chain, BSVD2) encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. COL4A2 in the ECM has been found to promote osteogenic differentiation of PDLSCs through negative regulation of the Wnt/β-catenin pathway (Wen Y, Yang H, Wu J, Wang A, Chen X, Hu S, Zhang Y, Bai D, Jin Z. COL4A2 in the tissue-specific extracellular matrix plays important role on osteogenic differentiation of periodontal ligament stem cells. Theranostics.2019 May 31;9(15):4265-4286). 95 WBD (US) 4854-8046-9185v2 The amino acid sequence of COL4A2 is SEQ ID NO: 195 and can be found under UniProt Accession No. P08572. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 195 and/or the protein level thereof. COL6A1: COL6A1 (also known as Collagen alpha-1(VI) chain, OPLL, BTHLM1, UCHMD1, collagen type VI alpha 1, collagen type VI alpha 1 chain) encodes the alpha1 polypeptide of collagen VI. COL6A1 has been found to stimulate tumor growth in vivo (Wan F, Wang H, Shen Y, Zhang H, Shi G, Zhu Y, Dai B, Ye D. Upregulation of COL6A1 is predictive of poor prognosis in clear cell renal cell carcinoma patients. Oncotarget.2015 Sep 29;6(29):27378-87). The amino acid sequence of COL6A1 is SEQ ID NO: 196 and can be found under UniProt Accession No. P12109. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 196 and/or the protein level thereof. COL6A2: COL6A2 (also known as Collagen alpha-2(VI) chain, PP3610, BTHLM1, UCMD1, collagen type VI alpha 2, collagen type VI alpha 2 chain) encodes a collagen VI subunit. High expression of COL6A2 has been found to be associated with glioma proliferation, migration, invasion, and immunity (Hong X, Zhang J, Zou J, Ouyang J, Xiao B, Wang P, Peng X. Role of COL6A2 in malignant progression and temozolomide resistance of glioma. Cell Signal. 2023 Feb;102:110560). The amino acid sequence of COL6A2 is SEQ ID NO: 197 and can be found under UniProt Accession No. P12110. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 197 and/or the protein level thereof. COL6A3: COL6A3 (also known as Collagen alpha-3(VI) chain, DYT27, BTHLM1, UCMD1, collagen type VI alpha 3, collagen type VI alpha 3 chain) encodes an alpha chain of type VI collagen that aids in microfibril formation. Increased adipocyte COL6A3 expression has 96 WBD (US) 4854-8046-9185v2 been found to be associated with insulin resistance in humans (Dankel SN, Svärd J, Matthä S, Claussnitzer M, Klöting N, Glunk V, Fandalyuk Z, Grytten E, Solsvik MH, Nielsen HJ, Busch C, Hauner H, Blüher M, Skurk T, Sagen JV, Mellgren G. COL6A3 expression in adipocytes associates with insulin resistance and depends on PPARγ and adipocyte size. Obesity (Silver Spring).2014 Aug;22(8):1807-13). The amino acid sequence of COL6A3 is SEQ ID NO: 198 and can be found under UniProt Accession No. P12111. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 198 and/or the protein level thereof. FGF7: FGF7 (also known as Keratinocyte growth factor, HBGF-7, KGF, fibroblast growth factor 7) encodes a protein that acts as a potent mitogen on epithelial cells, through interaction with the FGF7-specific receptor FGFR2/IIIb. FGF7 has been found to have a role in initiating invasion of prostatic epithelial cells in humans (Ropiquet F, Huguenin S, Villette JM, Ronflé V, Le Brun G, Maitland NJ, Cussenot O, Fiet J, Berthon P. FGF7/KGF triggers cell transformation and invasion on immortalised human prostatic epithelial PNT1A cells. Int J Cancer.1999 Jul 19;82(2):237-43). The amino acid sequence of FGF7 is SEQ ID NO: 199 and can be found under UniProt Accession No. P21781. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 199 and/or the protein level thereof. HLA-E: HLA-E (also known as HLA class I histocompatibility antigen, alpha chain E, MHC class I antigen E, EA1.2, EA2.1, HLA-6.2, MHC, QA1, major histocompatibility complex, class I, E) encodes a heterodimer involved in immune self-nonself discrimination. HLA-E is thought to be a ligand for the innate and adaptive immune system (Kraemer T, Blasczyk R, Bade-Doeding C. HLA-E: a novel player for histocompatibility. J Immunol Res. 2014;2014:352160. doi: 10.1155/2014/352160. Epub 2014 Oct 20). The amino acid sequence of HLA-E is SEQ ID NO: 200 and can be found under UniProt Accession No. P13747. 97 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 200 and/or the protein level thereof. IL6: IL6 (also known as BSF2, HGF, HSF, IFNB2, IL-6, BSF-2, CDF, IFN-beta-2, interleukin 6) encodes an interleukin that acts as both a pro-inflammatory cytokine and an anti- inflammatory myokine. IL-6 blockade has been proposed as a therapeutic strategy for acute systemic and chronic inflammatory diseases (Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL-6) Immunotherapy. Cold Spring Harb Perspect Biol.2018 Aug 1;10(8):a028456). The amino acid sequence of IL6 is SEQ ID NO: 201 and can be found under UniProt Accession No. P05231. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 201 and/or the protein level thereof. LAMB1: LAMB1 (also known as Laminin subunit beta-1, CLM, LIS5, Laminin, beta 1, laminin subunit beta 1) encodes the beta chain of laminin, an extracellular matrix protein. LAMB1 is involved in attachment, migration, and organization during development, and its elevated expression has been associated with several cancers including gastric cancer (Lee H, Kim WJ, Kang HG, Jang JH, Choi IJ, Chun KH, Kim SJ. Upregulation of LAMB1 via ERK/c- Jun Axis Promotes Gastric Cancer Growth and Motility. Int J Mol Sci.2021 Jan 10;22(2):626. doi: 10.3390/ijms22020626). The amino acid sequence of LAMB1 is SEQ ID NO: 202 and can be found under UniProt Accession No. P07942. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 202 and/or the protein level thereof. LAMC1: LAMC1 (also known as Laminin subunit gamma-1, LAMB2, Laminin, gamma 1, laminin subunit gamma 1) encodes the gamma chain of laminin, an extracellular matrix protein. LAMC1 has been proposed as a prognostic factor and a therapeutic target in gastric cancer (Xi D, Jia Q, Liu X, Zhang L, Xu B, Ma Z, Ma Y, Yu Y, Zhang F, Chen H. LAMC1 is a Novel Prognostic Factor and a Potential Therapeutic Target in Gastric Cancer. Int J Gen Med. 98 WBD (US) 4854-8046-9185v2 2022 Mar 19;15:3183-3198). The amino acid sequence of LAMC1 is SEQ ID NO: 203 and can be found under UniProt Accession No. P11047. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 203 and/or the protein level thereof. THBS2: THBS2 (also known as TSP2 and thrombospondin 2) encodes a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. THBS2 has been implicated in poor prognosis and immune infiltration of gastric cancer (Zhang S, Yang H, Xiang X, Liu L, Huang H, Tang G. THBS2 is Closely Related to the Poor Prognosis and Immune Cell Infiltration of Gastric Cancer. Front Genet.2022 Feb 3;13:803460). The amino acid sequence of THBS2 is SEQ ID NO: 204 and can be found under UniProt Accession No. P35442. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 204 and/or the protein level thereof. ALOXA5AP: ALOXA5AP (also known as Arachidonate 5-lipoxygenase-activating protein, 5-lipoxygenase activating protein, FLAP) encodes an integral protein within the nuclear membrane and is necessary for the synthesis of leukotriene, which are lipid mediators of inflammation. ALOX5AP is known to be present in adipose tissue and associated with inflammation and insulin resistance (Kaaman M, Rydén M, Axelsson T, Nordström E, Sicard A, Bouloumié A, Langin D, Arner P, Dahlman I. ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance. Int J Obes (Lond).2006 Mar;30(3):447-52). The amino acid sequence of ALOXA5AP is SEQ ID NO: 205 and can be found under UniProt Accession No. P20292. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 205 and/or the protein level thereof. 99 WBD (US) 4854-8046-9185v2 CALM2: CALM2 (also known as CAMII, PHKD, PHKD2, LQT15, caM, calmodulin 2 (phosphorylase kinase, delta), calmodulin 2, CAMC, CAM1, CAMIII, CAM3, CALM, CALML2) encodes a member of the CALM family that has been found to facilitate gastric cancer metastasis and angiogenesis by modulating the JAK2/STAT3/HIF-1/VEGFA axis and bolstering macrophage polarization (Mu G, Zhu Y, Dong Z, Shi L, Deng Y, Li H. Calmodulin 2 Facilitates Angiogenesis and Metastasis of Gastric Cancer via STAT3/HIF-1A/VEGF-A Mediated Macrophage Polarization. Front Oncol.2021 Sep 15;11:727306. doi: 10.3389/fonc.2021.727306). The amino acid sequence of CALM2 is SEQ ID NO: 206 and can be found under UniProt Accession No. P0DP24. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 206 and/or the protein level thereof. LGALS9: LGALS9 (also known as Galectin-9, HUAT, LGALS9A, galectin 9) encodes a 36 kDa beta-galactoside lectin protein. High LGALS9 expression has been found to be correlated with poor prognosis in multiple human cancers (Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, Yan M, Chang WC, Hsu JM, Cha JH, Hsu JL, Chou CW, Sun X, Deng Y, Chou CK, Yu D, Hung MC. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun.2021 Feb 5;12(1):832). The amino acid sequence of LGALS9 is SEQ ID NO: 207 and can be found under UniProt Accession No. O00182. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 207 and/or the protein level thereof. CDH1: CDH1 (also known as Arc-1, CD324, CDHE, ECAD, LCAM, UVO, cadherin 1, BCDS1, E-cadherin, uvomorulin) encodes a calcium-dependent cell–cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Germline mutations of CDH1 have been found to be associated with the development of multiple cancers (Corso G. Pleiotropic cancer manifestations of germline CDH1 mutations: Risks and management. J Surg Oncol.2022 Jun;125(8):1326-1331. doi: 100 WBD (US) 4854-8046-9185v2 10.1002/jso.26847. Epub 2022 Mar 12). The amino acid sequence of CDH1 is SEQ ID NO: 208 and can be found under UniProt Accession No. P55287. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 208 and/or the protein level thereof. IL22: IL22 (also known as Interleukin-22, IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL- 23, TIFa, zcyto18, interleukin 22) encodes an α-helical cytokine. IL22 has been proposed as a therapeutic target in diseases of the intestine, including inflammatory bowel disease, GvHD, and cancer (Keir M, Yi Y, Lu T, Ghilardi N. The role of IL-22 in intestinal health and disease. J Exp Med.2020 Feb 13;217(3):e20192195). The amino acid sequence of IL22 is SEQ ID NO: 209 and can be found under UniProt Accession No. Q9GZX6. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 209 and/or the protein level thereof. HLA-F: HLA-F (also known as HLA class I histocompatibility antigen, alpha chain F, CDA12, HLA-5.4, HLA-CDA12, major histocompatibility complex, class I, F) encodes a ~40- 41 kDa non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. HLA-F is thought to be involved in viral infections, cancer immunology, and may have a role in fertility and reproduction (Persson G, Jørgensen N, Nilsson LL, Andersen LHJ, Hviid TVF. A role for both HLA-F and HLA-G in reproduction and during pregnancy? Hum Immunol.2020 Apr;81(4):127-133). The amino acid sequence of HLA-F is SEQ ID NO: 210 and can be found under UniProt Accession No. P30511. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 210 and/or the protein level thereof. ANGPTL2: ANGPTL2 (also known as Angiopoietin-related protein 2, angiopoietin-like protein 2, ARP2, HARP, angiopoietin like 2) encodes a member of the vascular endothelial growth factor family that maintains tissue homeostasis by promoting adaptive inflammation and 101 WBD (US) 4854-8046-9185v2 subsequent tissue reconstruction. ANGPTL2 has been found to regulate autophagy and affect the progression of renal fibrosis in diabetic nephropathy (Huang H, Ni H, Ma K, Zou J. ANGPTL2 regulates autophagy through the MEK/ERK/Nrf-1 pathway and affects the progression of renal fibrosis in diabetic nephropathy. Am J Transl Res.2019 Sep 15;11(9):5472-5486). The amino acid sequence of ANGPTL2 is SEQ ID NO: 211 and can be found under UniProt Accession No. Q9UKU9. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 211 and/or the protein level thereof. DLL1: DLL1 (also known as Delta-like protein 1, DELTA1, DL1, Delta, Delta-like 1, delta like canonical Notch ligand 1, NEDBAS) encodes a human homolog of the Notch Delta ligand and is a member of the delta/serrate/jagged family that plays a role in mediating cell fate decisions during hematopoiesis (Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H. Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2. Mol Cell Biol. 2000 Sep;20(18):6913-22). The amino acid sequence of DLL1 is SEQ ID NO: 212 and can be found under UniProt Accession No. O00548. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 212 and/or the protein level thereof. JAG1: JAG1 (also known as Jagged1, ABE2, Gsfabe2, Htu, Ozz, Ser-1, AGS, AHD, AWS, CD339, HJ1, JAGL1, jagged 1, AGS1, DCHE, jagged canonical Notch ligand 1, CMT2HH) encodes a ligand that interact with four receptors in the mammalian Notch signaling pathway which helps to determine cellular fate and is active during many developmental stages. JAG1 has been proposed as a marker of immunotherapy resistance in lung adenocarcinoma (He J, Li L, Lv L, Chen X, Ge M, Ren Y, Tang X, Liu P, Gao W. JAG1 is correlated to suppressive immune microenvironment and predicts immunotherapy resistance in lung adenocarcinoma. Front Oncol.2023 Feb 27;13:1091488). The amino acid sequence of JAG1 is SEQ ID NO: 213 and can be found under UniProt Accession No. P78504. 102 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 213 and/or the protein level thereof. JAG2: JAG2 (also known as Jagged-2, HJ2, SER2, jagged 2, jagged canonical Notch ligand 2, LGMDR27) encodes a ligand that interact with four receptors in the mammalian Notch signaling pathway which helps to determine cellular fate and is active during many developmental stages. JAG2 overexpression has been found to correlate with poor outcomes in oral squamous cell carcinoma (Hatano K, Saigo C, Kito Y, Shibata T, Takeuchi T. Overexpression of JAG2 is related to poor outcomes in oral squamous cell carcinoma. Clin Exp Dent Res.2020 Apr;6(2):174-180). The amino acid sequence of JAG2 is SEQ ID NO: 214 and can be found under UniProt Accession No. Q9Y219. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 214 and/or the protein level thereof. TGFB1: TGFB1 (also known as Transforming growth factor beta 1, CED, DPD1, LAP, TGFB, TGFbeta, transforming growth factor beta 1, IBDIMDE, TGF-beta1) encodes a secreted protein member of the transforming growth factor beta superfamily of cytokines that is involved in cell growth, cell proliferation, cell differentiation, and apoptosis. TGFB1 has been found to enhance intestinal regeneration (Chen L, Dupre A, Qiu X, Pellon-Cardenas O, Walton KD, Wang J, Perekatt AO, Hu W, Spence JR, Verzi MP. TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration. bioRxiv [Preprint].2023 Jan 13:2023.01.13.523825). The amino acid sequence of TGFB1 is SEQ ID NO: 215 and can be found under UniProt Accession No. P01137. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 215 and/or the protein level thereof. TGFB3: TGFB3 (also known as Transforming growth factor beta-3, ARVD, ARVD1, RNHF, TGF-beta3, Transforming growth factor, beta 3, LDS5, transforming growth factor beta 103 WBD (US) 4854-8046-9185v2 3, TGF beta 3) encodes encodes a secreted protein member of the transforming growth factor beta superfamily of cytokines that is involved in cell differentiation, embryogenesis and development. TGFB3 has been identified as a potential mitgator of radiation and chemotherapy induced toxicity (Hanson I, Pitman KE, Edin NFJ. The Role of TGF-β3 in Radiation Response. Int J Mol Sci.2023 Apr 20;24(8):7614). The amino acid sequence of TGFB3 is SEQ ID NO: 216 and can be found under UniProt Accession No. P10600. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 216 and/or the protein level thereof. VEGFC: VEGFC (also known as Vascular endothelial growth factor C, Flt4-L, LMPH1D, VRP, vascular endothelial growth factor C, LMPHM4) encodes a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family that functions to promote the growth of lymphatic vessels. Macrophage produced VEGFC has been found to ameliorate cardiac injury and inflammation (Glinton KE, Ma W, Lantz C, Grigoryeva LS, DeBerge M, Liu X, Febbraio M, Kahn M, Oliver G, Thorp EB. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation. J Clin Invest.2022 May 2;132(9):e140685). The amino acid sequence of VEGFC is SEQ ID NO: 217 and can be found under UniProt Accession No. P49767. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 217 and/or the protein level thereof. PGF: PGF (also known as D12S1900, PGFL, PLGF, PlGF-2, SHGC-10760, Placental growth factor, PIGF) encodes a member of the VEGF (vascular endothelial growth factor) sub- family and plays a key role in angiogenesis and vasculogenesis. High levels of PGF has been associated with diabetic retinopathy in the vitreous of patients (Nguyen QD, De Falco S, Behar- Cohen F, Lam WC, Li X, Reichhart N, Ricci F, Pluim J, Li WW. Placental growth factor and its potential role in diabetic retinopathy and other ocular neovascular diseases. Acta Ophthalmol. 2018 Feb;96(1):e1-e9. doi: 10.1111/aos.13325. Epub 2016 Nov 22). The amino acid sequence of PGF is SEQ ID NO: 218 and can be found under UniProt Accession No. P49763. 104 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 218 and/or the protein level thereof. IL18: IL18 (also known as Interleukin-18, IGIF, IL-18, IL-1g, IL1F4, interleukin 18, interferon-gamma inducing factor) encodes a proinflammatory cytokine. IL18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells (Yasuda K, Nakanishi K, Tsutsui H. Interleukin-18 in Health and Disease. Int J Mol Sci.2019 Feb 2;20(3):649. doi: 10.3390/ijms20030649). The amino acid sequence of IL18 is SEQ ID NO: 219 and can be found under UniProt Accession No. Q14116. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 219 and/or the protein level thereof. APP: APP (also known as Amyloid-beta precursor protein, AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II, PN2, amyloid beta precursor protein, preA4, alpha-sAPP) encodes an integral membrane protein and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is thought to be critical in the pathogenesis of Alzheimer's disease (Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci.2006 Jul 5;26(27):7212-21). The amino acid sequence of APP is SEQ ID NO: 220 and can be found under UniProt Accession No. P05067. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 220 and/or the protein level thereof. TNFSF15: TNFSF15 (also known as TL1, TL1A, VEGI, VEGI192A, Vascular endothelial growth inhibitor, TNLG1B, tumor necrosis factor superfamily member 15, TNF superfamily member 15) encodes an anti-angiogenic protein that belongs to the tumor necrosis factor superfamily. It is the sole ligand of death receptor 3 (Wang EC. On death receptor 3 and 105 WBD (US) 4854-8046-9185v2 its ligands. Immunology.2012 Sep;137(1):114-6). The amino acid sequence of TNFSF15 is SEQ ID NO: 221 and can be found under UniProt Accession No. O95150. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 221 and/or the protein level thereof. VCAM1: VCAM1 (also known as Vascular cell adhesion protein 1, cluster of differentiation 106, CD106, INCAM-100, vascular cell adhesion molecule 1) encodes a cell adhesion molecule and is a member of the immunoglobulin superfamily. VCAM1 has been found to be expressed in a subpopulation of mesenchymal stem cells with unique immunomodulatory properties (Yang ZX, Han ZB, Ji YR, Wang YW, Liang L, Chi Y, Yang SG, Li LN, Luo WF, Li JP, Chen DD, Du WJ, Cao XC, Zhuo GS, Wang T, Han ZC. CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One.2013;8(3):e59354). The amino acid sequence of VCAM1 is SEQ ID NO: 222 and can be found under UniProt Accession No. P19320. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 222 and/or the protein level thereof. ITGAM: ITGAM (also known as CD11B, CR3A, MAC-1, MAC1A, MO1A, SLEB6, integrin subunit alpha M) encodes one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is known to be highly expressed on the surface of innate immune cells, including macrophages and neutrophils (Khan SQ, Khan I, Gupta V. CD11b Activity Modulates Pathogenesis of Lupus Nephritis. Front Med (Lausanne).2018 Mar 15;5:52. doi: 10.3389/fmed.2018.00052). The amino acid sequence of ITGAM is SEQ ID NO: 223 and can be found under UniProt Accession No. P11215. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 223 and/or the protein level thereof. 106 WBD (US) 4854-8046-9185v2 FGF2: FGF2 (also known as basic fibroblast growth factor (bFGF), BFGF, FGF-2, FGFB, HBGF-2, fibroblast growth factor 2) encodes a growth factor and signaling protein involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGF2 is known to interact with APoptosis Inhibitor 5 (API5) to regulate mRNA export (Bong SM, Bae SH, Song B, Gwak H, Yang SW, Kim S, Nam S, Rajalingam K, Oh SJ, Kim TW, Park S, Jang H, Lee BI. Regulation of mRNA export through API5 and nuclear FGF2 interaction. Nucleic Acids Res.2020 Jun 19;48(11):6340-6352). The amino acid sequence of FGF2 is SEQ ID NO: 224 and can be found under UniProt Accession No. P09038. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 224 and/or the protein level thereof. POSTN: POSTN (also known as OSF-2, OSF2, PDLPN, periostin) encodes a ligand for alpha-V/beta-3 and alpha-V/beta-5 integrins to support adhesion and migration of epithelial cells. POSTN has been found to be expressed by mesenchymal stromal cells (Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J. Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells. J Biol Chem.2008 Jun 27;283(26):17991-8001 ). The amino acid sequence of POSTN is SEQ ID NO: 225 and can be found under UniProt Accession No. Q15063. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 225 and/or the protein level thereof. LAMA5: LAMA5 (also known as Laminin subunit alpha-5, Laminin, alpha 5, laminin subunit alpha 5) encodes the alpha subunit of laminin which is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It has been found to play a role in skeletogenesis (Barad M, Csukasi F, Bosakova M, Martin JH, Zhang W, Paige Taylor S, Lachman RS, Zieba J, Bamshad M, Nickerson D, Chong JX, Cohn DH, Krejci P, Krakow D, Duran I. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a 107 WBD (US) 4854-8046-9185v2 distinct bent bone dysplasia. EBioMedicine.2020 Dec;62:103075). The amino acid sequence of LAMA5 is SEQ ID NO: 226 and can be found under UniProt Accession No. O15230. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 226 and/or the protein level thereof. LAMB3: LAMB3 (also known as BM600-125KDA, LAM5, LAMNB1, AI1A, Laminin, beta 3, laminin subunit beta 3, JEB1B, JEB1A) encodes the beta subunit of laminin which is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. LAMB3 has been identified as a potential therapeutic target in colorectal cancer that can be targeted by BET inhibitors and MEK inhibitors (Zhu Z, Song J, Guo Y, Huang Z, Chen X, Dang X, Huang Y, Wang Y, Ou W, Yang Y, Yu W, Liu CY, Cui L. LAMB3 promotes tumour progression through the AKT-FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer. Oncogene.2020 Jun;39(24):4666-4680). The amino acid sequence of LAMB3 is SEQ ID NO: 227 and can be found under UniProt Accession No. Q13751. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 227 and/or the protein level thereof. GZMA: GZMA (also known as Granzyme A, CTLA3, HuTPS, T-cell associated protease 1, cytotoxic T lymphocyte serine protease, TSP-1, T-cell derived serine proteinase) encodes a proinflammatory protease that promotes colorectal cancer development. Extracellular GzmA has been found to induce NF-κB-dependent IL-6 production in macrophages (Santiago L, Castro M, Sanz-Pamplona R, Garzón M, Ramirez-Labrada A, Tapia E, Moreno V, Layunta E, Gil-Gómez G, Garrido M, Peña R, Lanuza PM, Comas L, Jaime-Sanchez P, Uranga-Murillo I, Del Campo R, Pelegrín P, Camerer E, Martínez-Lostao L, Muñoz G, Uranga JA, Alcalde A, Galvez EM, Ferrandez A, Bird PI, Metkar S, Arias MA, Pardo J. Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation. Cell Rep.2020 Jul 7;32(1):107847). The amino acid sequence of GZMA is SEQ ID NO: 228 and can be found under UniProt Accession No. P12544. 108 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 228 and/or the protein level thereof. PRSS3: PRSS3 (also known as MTG, PRSS4, T9, TRY3, TRY4, protease, serine 3, serine protease 3) encodes trypsinogen, which is a member of the trypsin family of serine proteases. PRSS3 has been proposed as a biomarker for invasive ductal carcinoma of the breast (Qian L, Gao X, Huang H, Lu S, Cai Y, Hua Y, Liu Y, Zhang J. PRSS3 is a prognostic marker in invasive ductal carcinoma of the breast. Oncotarget.2017 Mar 28;8(13):21444-21453). The amino acid sequence of PRSS3 is SEQ ID NO: 229 and can be found under UniProt Accession No. P35030. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 229 and/or the protein level thereof. SERPING1: SERPING1 (also known as C1-inh, C1 esterase inhibitor, C1IN, C1INH, C1NH, HAE1, HAE2, serpin family G member 1) encodes a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. Recombinant SERPING1 is used in the treatment of hereditary angioedema (Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B. C1 inhibitor: molecular and clinical aspects. Springer Semin Immunopathol.2005 Nov;27(3):286-98. doi: 10.1007/s00281- 005-0001-4. Epub 2005 Nov 11.). The amino acid sequence of SERPING1 is SEQ ID NO: 230 and can be found under UniProt Accession No. P05155. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 230 and/or the protein level thereof. EDN1: EDN1 (also known as preproendothelin-1, ARCND3, ET1, HDLCQ7, QME, endothelin 1, PPET1) encodes a potent vasoconstrictor peptide produced by vascular endothelial cells and is proteolytically processed to release endothelin 1. EDN1 has been found to be sensitive to glucose and glutamine deprivations (Minchenko DO, Khita OO, Tsymbal DO, 109 WBD (US) 4854-8046-9185v2 Viletska YM, Sliusar MY, Yefimova YV, Levadna LO, Krasnytska DA, Minchenko OH. ERN1 knockdown modifies the impact of glucose and glutamine deprivations on the expression of EDN1 and its receptors in glioma cells. Endocr Regul.2021 May 21;55(2):72-82. doi: 10.2478/enr-2021-0009). The amino acid sequence of EDN1 is SEQ ID NO: 231 and can be found under UniProt Accession No. P05305. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 231 and/or the protein level thereof. EDN3: EDN3 (also known as ET-3, ET3, HSCR4, PPET3, WS4B, endothelin 3) encodes an endothelium-derived vasoactive peptide. EDN3 is a frequent target of epigenetic inactivation in human breast cancer and has been proposed to act as a natural tumor suppressor in the human mammary gland (Wiesmann F, Veeck J, Galm O, Hartmann A, Esteller M, Knüchel R, Dahl E. Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer. Breast Cancer Res.2009;11(3):R34. doi: 10.1186/bcr2319. Epub 2009 Jun 15). The amino acid sequence of EDN3 is SEQ ID NO: 232 and can be found under UniProt Accession No. P14138. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 232 and/or the protein level thereof. HLA.DRA: HLA.DRA (also known as HLA-DRA, HLA class II histocompatibility antigen, DR alpha chain, HLA-DRA1, MLRW, major histocompatibility complex, class II, DR alpha) encodes the the alpha subunit of HLA-DR, which plays a central role in the immune system by presenting peptides derived from extracellular proteins. HLA-DRA has been proposed to identify immuno-hot tumors and predict the therapeutic response to anti-PD-1 immunotherapy in NSCLC (Mei J, Jiang G, Chen Y, Xu Y, Wan Y, Chen R, Liu F, Mao W, Zheng M, Xu J. HLA class II molecule HLA-DRA identifies immuno-hot tumors and predicts the therapeutic response to anti-PD-1 immunotherapy in NSCLC. BMC Cancer.2022 Jul 6;22(1):738. doi: 10.1186/s12885-022-09840-6). The amino acid sequence of HLA.DRA is SEQ ID NO: 233 and can be found under UniProt Accession No. P01903. 110 WBD (US) 4854-8046-9185v2 In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 233 and/or the protein level thereof. CD1D: CD1D (also known as CD1A, R3, R3G1) encodes a member of the family of glycoproteins expressed on the surface of various human antigen-presenting cells. CD1d- deficient macrophages have been found to exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import (Brailey PM, Evans L, López-Rodríguez JC, Sinadinos A, Tyrrel V, Kelly G, O'Donnell V, Ghazal P, John S, Barral P. CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses. Nat Commun.2022 Nov 7;13(1):6723. doi: 10.1038/s41467-022-34532-x). The amino acid sequence of CD1D is SEQ ID NO: 234 and can be found under UniProt Accession No. P15813. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 234 and/or the protein level thereof. TNFSF10: TNFSF10 (also known as APO2L, Apo-2L, CD253, TL2, TRAIL, TNLG6A, tumor necrosis factor superfamily member 10, TNF superfamily member 10) encodes a cytokine that is produced and secreted by most normal tissue cells and is involved in the apoptosis of tumor cells. TNFSF10 has been found to be a prognostic and immune infiltration marker in skin cutaneous melanoma (Xue L, Zhang W, Ju Y, Xu X, Bo H, Zhong X, Hu Z, Zheng C, Fang B, Tang S. TNFSF10, an autophagy related gene, was a prognostic and immune infiltration marker in skin cutaneous melanoma. J Cancer.2023 Jul 31;14(13):2417-2430. doi: 10.7150/jca.86735). The amino acid sequence of TNFSF10 is SEQ ID NO: 235 and can be found under UniProt Accession No. P50591. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 235 and/or the protein level thereof. 111 WBD (US) 4854-8046-9185v2 VWF: VWF (also known as F8VWD and von Willebrand factor) encodes a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF in endothelium, megakaryocytes, and subendothelial connective tissue (Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem.1998;67:395-424. doi: 10.1146/annurev.biochem.67.1.395.). The amino acid sequence of VWF is SEQ ID NO: 236 and can be found under UniProt Accession No. P04275. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 236 and/or the protein level thereof. LIF: LIF (also known as CDF, DIA, HILDA, MLPLI, leukemia inhibitory factor, interleukin 6 family cytokine, LIF interleukin 6 family cytokine) encodes an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. LIF expression has been linked to hallmarks of cancer, such as proliferation, metastasis, and chemoresistance, as well as overall patient survival (Jorgensen MM, de la Puente P. Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer. Biomolecules.2022 Jan 27;12(2):217. doi: 10.3390/biom12020217). The amino acid sequence of LIF is SEQ ID NO: 237 and can be found under UniProt Accession No. P15018. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 237 and/or the protein level thereof. ADAM12: ADAM12 (also known as Disintegrin and metalloproteinase domain- containing protein 12, Meltrin, ADAM12-OT1, CAR10, MCMP, MCMPMltna, MLTN, MLTNA, ADAM metallopeptidase domain 12) encodes a membrane-anchored protein implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, such as fertilization, muscle development, and neurogenesis. High expression of ADAM12 has been implicated in poor prognosis for patients with primary liver cancer (Du S, Sun L, Wang Y, Zhu W, Gao J, Pei W, Zhang Y. ADAM12 is an independent predictor of poor prognosis in liver cancer. Sci Rep.2022 Apr 22;12(1):6634. doi: 10.1038/s41598-022-10608-y). The amino acid 112 WBD (US) 4854-8046-9185v2 sequence of ADAM12 is SEQ ID NO: 238 and can be found under UniProt Accession No. O43184. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 238 and/or the protein level thereof. HLA-DQB1: HLA-DQB1 (also known as Major histocompatibility complex, class II, DQ beta 1, CELIAC1, HLA-DQB, IDDM1, major histocompatibility complex, class II, DQ beta 1, HLA-DRB1) encodes one of two proteins that are required to form the DQ heterodimer, a cell surface receptor essential to the function of the immune system. HLA-DQB1 polymorphisms have been found to be associated with rheumatoid arthritis (Wu J, Li J, Li S, Zhang TP, Li LJ, Lv TT, Pan HF, Ye DQ. Association of HLA-DQB1 polymorphisms with rheumatoid arthritis: a meta-analysis. Postgrad Med J.2017 Oct;93(1104):618-625. doi: 10.1136/postgradmedj-2016- 134724. Epub 2017 Apr 28). The amino acid sequence of HLA-DQB1 is SEQ ID NO: 239 and can be found under UniProt Accession No. P01920. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 239 and/or the protein level thereof. GZMB: GZMB (also known as CCPI, CGL-1, CGL1, CSP-B, CSPB, CTLA1, CTSGL1, HLP, SECT, granzyme B, C11) encodes a serine protease expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. GZMB expression is known to be elevated in chronic disease and inflammatory skin disorders, such as diabetic ulcers, hypertrophic scarring, autoimmune skin disorders, cutaneous leishmaniasis and aging skin (Turner CT, Lim D, Granville DJ. Granzyme B in skin inflammation and disease. Matrix Biol.2019 Jan;75-76:126- 140. doi: 10.1016/j.matbio.2017.12.005. Epub 2017 Dec 14). The amino acid sequence of GZMB is SEQ ID NO: 240 and can be found under UniProt Accession No. P10144. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 240 and/or the protein level thereof. 113 WBD (US) 4854-8046-9185v2 CCL20: CCL20 (also known as CKb4, Exodus, LARC, MIP-3-alpha, MIP-3a, MIP3A, SCYA20, ST38, chemokine (C-C motif) ligand 20, C-C motif chemokine ligand 20, Macrophage Inflammatory Protein-3, liver activation regulated chemokine) encodes a small cytokine belonging to the CC chemokine family and that attracts immature dendritic cells and memory T lymphocytes. CCL20 has been found to be primarily produced by epithelial cells and inflammatory conditions are known to increase its expression (Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev.2021 Jul;20(7):102846. doi: 10.1016/j.autrev.2021.102846). The amino acid sequence of CCL20 is SEQ ID NO: 241 and can be found under UniProt Accession No. P78556. In one embodiment, the methods disclosed herein include determining a level of expression of a gene (mRNA response marker) encoding SEQ ID NO: 241 and/or the protein level thereof. In certain embodiments, the response markers are selected from any one of (or a combination of, or combinations of) CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, 114 WBD (US) 4854-8046-9185v2 NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and CCL20. In an embodiment, a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty- five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty- five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty-nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, at least seventy-two, at least seventy-three, at least seventy-four, at least seventy-five, at least seventy-six, at least seventy-seven, at least seventy-eight, at least seventy-nine, at least eighty, at least eighty-one, at least eighty-two, at least eighty-three, at least eighty-four, at least eighty-five, at least eighty-six, at least eighty-seven, at least eighty-eight, at least eighty-nine, at least ninety, at least ninety-one, at least ninety-two, at least ninety-three, at least ninety-four, at least ninety- five, at least ninety-six, at least ninety-seven, at least ninety-eight, at least ninety-nine, at least one hundred or more biomarkers selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, 115 WBD (US) 4854-8046-9185v2 IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL- 11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and CCL20. In an embodiment, a human subject having moderately-to-severely active ulcerative colitis is predicted not to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least 116 WBD (US) 4854-8046-9185v2 thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty- four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty- nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty-nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty- five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, at least seventy-two, at least seventy-three, at least seventy-four, at least seventy-five, at least seventy-six, at least seventy-seven, at least seventy-eight, at least seventy- nine, at least eighty, at least eighty-one, at least eighty-two, at least eighty-three, at least eighty- four, at least eighty-five, at least eighty-six, at least eighty-seven, at least eighty-eight, at least eighty-nine, at least ninety, at least ninety-one, at least ninety-two, at least ninety-three, at least ninety-four, at least ninety-five, at least ninety-six, at least ninety-seven, at least ninety-eight, at least ninety-nine or more biomarkers selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL- 11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, 117 WBD (US) 4854-8046-9185v2 COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and CCL20. While individual markers are useful in identifying a subject having ulcerative colitis who will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin, a combination of markers may also be used to provide a greater predictive value of response or non-response to treatment. Specifically, the detection of a plurality (or combination) of markers can increase the accuracy, sensitivity, and/or specificity of the prediction. Accordingly, the present invention includes the individual markers described herein, as well as marker combinations, and their use in methods, composition and systems described herein. Optionally, the methods may include the measurement of at least one additional marker to facilitate identifying a subject having ulcerative colitis who will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin. Determining whether a level of a biomarker in a biological sample derived from a “test” subject is different from the level of the biomarker present in a control (e.g., non-response control) subject may be ascertained by comparing the level of the biomarker in the sample from the “test” subject with a suitable control of the same biomarker. The skilled person can select an appropriate control for the assay in question. For example, a suitable control may be a biological sample derived from a known subject (e.g., a non-response control, or e.g., a standard control level, or e.g., a known standard, or, e.g., a reference level). In another example related to mucosal tissue biopsy sample in a UC patient, a control level can result from measurement of the level of a marker in a non-inflamed sample from the patient, such as a non-inflamed colonic biopsy distal from the site where an inflamed biopsy is harvested. Generally, a suitable control may also be a reference standard. A reference standard serves as a reference level for comparison, such that test samples can be compared to the reference standard in order to predict if a UC patient will respond or not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin. A reference standard may be representative of the level of one or more biomarkers in a sample from a known subject, e.g., a subject known to respond to treatment or a subject known to not respond to 118 WBD (US) 4854-8046-9185v2 treatment with an antibody having binding specificity for human α4β7 integrin. Likewise, a reference standard may be representative of the level of one or more biomarkers in a population of known subjects, e.g., a population of subjects known to respond to treatment or a population of subjects known to not respond to treatment with an antibody having binding specificity for human α4β7 integrin. The reference standard may be obtained, for example, by pooling samples from a plurality of individuals and determining the level of a biomarker in the pooled samples, to thereby produce a standard over an averaged population. Such a reference standard represents an average level of a biomarker among a population of individuals. A reference standard may also be obtained, for example, by averaging the level of a biomarker determined to be present in individual samples obtained from a plurality of individuals. Such a standard is also representative of an average level of a biomarker among a population of individuals. A reference standard may also be a collection of values each representing the level of a biomarker in a known subject in a population of individuals. In certain embodiments, test samples may be compared against such a collection of values in order to determine if a subject with UC will respond or not respond to treatment with an antibody having binding specificity for human α4β7 integrin. In certain embodiments, the reference standard is an absolute value. In such embodiments, test samples may be compared against the absolute value in order to determine if a subject with UC will respond or not respond to treatment with an antibody having binding specificity for human α4β7 integrin. In one embodiment, a comparison between the level of at least one biomarker in a sample relative to a suitable control is made by executing a software classification algorithm. The skilled person can readily envision additional suitable controls that may be appropriate depending on the assay in question. The aforementioned suitable controls are exemplary, and are not intended to be limiting. In certain embodiments, a human subject having ulcerative colitis is determined to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin if the level of the at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, 119 WBD (US) 4854-8046-9185v2 CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 in a biological sample correlates with a reference level for a human subject who has responded to treatment with the humanized antibody. In certain embodiments, a human subject having ulcerative colitis is determined to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin if the level of the at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, 120 WBD (US) 4854-8046-9185v2 CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 in a biological sample correlates with a reference level for a human subject who has not responded to treatment with the humanized antibody. In certain embodiments, a human subject having ulcerative colitis is treated by determining an expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, 121 WBD (US) 4854-8046-9185v2 CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 in a biological sample, determining that the level correlates with a reference level for a human subject with UC who has responded to treatment with a humanized antibody having binding specificity for human α4β7 integrin, and administering a humanized antibody having binding specificity for human α4β7 integrin to treat the human subject. In certain embodiments, a human subject having ulcerative colitis is treated by determining an expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, 122 WBD (US) 4854-8046-9185v2 WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 in a biological sample, determining that the level correlates with a reference level for a human subject with UC who has not responded to treatment with a humanized antibody having binding specificity for human α4β7 integrin, and administering a humanized antibody having binding specificity for human α4β7 integrin at a higher dose, with more frequent dosing, or in combination with another agent to treat the human subject. In certain embodiments, the humanized antibody having binding specificity for human α4β7 integrin is given in combination with another agent such as a JAK inhibitor, an anti-TNFα inhibitor, or an IL-23 inhibitor. In some embodiments, the other agent given in combination with the humanized antibody having binding specificity for human α4β7 integrin is infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, risankizumab, guselkumab, mirikizumab, or tofacitinib to treat a UC patient predicted to not respond to treatment with an anti-α4β7 integrin antibody. In certain embodiments, the human subject having ulcerative colitis has not previously received an anti-α4β7 integrin antibody for treatment. In certain embodiments, the human subject having ulcerative colitis is treatment naïve or not previously exposed to biologic therapy. Multiple studies have shown that IBD patients with no prior use of anti-TNFα agents were significantly more likely to respond to VDZ treatment compared to patients previously exposed to anti-TNFα agents (Sands BE, et al., Inflamm Bowel Dis. (2017); Stallmach A, et al., Aliment Pharmacol Therapeut. (2016); Narula N, et al., Am J Gastroenterol. (2018)). One possible explanation for this difference in response rates is that the failure of anti-TNFα agents may lead to increased immunogenicity, which might affect the efficacy of a subsequent biological treatment such as vedolizumab. In other embodiments, the human subject having ulcerative colitis had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof. 123 WBD (US) 4854-8046-9185v2 In certain embodiments, the mRNA expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 is determined from cells collected from a peripheral blood sample (i.e., PBMCs) or a gut mucosal biopsy sample from a human subject having ulcerative colitis. Subsets of PBMCs may include myeloid cells, including monocytes, natural killer cells (NKs) and innate lymphoid cells (ILCs), B cells, and T cells, including regulatory T cells (Tregs). In certain embodiments, the protein expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, 124 WBD (US) 4854-8046-9185v2 DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 is determined from cells collected from a peripheral blood sample (i.e., PBMCs) or a gut mucosal biopsy sample from a human subject having ulcerative colitis. Subsets of PBMCs may include myeloid cells, including monocytes, natural killer cells (NKs) and innate lymphoid cells (ILCs), B cells, and T cells, including regulatory T cells (Tregs). In an embodiment, PBMCs may include CD4+ T cells, such as CD4+ naïve cells, CD4+ TCM cells, CD4+ TEM cells, CD4+ CTL cells, CD4+ proliferating cells, and/or Tregs. In another embodiment, PBMCs may include CD8+ T cells, such as CD8+ naïve cells, CD8+ TCM cells, CD8+ TEM cells, CD8+ proliferating cells, and/or MAIT cells. In another embodiment, PBMCs may include Gamma delta (γδ) T cells and/or CD3+CD4−CD8− T cells (double- negative T cells; DNT cells). In another embodiment, PBMCs may include B cells, such as naïve 125 WBD (US) 4854-8046-9185v2 B cells, intermediate B cells, memory B cells, and/or plasmablasts. In another embodiment, PBMCs may include NK cells, such as CD56bright NK cells and/or proliferating NK cells. In another embodiment, PBMCs may include myeloid cells, such as conventional type 1 dendritic cells (cDC1s), conventional type 2 dendritic cells (cDC1s), plasmacytoid dendritic cells (pDCs), ASDCs (AXL+SIGLEC6+ dendritic cells), CD14+ monocytes, and/or CD16+ monocytes. In some embodiments, PBMCs may include erythrocytes, hematopoietic stem and progenitor cells (HSPCs), and/or platelet cells. Subsets of gut mucosal biopsy cells may include epithelial cells, including M cells, fibroblasts, including inflammatory fibroblasts, myeloid cells, including dendritic cells and inflammatory monocytes, B cells, and T cells, including Tregs and CD8 positive/IL17 positive T cells, NKs, and ILCs. M cells (microfold cells) are specialized intestinal epithelial cells that primarily overlie GALT structures, such as Peyer's patches in ileum. Secretory CD8 positive/IL17 positive T cells make pro-inflammatory cytokine IL17A. In an embodiment, gut mucosal biopsy cells may include T cells, such as CD4+ activated Fos-hi cells, CD4+ activated Fos-lo cells, CD4+ memory cells, CD+ PD1+ cells, Tregs, CD8+ intraepithelial intestinal lymphocytes (IELs), CD8+ IL17+ cells, CD8+ lymphocyte-predominant (LP) cells, and/or cycling cells. In an embodiment, gut mucosal biopsy cells may include B cells, such as follicular B cells, germinal center (GC) B cells, and/or cycling B cells. In an embodiment, gut mucosal biopsy cells may include IgA cells, IgG cells, IgM cells, or Ig-negative cells. In an embodiment, gut mucosal biopsy cells may include myeloid cells, NK cells, and/or ILCs. In an embodiment, gut mucosal biopsy cells may include CD69- mast cells, CD69+ mast cells, macrophages, inflammatory monocytes, DC1 cells, DC2 cells, pDC cells. In an embodiment, gut mucosal biopsy cells may include enterocytes, for example, BEST4+ enterocytes. In another embodiment, gut mucosal biopsy cells may include enterocyte progenitors, immature enterocytes 1, and/or immature enterocytes 2. In another embodiment, gut mucosal biopsy cells may include secretory cells, such as enteroendocrine cells, goblet cells, immature goblet cells, tuft cells, Paneth-like cells, and M cells. In another embodiment, gut mucosal biopsy cells may include stem cells, transit-amplifying (TA) 1 cells, transit-amplifying (TA) 2 cells, secretory TA cells, and/or cycling TA cells. In some embodiments, gut mucosal cells may include post-capillary venules, microvascular cells, endothelial cells, and/or pericytes. In another embodiment, gut mucosal cells 126 WBD (US) 4854-8046-9185v2 may include myofibroblasts, WNT5B+ 2 cells, WNT5B+ 1 cells, WNT2B+ Fos-lo 1 cells, WNT2B+ Fos-lo 2 cells, WNT2B+ Fos-hi cells, RSPO3+ cells, and/or inflammatory fibroblasts. In some embodiments, gut mucosal cells may include glia. In certain embodiments, the expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, ITGB2, PECAM1, MIF, NAMPT, LGALS9, CD99, HLA-F, IL10, ADGRE5, VCAM1, VEGFA, AREG, CD46, CXCL10, HBEGF, HLA-DRB1, ICAM1, SELL, TNFSF13B, ITGA5, CXCR4, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, IL1RAP, FPR2, IL1R1, TGM2 , S10011A, S100A6, S100A4, LGALS1, LGALS3, SELE, LTB, OSM, ALOX5, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, IL6ST/LIFR, and/or HLA-E is determined in colonic inflammatory monocytes. In another embodiment, the inflammatory monocytes express galectin-3 and CD68 at immunofluorescence staining. In an embodiment, cell-types (e.g., inflammatory monocytes) as described herein are based on the annotations described in Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019). In certain embodiments, the expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, 127 WBD (US) 4854-8046-9185v2 CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, ITGB2, PECAM1, MIF, NAMPT, LGALS9, CD99, HLA-F, IL10, ADGRE5, VCAM1, VEGFA, AREG, CD46, CXCL10, HBEGF, HLA-DRB1, ICAM1, SELL, TNFSF13B, ITGA5, CXCR4, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, IL1RAP, FPR2, and/or IL1R1 is determined in colonic inflammatory monocytes and the human subject is determined to respond to treatment. In certain embodiments, the expression level of at least one response marker selected from the group consisting of TREM1, TGM2 , S10011A, S100A6, S100A4, LGALS1, LGALS3, SELE, LTB, OSM, CXCL10, IL1R1, IL1RAP, ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, IL6ST, MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, IL6ST/LIFR, ADGRE5, HLA-E, ITGB2, and/or CXCR4 is determined in colonic inflammatory monocytes and the human subject is determined to not respond to treatment. In certain embodiments, the expression level of at least one response marker selected from RGS2 and MAFB is determined in colonic mucosal macrophages. In certain embodiments, the expression level of at least one response marker selected from RGS2 and MAFB is determined in colonic mucosal macrophages and the human subject is determined to respond to treatment. In certain embodiments, the expression level of at least one response marker selected from the group consisting of ADAM17, TNF, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, TNFRSF25, HLA-F, SEMA4D, BTLA, ITGB2, ITGAL, CD28, CD46, ITGA4, LTB, CD44, IL1R2, IL1R1, IL12RB, CXCR4, ITGB1, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, ALOXA5AP, CALM2, AREG, and/or HLA-E is determined in regulatory T cells (Tregs). In certain embodiments, the expression level of at least one response marker selected from the group consisting of ADAM17, TNF, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, TNFRSF25, HLA-F, SEMA4D, BTLA, ITGB2, ITGAL, CD28, CD46, ITGA4, LTB, CD44, IL1R2, and/or IL1R1 is determined in Tregs and the human subject is determined to respond to treatment. 128 WBD (US) 4854-8046-9185v2 In certain embodiments, the expression level of at least one response marker selected from the group consisting of IL12RB, IL2RG, TNFRSF1B, CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, CCR6, ALOXA5AP, CALM2, AREG, and/or HLA-E is determined in Tregs and the human subject is determined to not respond to treatment. In certain embodiments, the expression level of at least one response marker selected from the group consisting of TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, CD74, MIF, THBS2, CD99, ANGPTL2, LAMA2, LAMB2, DLL1, TSLP, CD40, IL11, VEGFA, FGF, POSTN, LAMA4, LAMB1, LAMC1, COL1A2, COL4A2, COL6A1, COL6A3, TNC, BMP7, ANXA1, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, IL-11, NAMPT, NRG1, WNT5A, ITGB1, LRP6, ITGB8, CXCL12, CXCL16, CCL2, MYLK, ITGA1, SDC4_ITGB1, RPSA, IL6ST/LIFR, APOE, COL6A2, FGF7, HLA-E, and/or IL6 is determined in inflammatory fibroblasts. In certain embodiments, the expression level of at least one response marker selected from the group consisting of TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, CD74, MIF, THBS2, CD99, ANGPTL2, LAMA2, LAMB2, DLL1, TSLP, CD40, IL11, VEGFA, FGF, POSTN, LAMA4, LAMB1, LAMC1, COL1A2, COL4A2, COL6A1, COL6A3, TNC, BMP7, ANXA1, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, IL-11, NAMPT, NRG1, WNT5A, ITGB1, LRP6, and/or ITGB8 is determined in inflammatory fibroblasts and the human subject is determined to respond to treatment. In certain embodiments, the expression level of at least one response marker selected from the group consisting of CXCL12, CXCL16, CCL2, MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, IL6ST/LIFR, APOE, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, and/or ITGB1 is determined in inflammatory fibroblasts and the human subject is determined to not respond to treatment. 129 WBD (US) 4854-8046-9185v2 In certain embodiments, the expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 is determined in cells from a subject with UC collected within two weeks prior to treatment. In certain embodiments, the expression level of at least one response marker is determined in cells from a subject with UC 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 0 days prior to treatment. In certain embodiments, the expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, 130 WBD (US) 4854-8046-9185v2 ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 is determined in a biological sample from a UC patient only with left- sided disease or pancolitis (i.e., not a patient with exclusively right-sided disease). In certain embodiments, response is evaluated at 14 weeks after the start of treatment with a humanized antibody having binding specificity for human α4β7 integrin, such as vedolizumab. In an embodiment, response is evaluated by Physician Global Assessment (PGA). In an embodiment, PGA incorporates clinical response, endoscopic response and biochemical measurements such as C-Reactive Protein, hemoglobin, and calprotectin. In an embodiment, PGA is scored by three independent physicians. In certain embodiments, response is evaluated by Mayo score (i.e., Mayo Scoring System for Assessment of Ulcerative Colitis Activity). In an embodiment, a response with reference to ulcerative colitis subjects refers to a reduction in complete Mayo score of 3 or greater points and 30% from baseline, (or a partial Mayo score of 2 or greater points and 25% or greater from 131 WBD (US) 4854-8046-9185v2 baseline, if the complete Mayo score was not performed at the visit) with an accompanying decrease in rectal bleeding subscore of 1 or greater points or absolute rectal bleeding score of 1 or less point. In certain embodiments, clinical remission as used herein with reference to ulcerative colitis subjects refers to a complete Mayo score of 2 or less points and no individual subscore greater than 1 point. In certain embodiments, clinical remission with reference to ulcerative colitis subjects refers to a stool frequency (SF) subscore ≤1, a rectal bleeding subscore (RBS) of 0, and an endoscopic subscore of ≤1. The SF subscore, rectal bleeding subscore, and endoscopic subscore refer to the subscores used in the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. This is also referred to as “clinical remission per Adapted Mayo Score”. In an embodiment, a response with reference to ulcerative colitis subjects refers to a decrease from baseline in the Adapted Mayo score ≥2 points and ≥30% from baseline accompanied by a decrease in RBS≥1 or an absolute RBS≤1. In certain embodiments, a response with reference to ulcerative colitis subjects refers to at least one response selected from the group consisting of a clinical response of a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding, endoscopic response, and mucosal healing. In certain embodiments, a responder has corticosteroid-free [CSF] symptomatic remission. In other embodiments, a responder has corticosteroid-free [CSF] symptomatic remission and corticosteroid-free [CSF] endoscopic remission. In other embodiments, a responder has corticosteroid-free [CSF] symptomatic remission, corticosteroid-free [CSF] endoscopic remission, and corticosteroid-free [CSF] histologic remission. CSF symptomatic remission is defined as Mayo rectal bleeding subscore=0, CSF endoscopic remission is defined as Mayo Endoscopic Score [MES]≤1, and CSF histologic remission is defined as Geboes score<2B.0. The level of one or more mRNA biomarkers in a biological sample may be determined by any suitable method. Any reliable method for measuring the level or amount of mRNA in a sample may be used. Generally, mRNA can be detected and quantified from a sample (including fractions thereof), such as samples of isolated RNA by various methods known for mRNA, including, for example, amplification-based methods (e.g., Polymerase Chain Reaction (PCR), 132 WBD (US) 4854-8046-9185v2 Real-Time Polymerase Chain Reaction (RT-PCR), Quantitative Polymerase Chain Reaction (qPCR), rolling circle amplification, etc.), hybridization-based methods (e.g., hybridization arrays (e.g., microarrays), NanoString analysis, Northern Blot analysis, branched DNA (bDNA) signal amplification, in situ hybridization, etc.), and sequencing-based methods (e.g., transcriptome sequencing via next-generation sequencing methods, for example, using a MGI2000 sequencer or Illumina or IonTorrent platforms). In some embodiments, RNA is converted to DNA (cDNA) prior to analysis. cDNA can be generated by reverse transcription of isolated mRNA using conventional techniques. Other exemplary techniques include ribonuclease protection assay (RPA) and mass spectroscopy. In one embodiment, the level of the mRNA in a sample is determined using quantitative PCR (qPCR) or a Northern blot. In certain embodiments, the protein product of one or more biomarkers in a biological sample may be determined by any suitable method. In certain embodiments, it may be possible to assay for the expression of one or more biomarkers at the protein level using a detection reagent that detects the protein product encoded by the mRNA of the biomarker(s). In some embodiments of the present teachings an antibody binding assay is used to detect a protein biomarker; e.g., a sample from the subject is contacted with an antibody reagent that binds the biomarker analyte, a reaction product (or complex) comprising the antibody reagent and analyte is generated, and the presence (or absence) or amount of the complex is determined. The antibody reagent useful in detecting biomarker analytes can be monoclonal, polyclonal, chimeric, recombinant, or a fragment of the foregoing, and the step of detecting the reaction product can be carried out with any suitable immunoassay. For example, if an antibody reagent is available that binds specifically to the biomarker protein product to be detected, and not to other proteins, then such an antibody reagent can be used to detect the expression of the biomarker of interest in a cellular sample from the subject, or a preparation derived from the cellular sample, using standard antibody-based techniques known in the art, such as flow cytometry (e.g., Fluorescence-Activated Cell Sorting (FACS); multi-color flow cytometry), mass cytometry (CyTOF), immunohistochemistry, oligonucleotide sequencing (e.g., CITE-Seq), ELISA and the like. In one embodiment, the protein product of one or more biomarkers in a biological sample is determined by flow cytometry (e.g., FACS). 133 WBD (US) 4854-8046-9185v2 In one embodiment, the protein product of one or more biomarkers in a biological sample is determined by mass cytometry (e.g., CyTOF). In one embodiment, the protein product of one or more biomarkers in a biological sample is determined by immunohistochemistry. In certain embodiments, the present invention involves detection of biomarkers by in situ hybridization. In certain embodiments, the present invention involves single cell RNA sequencing (scRNAseq). In certain embodiments, the invention involves high-throughput single-cell RNA-seq where the RNAs from different cells are tagged individually, allowing a single library to be created while retaining the cell identity of each read. In this regard, reference is made to Stoeckius, M. et al. “Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics”. Genome Biol 19, 224 (2018). It will be readily understood by the ordinarily skilled artisan that essentially any technical means established in the art for detecting biomarkers, at either the nucleic acid or protein level, can be adapted to detection of the biomarkers discussed herein and applied in the methods of the current invention. In certain embodiments, the expression level of at least one response marker selected from the group consisting of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, IL1RN, PLAU, SMAD3, REV3L, HCAR3, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, PDPN, RGS2, MAFB, CCL2, ANXA1, ADAM17, TNF, CCL3, CCL4, CXCL2, CXCL3, S10011A, S100A6, S100A4, LGALS1, LGALS3, TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4, WNT2B, CCL5, CEBPB, IL23A, DCHS2, SELE, LTB, OSM, CXCL10, SEC63, TNFRSF17, TNFRSF13C, SDC1, ITGB1, IL17RA, IL10RA, IFNGR1, IFNGR2, IL1R1, IL1RAP, TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL7R, TNFRSF14, IL12RB, TNFRSF1B, IL-11, CXCL12, CXCL16, ICAM1, PECAM1, CXCR4, CD44, PTPRC, ITGAE, ITGA5, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, TLR4, ITGA4, CD47, NOTCH2, TGFBR2, NRP2, CD99, TIGIT, IL6ST, TGFB2, CD74, TNFRSF25, CD55, NRP1, FGFR1, ITGAV, JAM3, JAM2, F11R, PTPRM, ITGA8, ACVR1, BMPR2, F2R, TGFBR1, LRP1, EDNRB, ITGB5, ITGB8, ACVRL1, GLG1, ITGA6, 134 WBD (US) 4854-8046-9185v2 ALOX5, CD4, CEACAM5, ITGAX, TNFRSF10B, CSF3R, CSF1R, LILRB3, FPR3, CD28, CTLA4, IGF2R, ITGAL, RPSA, MYLK, ITGA1, SDC4, ITGB2, TNFRSF10D, FPR2, LIFR, AREG, CD46, HBEGF, HLA-DRB1, IL10, SELL, TNFSF13B, BMP7, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, LAMA2, LAMB2, MIF, NAMPT, NRG1, TNC, TSLP, VEGFA, WNT5A, LRP6, BTLA, SEMA4D, ADGRE5, APOE, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, FGF7, HLA-E, IL6, LAMB1, LAMC1, THBS2, ALOXA5AP, CALM2, LGALS9, CDH1, IL22, HLA-F, ANGPTL2, DLL1, JAG1, JAG2, TGFB1, TGFB3, VEGFC, PGF, IL18, APP, TNFSF15, VCAM1, ITGAM, FGF2, POSTN, LAMA5, LAMB3, GZMA, PRSS3, SERPING1, EDN1, EDN3, HLA.DRA, CD1D, TNFSF10, VWF, LIF, ADAM12, HLA-DQB1, GZMB, and/or CCL20 is determined in a biological sample from a UC patient using single cell RNA sequencing (RNAseq). The molecular signatures identified by single cell RNAseq can include cytokines gene signatures, transcription factors gene signatures, lipopolysaccharide (LPS) signatures, immune complexes (IC) signatures, and resident macrophage genes signatures. In this regard, reference is made to Uzzan et al. Nat Med.2022 Apr;28(4):766-779. doi: 10.1038/s41591-022-01680-y. In certain embodiments, a human subject having ulcerative colitis is determined to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin based on measurements of cell level. In some embodiments, the level of dendritic cells (DCs), innate lymphoid cells (ILCs), natural killer (NK) cells, and/or inflammatory monocytes is measured. Applicant found that increased level of DCs, ILCs, NK cells, and/or inflammatory monocytes in the colonic mucosa is associated with non-response to treatment with vedolizumab in patients with UC. Thus, in some embodiments, an increased level of DCs, ILCs, NK cells, and/or inflammatory monocytes in a biological sample from a human subject with UC relative to a response control indicates that the human subject will not respond to treatment with vedolizumab. In addition, Applicant found that mucosal inflammatory monocytes of non- responders to vedolizumab have aberrant phenotypes, which could be a causally related to non- response to therapy. In peripheral blood, increased abundance of NK cells, monocytes, ILCs and DCs at baseline is associated with non-response to treatment. Analysis of cell level or cell abundance can be performed, for example, using scRNAseq data or high-dimension flow cytometry (e.g., Cytek Aurora analysis). 135 WBD (US) 4854-8046-9185v2 In some embodiments, non-response to treatment with vedolizumab is associated with Tregs that do not send signals to inflammatory monocytes or IgG cells, whereas response to treatment with vedolizumab is associated with Tregs that do send signals to inflammatory monocytes or IgG cells. In some embodiments, response to treatment with vedolizumab is associated with IL-10 mediated self-regulation of inflammatory monocytes, whereas non-response to treatment with vedolizumab is associated with the lack of IL-10 mediated self-regulation of inflammatory monocytes. In some embodiments, a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from a gene based on gene ontology (GO) analysis. In some embodiments, the marker, or group of markers, is selected from a gene involved in neutrophil mediated immunity (GO:0002446), cellular response to lipopolysaccharide (GO:0071222), the interferon-gamma-mediated signaling pathway (GO:0060333), and/or the cytokine-mediated signaling pathway (GO:0019221). In a preferred embodiment, increased expression of gene involved in neutrophil mediated immunity (GO:0002446), cellular response to lipopolysaccharide (GO:0071222), the interferon-gamma- mediated signaling pathway (GO:0060333), and/or the cytokine-mediated signaling pathway (GO:0019221) in colonic inflammatory monocytes indicates that a UC patient will respond to treatment. In some embodiments, upregulation of a gene in immune-mediating pathways in mucosal T regulatory cells, e.g., inflammatory response (GO:0006954), humoral immune response (GO:0006959) and/or defense response to other organism (GO:0098542), indicates that a UC patient will respond to treatment. In some embodiments, upregulation of a gene in fibroblast pathways in mucosal inflammatory fibroblasts, e.g., wound healing (GO:0042060), indicates that a UC patient will respond to treatment. In some embodiments, a human subject having moderately-to-severely active ulcerative colitis is predicted not to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response 136 WBD (US) 4854-8046-9185v2 marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from a gene involved in the regulation of T cell apoptotic process (GO:0070232), ribosome assembly and biogenesis (GO:0042255), and/or cellular metabolic process (GO:0044267). In a preferred embodiment, increased expression of gene involved in the regulation of T cell apoptotic process (GO:0070232), ribosome assembly and biogenesis (GO:0042255), and/or cellular metabolic process (GO:0044267) in colonic inflammatory monocytes indicates that a UC patient will not respond to treatment. In some embodiments, a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN. In a preferred embodiment, increased expression of CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN in colonic inflammatory monocytes indicates that the human subject will respond to treatment. In another embodiment, increased expression of the at least one response marker in colonic inflammatory monocytes selected from HIF1A, SOCS3, and/or IL1RN indicates that the human subject will respond to treatment. In some embodiments, a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 and/or IL1RN. In a preferred embodiment, increased expression of PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 137 WBD (US) 4854-8046-9185v2 and/or IL1RN in colonic inflammatory monocytes indicates that the human subject will respond to treatment. In some embodiments, a human subject having moderately-to-severely active ulcerative colitis is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from RGS2 and/or MAFB. In a preferred embodiment, increased expression of RGS2 and/or MAFB in colonic mucosal macrophages indicates that the human subject will respond to treatment. In some embodiments, a human subject having moderately-to-severely active ulcerative colitis is predicted not to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TREM1 and/or TGM2. In a preferred embodiment, increased expression of TREM1 and/or TGM2 in colonic inflammatory monocytes indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF. In a preferred embodiment, increased expression of IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF in colonic inflammatory monocytes indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ADAM17 and/or TNF. In a preferred embodiment, increased expression of ADAM17 and/or TNF in regulatory T cells (Tregs) indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining 138 WBD (US) 4854-8046-9185v2 an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from those indicative of a pro- inflammatory macrophage profile. In some embodiments, increased expression of IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3 in inflammatory monocytes indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3. In some embodiments, increased expression of S10011A, S100A6, S100A4, LGALS1 and/or LGALS3 in inflammatory monocytes indicates that the human subject will not respond to treatment.In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B. In a preferred embodiment, increased expression of TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B in inflammatory fibroblasts indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CCL5, CEBPB, IL23A, and/or DCHS2. In a preferred embodiment, increased expression of CCL5, CEBPB, IL23A, and/or DCHS2 in colonic inflammatory monocytes indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from SELE, LTB, OSM, and/or CXCL10. In a preferred embodiment, increased expression of SELE, LTB, OSM, and/or 139 WBD (US) 4854-8046-9185v2 CXCL10 in colonic inflammatory monocytes indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the at least one response marker is SEC63. In a preferred embodiment, increased expression of SEC63 in IgG plasma cells indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TNFRSF17, TNFRSF13C, and/or SDC1. In a preferred embodiment, increased expression of TNFRSF17, TNFRSF13C, and/or SDC1 in IgG plasma cells indicates that the human subject will not respond to treatment. In another embodiment, increased expression of SDC1 in IgG plasma cells indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2. In a preferred embodiment, increased expression of IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2 in colonic inflammatory monocytes indicates that the human subject will respond to treatment. In another embodiment, increased expression of ITGB1 or IL10RA in colonic inflammatory monocytes indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is IL1R1 and/or IL1RAP. In a preferred embodiment, increased expression of IL1R1 and/or IL1RAP in colonic inflammatory monocytes indicates that the human subject will not respond to treatment. 140 WBD (US) 4854-8046-9185v2 In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF. In a preferred embodiment, increased expression of TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF in regulatory T cells (Tregs) indicates that the human subject will respond to treatment. In another embodiment, increased expression of CD40LG, IL18R1, IL10RA, IL7R, or TNFRSF14 in Tregs indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is IL12RB, IL2RG, and/or TNFRSF1B. In a preferred embodiment, increased expression of IL12RB, IL2RG, and/or TNFRSF1B in regulatory T cells (Tregs) indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL-11, CXCL2, and/or CXCL14. In a preferred embodiment, increased expression of IL-11, CXCL2, and/or CXCL14 in inflammatory fibroblasts indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CXCL12, CXCL16, and/or CCL2. In a preferred embodiment, increased expression of CXCL12, CXCL16, and/or CCL2 in inflammatory fibroblasts indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human 141 WBD (US) 4854-8046-9185v2 subject, wherein the marker, or group of markers, is selected from ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE. In a preferred embodiment, increased expression of ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE in IgG plasma cells indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD36, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, and/or FLT1. In a preferred embodiment, increased expression of ICAM1, PECAM1, CD74_CXCR4, CD74_CD44, PTPRC, and/or ITGAE in inflammatory monocytes indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25. In a preferred embodiment, increased expression of CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25 in regulatory T cells (Tregs) indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74. In a preferred embodiment, increased expression of TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, 142 WBD (US) 4854-8046-9185v2 PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74 in inflammatory fibroblasts indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CD44/SDC1, CD40, GLG1, and/or ITGA6. In a preferred embodiment, increased expression of CD44/SDC1, CD40, GLG1, and/or ITGA6 in IgG plasma cells indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST. In a preferred embodiment, increased expression of ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST in inflammatory monocytes indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6. In a preferred embodiment, increased expression of CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6 in regulatory T cells (Tregs) indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the 143 WBD (US) 4854-8046-9185v2 human subject, wherein the marker, or group of markers, is selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR. In a preferred embodiment, increased expression of MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR in inflammatory fibroblasts indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1. In a preferred embodiment, increased expression of ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1 in inflammatory monocytes indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV. In a preferred embodiment, increased expression of ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV in inflammatory fibroblasts indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human 144 WBD (US) 4854-8046-9185v2 subject, wherein the marker, or group of markers, is selected from BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1. In a preferred embodiment, increased expression of BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1 in regulatory T cells (Tregs) indicates that the human subject will respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5. In a preferred embodiment, increased expression of ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5 in inflammatory monocytes indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK. In a preferred embodiment, increased expression of APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK in inflammatory fibroblasts indicates that the human subject will not respond to treatment. In certain embodiments, a human subject having UC is predicted to respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin by determining an expression level of at least one response marker in a biological sample from the human subject, wherein the marker, or group of markers, is selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4. In a preferred embodiment, increased expression of ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4 in regulatory T cells (Tregs) indicates that the human subject will not respond to treatment. In some embodiments, upregulation of a gene in a pathway in mucosal inflammatory fibroblasts that actively promote immune cell functions, e.g. chemokine-mediated signaling 145 WBD (US) 4854-8046-9185v2 pathway (GO:0070098), extracellular matrix disassembly (GO:0022617) and/or response to type II interferon (GO:0034341), which enables them to regulate migration and chemotaxis of leukocytes, mononuclear cells and granulocytes indicates that a UC patient will not respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin. III. Therapeutic Methods In one aspect, the invention relates to a method of treating UC in a subject identified as a responder using the methods disclosed. The responder patient is administered an anti-α4β7 antibody in an amount effective to treat UC. The human subject may be an adult (e.g., 18 years or older), an adolescent, or a child. The anti-α4β7 antibody used to treat a responder can bind to an epitope on the α4 chain (e.g., humanized MAb 21.6 (Bendig et al., U.S. Pat. No.5,840,299), on the β7 chain (e.g., FIB504 or a humanized derivative (e.g., Fong et al., U.S. Pat. No.7,528,236)), or to a combinatorial epitope formed by the association of the α4 chain with the β7 chain. In one aspect, the antibody binds a combinatorial epitope on the α4β7 complex, but does not bind an epitope on the α4 chain or the β7 chain unless the chains are in association with each other. The association of α4 integrin with β7 integrin can create a combinatorial epitope for example, by bringing into proximity residues present on both chains which together comprise the epitope or by conformationally exposing on one chain, e.g., the α4 integrin chain or the β7 integrin chain, an epitopic binding site that is inaccessible to antibody binding in the absence of the proper integrin partner or in the absence of integrin activation. In another aspect, the anti-α4β7 antibody binds both the α4 integrin chain and the β7 integrin chain, and thus, is specific for the α4β7 integrin complex. Antibodies can bind α4β7 but not bind α4β1, and/or not bind αEβ7, for example. In another aspect, the anti-α4β7 antibody binds to the same or substantially the same epitope as the Act-1 antibody (Lazarovits, A. I. et al., J. Immunol., 133(4): 1857-1862 (1984), Schweighoffer et al., J. Immunol., 151(2): 717-729, 1993; Bednarczyk et al., J. Biol. Chem., 269(11): 8348-8354, 1994). Murine ACT-1 Hybridoma cell line, which produces the murine Act-1 monoclonal antibody, was deposited under the provisions of the Budapest Treaty on Aug.22, 2001, on behalf of Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Mass.02139, U.S.A., at the American Type Culture Collection, 10801 University Boulevard, Manassas, Va.20110- 146 WBD (US) 4854-8046-9185v2 2209, U.S.A., under Accession No. PTA-3663. In another aspect, the anti-α4β7 antibody is a human antibody or an α4β7 binding protein using the CDRs provided in U.S. Patent Application Publication No.2010/0254975. In one aspect, the anti-α4β7 antibody inhibits binding of α4β7 to one or more of its ligands (e.g. the mucosal addressin, e.g., MAdCAM (e.g., MAdCAM-1), fibronectin, and/or vascular addressin (VCAM)). Primate MAdCAMs are described in the PCT publication WO 96/24673, the entire teachings of which are incorporated herein by this reference. In another aspect, the anti-α4β7 antibody inhibits binding of α4β7 to MAdCAM (e.g., MAdCAM-1) and/or fibronectin without inhibiting the binding of VCAM. In one aspect, the anti-α4β7 antibody used in the therapeutics methods disclosed herein is a humanized version of the mouse Act-1 antibody. Suitable methods for preparing humanized antibodies are well-known in the art. Generally, the humanized anti-α4β7 antibody will contain a heavy chain that contains the 3 heavy chain complementarity determining regions (CDRs, CDR1 SEQ ID NO:1; CDR2 SEQ ID NO:2; and CDR3 SEQ ID NO:3) of the mouse Act-1 antibody and suitable human heavy chain framework regions; and also contain a light chain that contains the 3 light chain CDRs (CDR1 SEQ ID NO:4, CDR2 SEQ ID NO:5, CDR3 SEQ ID NO:6) of the mouse Act-1 antibody and suitable human light chain framework regions. The humanized Act-1 antibody can contain any suitable human framework regions, including consensus framework regions, with or without amino acid substitutions. For example, one or more of the framework amino acids can be replaced with another amino acid, such as the amino acid at the corresponding position in the mouse Act-1 antibody. The human constant region or portion thereof, if present, can be derived from the κ or λ light chains, and/or the γ (e.g., γ1, γ2, γ3, γ4), µ, α (e.g., α1, α2), δ or ε heavy chains of human antibodies, including allelic variants. A particular constant region (e.g., IgG1), variant or portions thereof can be selected in order to tailor effector function. For example, a mutated constant region (variant) can be incorporated into a fusion protein to minimize binding to Fc receptors and/or ability to fix complement (see e.g., Winter et al., GB 2,209,757 B; Morrison et al., WO 89/07142; Morgan et al., WO 94/29351, Dec.22, 1994). Humanized versions of Act-1 antibody were described in PCT publications nos. WO98/06248 and WO07/61679, the entire teachings of each of which are incorporated herein by this reference. 147 WBD (US) 4854-8046-9185v2 In one aspect, the anti-α4β7 antibody is vedolizumab. Vedolizumab (also called MLN0002, ENTYVIO™ or KYNTELES™) is a humanized immunoglobulin (Ig) G1 mAb directed against the human lymphocyte integrin α4β7. Vedolizumab binds the α4β7 integrin, antagonizes its adherence to MAdCAM-1 and as such, impairs the migration of gut homing leukocytes into GI mucosa. Vedolizumab is an integrin receptor antagonist indicated for adult patients with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator, or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids. For UC, vedolizumab is for inducing and maintaining clinical response, inducing and maintaining clinical remission, improving endoscopic appearance of the mucosa, and/or achieving corticosteroid-free remission. In another aspect, the humanized anti-α4β7 antibody for use in the treatment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10. The humanized light chain of vedolizumab (e.g., Chemical Abstract Service (CAS, American Chemical Society) Registry number 943609-66-3), with two mouse residues switched for human residues, is more human than the light chain of LDP-02, another humanized anti-α4β7 antibody. In addition, LDP-02 has the somewhat hydrophobic, flexible alanine 114 and a hydrophilic site (Aspartate 115) that is replaced in vedolizumab with the slightly hydrophilic hydroxyl-containing threonine 114 and hydrophobic, potentially inward facing valine 115 residue. Vedolizumab may be administered by any suitable method, such as by one or more of intravenous injection, subcutaneous injection, or infusion. In some embodiments, vedolizumab is administered at a dose of 50 mg, 100 mg, 180 mg, 300 mg, or 600 mg. In some embodiments, the vedolizumab is administered, for example subcutaneously, at a dose of 108 mg. Vedolizumab may be administered once per day, per week, per month, or per year. A vedolizumab dosing regimen may have an initial or induction phase and a maintenance phase. An induction phase may be one or more than one, e.g., two, three or four doses, of high amounts or without long times, such as only one week, two weeks, three weeks or four weeks between each dose. For example, an induction regimen may have two doses, one at day (week) zero and one at week 2 (day 14). A maintenance phase, e.g., to maintain remission of the IBD, may have lower doses or doses further apart than in the induction phase. In some embodiments, the 148 WBD (US) 4854-8046-9185v2 vedolizumab is administered at zero, two and six weeks, and then every two weeks, four weeks or every eight weeks thereafter. Patients with IBD refractory to other therapies may need longer induction periods, e.g., 8, 10 or 12 weeks, before beginning maintenance therapy. In an embodiment, vedolizumab is administered intravenously at zero, two and six weeks, then every eight weeks thereafter. In some embodiments, vedolizumab is administered one or more times, and then at least one month, at least six months, or at least one year later, vedolizumab is again administered one or more times. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at four weeks intervals or eight week intervals thereafter. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero and two weeks, and then at six weeks and at two-, three- or four-week intervals, 108 mg of vedolizumab may be administered subcutaneously. In some embodiments, 300 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at two-, three- or four-week intervals, 108 mg of vedolizumab may be administered subcutaneously. Treatment methods using anti-α4β7 integrin antibodies are described in publication nos. U.S.2005/0095238, U.S.10143752, U.S.10040855, WO2012151248 and WO 2012/151247, each of which is incorporated by reference herein. EXAMPLES The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Commercially available reagents referred to in the example were used according to manufacturer's instructions unless otherwise indicated. 149 WBD (US) 4854-8046-9185v2 EXAMPLE 1. High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab (VDZ) therapy in ulcerative colitis (UC) Summary To gain new insights into the basis of primary (non-)response to VDZ, single-cell transcriptome sequencing and high-dimensional spectral flow cytometry (Cytek) was performed of gut mucosal biopsies and peripheral blood mononuclear cells (PBMCs) collected from 25 UC patients with active inflammation 2 weeks prior and 14 weeks after the initiation of VDZ therapy. 159,188 mucosal and 95,057 PBMC transcriptomes were generated, and results were validated using Cytek immunoprofiles of additional 797,670 CD45+ mucosal cells and 900,000 PBMCs. Response to VDZ at week 14 manifested through a partial recovery of the epithelial and stromal compartments, and by depleted T cells (CD8+IL17+ and CD4+PD1+ subsets) and innate immune cells (dendritic cells, NKs and inflammatory monocytes) in the colon mucosa. In contrast, expansion of inflammatory fibroblasts, persistent post-capillary venules, depletion of most epithelial subsets as well as the stable presence of adaptive and innate immune cells exposed an ongoing mucosal inflammation in epithelium and stroma in non-responders. No evidence was found that alternative integrin pathways are responsible for the sustained presence of leukocytes in the mucosa of non-responders after VDZ treatment, despite a significantly diminished surface presence of β7 on circulating T cells in all patients. An innate cellular signature of non-response to VDZ was identified that consisted of dendritic cells, NKs, ILCs, γδ-T cells and inflammatory monocytes, detected in the mucosa and peripheral blood of UC patients prior to treatment. Furthermore, inflammatory monocytes in non-responders showed a dysregulated state of function marked by the absence of “neutrophil mediated immunity” and “response to IFNγ” pathways – hallmarks of an adequate response to their inflammatory environment. This is the largest prospective single-cell RNAseq study addressing the response to biological therapy in UC. This Example shows that primary non-response to VDZ is marked by active, innate immune cell-mediated inflammation that is present prior to and persists throughout the treatment, and that can be detected in peripheral blood before start of treatment. The aim of this study was to identify cellular and molecular signatures that mark (non-) response to VDZ in UC patients, and thus, gain a better understanding of the mechanism of 150 WBD (US) 4854-8046-9185v2 action of VDZ by performing high-resolution single-cell transcriptomic and surface protein profiling of gut mucosal and peripheral blood cells. Methods Patients This study included patients with UC that were undergoing ileocolonoscopy to determine the extent of active disease before the start of treatment with VDZ. Both patients with left-sided disease or pancolitis were included, and excluded patients with exclusively right-sided disease, in order to make evaluation of treatment response with a sigmoidoscopy possible. A minimal Mayo score for inclusion was not used; active disease that in clinical care warrants treatment with VDZ was sufficient. This results in the inclusion of patients with proctitis and mild pancolitis that might have been underrepresented in previous clinical trials. Anti-TNFα naive and anti-TNFα experienced patients were both included. A total of 25 patients with UC who received VDZ were included. The clinical characteristics of these patients are shown in Table 1. Table 1. Patient cohort description All patients Responders Non- p- (N=25) (N=15) responders value (N=10) * Sex Male 12 (48.0%) 7 (46.7%) 5 (50.0%) 1.000 Female 13 (52.0%) 8 (53.3%) 5 (50.0%) Diagnosis PSC-UC 3 (12.0%) 2 (13.3%) 1 (10.0%) 1.000 UC 22 (88.0%) 13 (86.7%) 9 (90.0%) Age at endoscopy (years)** Mean (SD) 41.3 (12.7) 42.7 (11.1) 39.3 (15.2) 0.555 Median [Min, Max] 39.0 [19.0, 39.0 [26.0, 41.5 [19.0, 66.0] 66.0] 59.0] Disease duration (years)
Figure imgf000152_0001
151 WBD (US) 4854-8046-9185v2 Mean (SD) 11.6 (13.0) 11.1 (12.7) 12.4 (14.2) 0.813 Median [Min, Max] 6.00 [0, 39.0] 5.00 [0, 39.0] 7.00 [1.00, 39.0] Disease location Left sided proctitis 3 (12.0%) 2 (13.3%) 1 (10.0%) 0.7 Left sided colitis 7 (28.0%) 5 (33.3%) 2 (20.0%) Pancolitis 15 (60.0%) 8 (53.3%) 7 (70.0%) Prior exposure to anti-TNFα agents Exposed 16 (64.0%) 7 (46.7%) 9 (90.0%) 0.074 Naïve 9 (36.0%) 8 (53.3%) 1 (10.0%) Concurrent IBD medication*** None 5 (20.0%) 4 (26.7%) 1 (10.0%) 0.318 Azathiopurine 1 (4.0%) 0 (0%) 1 (10.0%) Thioguanine 3 (12.0%) 2 (13.3%) 1 (10.0%) Prednisolone 6 (24.0%) 3 (20.0%) 3 (30.0%) Mesalazine 2 (8.0%) 2 (13.3%) 0 (0%) Mesalazine/Azathioprine 1 (4.0%) 0 (0%) 1 (10.0%) Mesalazine/Thioguanine 1 (4.0%) 1 (6.7%) 0 (0%) Mesalazine/Prednisolone 2 (8.0%) 0 (0%) 2 (20.0%) Mesalazine/Budesonide 1 (4.0%) 0 (0%) 1 (10.0%) Mesalazine/Budesonide/Azathio 1 (4.0%) 1 (6.7%) 0 (0%) prine Mesalazine/Budesonide/Thiogua 1 (4.0%) 1 (6.7%) 0 (0%) nine Budesonide/Thiosix 1 (4.0%) 1 (6.7%) 0 (0%) Prior surgery (related to the gut) 152 WBD (US) 4854-8046-9185v2 none 23 (92.0%) 14 (93.3%) 9 (90.0%) 0.337 temporary ileostomy 1 (4.0%) 0 (0%) 1 (10.0%) cholecystectomy 1 (4.0%) 1 (6.7%) 0 (0%) *P-value was calculated between responders and non-responders. For numeric variables, a standard 2-sample t-test was performed, while for categorical variables a chi-squared test of independence was performed. **Recorded age at the time of the endoscopy that marked 2 weeks prior to start of vedolizumab treatment ***Recorded medication use prior to start of vedolizumab treatment N, number; PSC-UC, primary sclerosing cholangitis ulcerative colitis; UC, ulcerative colitis; SD, standard deviation; Min, minimal; Max, maximal; anti-TNFα, anti tumor necrosis factor alpha; IBD, inflammatory bowel disease. Patient clinical care was conformed to the standard treatment protocols (Guidelines of Dutch Association of Gastrointestinal and Liver Physicians). All subjects provided written informed consent. Sample collection and cryopreservation Patients underwent ileocolonoscopy 2 weeks before the start of VDZ treatment (hereafter named pre-VDZ) and at week 14 after the start of VDZ treatment (hereafter named post-VDZ). At both time points, mucosal biopsies and 10 mL of peripheral blood (EDTA) were obtained. When possible, paired biopsies from inflamed and non-inflamed regions of the colon were collected from the same patient. The biopsies were collected in RPMI1640 supplemented with 10% FCS at 4°C, and were preserved in cold freezing medium containing 90% fetal calf serum (FCS) with 10% dimethyl sulfoxide (DMSO) after collection. The procedures of cryopreservation and thawing were performed as previously described.15,16 In short, biopsies were stored at -80°C overnight, and then were transferred to liquid nitrogen for long-term storage. Upon thawing, cryovials containing frozen biopsies were quickly thawed at 37°C and washed twice with cold thawing solution (PBS with 5% FCS). Sample dissociation 153 WBD (US) 4854-8046-9185v2 After the collection of the blood, plasma was removed by washing it with phosphate- buffered saline (PBS) at room temperature. Erythrocytes were lysed and peripheral blood mononuclear cells (PBMCs) were isolated. The gut mucosal biopsies were dissociated using the 'one-step collagenase' protocol, as described previously (Uniken Venema, W. T. C. et al. Gut mucosa dissociation protocols influence cell type proportions and single-cell gene expression levels. Sci Rep 12, 9897 (2022)). In short, biopsies were washed with cold thawing solution, and incubated for 30 minutes in the digestion medium (RPMI1640 supplemented with GlutaMax, 200 iU/mL collagenase IV C1889, 10 iU/mL DNAse II D8764, 35 iU/mL SUPERaseIn AM2694, 2% heat-inactivated FCS), pipette-strained after 10 minutes, and after 30 minutes of incubation, shortly incubated in TrypLE, filtered over a 70 μm filter and washed using cold wash buffer (PBS -/- supplemented with 0.4% BSA and 10 iU/mL DNase II). Definition of response For each patient, response was evaluated at week 14 after the start of VDZ treatment (Table 2). Table 2. Response outcomes Patient Resp SCC SCC SSCAI Clinic Mayo Mayo Mayo Endosc Mucosa onse AI AI differe al pre- post- differen opic l by pre- post- nce* respo VDZ VDZ ce** respons healing PGA VDZ VDZ nse e 1 yes 3 2 1 no 3-3-3- x-x-1- 4 yes no 3-1 1-1 2 yes 13 5 8 yes 0-0-1- x-x-1- 2 no no 2-2 1-1 3 no 10 5 5 yes x-x-3- x-x-3- 0 no no 3-3 3-3 4 yes 7 4 3 yes x-x-0- x-x-0- 1 no yes 0-2 0-1 5 yes 10 2 8 yes 0-0-1- x-x-0- 5 yes yes 2-2 0-0 6 no 1 1 0 no 1-1-1- 1-1-1- 0 no no 1-0 1-0 7 yes 2 4 -2 no 0-0-1- 0-0-0- 2 no yes 1-0 0-0 8 yes 5 1 4 yes 0-0-1- 0-0-0- 1 no no 154 WBD (US) 4854-8046-9185v2 Patient Resp SCC SCC SSCAI Clinic Mayo Mayo Mayo Endosc Mucosa onse AI AI differe al pre- post- differen opic l by pre- post- nce* respo VDZ VDZ ce** respons healing PGA VDZ VDZ nse e 1-1 0-2 9 no 11 11 0 no 0-0-0- x-x-0- 2 no no 2-3 0-3 10 yes 8 0 8 yes 3-3-3- x-x-0- 9 yes yes 3-3 0-0 11 yes 7 4 3 yes 0-0-0- x-0-1- 1 no no 2-3 2-1 12 yes 12 1 11 yes 3-3-2- x-2-0- 5 yes no 2-1 0-0 13 no 7 3 4 yes 3-0-0- 0-0-0- -4 no no 1-0 2-3 14 no 6 4 2 no 0-0-1- x-x-1- 1 no no 2-1 1-1 15 no 5 4 1 no 2-2-2- x-x-1- 1 no yes 2-2 2-2 16 yes 3 3 0 no 0-0-0- x-x-0- 0 no yes 1-0 0-1 17 yes 7 4 3 yes 0-3-0- x-x-0- 2 no no 3-3 2-2 18 yes 4 1 3 yes 2-2-2- x-0-1- 5 yes no 2-2 0-0 19 yes 7 1 6 yes 0-0-0- x-x-0- 3 yes no 3-3 3-0 20 no 1 1 1 no 0-0-0- x-x-0- 3 yes no 3-3 0-3 21 no 8 3 5 yes x-x-0- x-x-0- 0 no no 0-3 0-3 22 yes 1 1 0 no 0-0-0- x-x-0- 1 no yes 0-2 0-1 23 yes 12 0 12 yes 1-2-2- x-x-0- 7 yes yes 3-3 0-1 24 no 5 5 0 no 3-2-2- x-2-2- 1 no no 3-3 3-2 25 no 2 1 1 no 1-1-1- x-x-1- 1 no no 1-1 1-0 For each patient, response was evaluated at week 14 after the start of vedolizumab treatment. The main response outcome was scored according to Physician Global Assessment (PGA), which incorporates clinical response, endoscopic response and biochemical measurements such as C-Reactive Protein, hemoglobin, and calprotectin. Response by PGA was scored by three independent physicians (one treating, and two unrelated); in cases of dispute, the majority votes were considered. The table further details the assessment of clinical response, endoscopic 155 WBD (US) 4854-8046-9185v2 response and mucosal healing. Clinical response was defined as a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding. Endoscopic response was defined as a decrease in total Mayo score by at least 3 points post-VDZ in the last three segments of the intestinal tract. Mucosal healing was recognized when a maximum one segment of the intestinal tract was scored a maximum Mayo 1 during post-VDZ (week 14) endoscopy. *Difference in SSCAI between pre-VDZ and post-VDZ **Difference in Mayo scores between pre-VDZ endoscopy and post-VDZ endoscopy; only the last three segments of the intestinal tract are considered, therefore maximum difference in total Mayo score is 9 (from x-x-3-3-3 to x-x-0-0-0) PGA, Physician global assessment; SCCAI, Simple Clinical Colitis Activity Index; VDZ, vedolizumab; pre-VDZ, study time point of 2 weeks prior to start of vedolizumab treatment; post-VDZ, study time point of 14 weeks after the start of vedolizumab treatment The main response outcome was considered Physician Global Assessment (PGA), since it incorporates clinical response, endoscopic response and biochemical measurements such as C- Reactive Protein, hemoglobin, and calprotectin. Response by PGA was scored by three independent physicians (one treating, and two unrelated); in cases of dispute, the majority votes were considered. Furthermore, individual scores for clinical response, endoscopic response and mucosal healing were recorded for all patients. Clinical response was defined as a decrease in Simple Clinical Colitis Activity Index (SCCAI) by at least 3 points post-VDZ with no reported rectal bleeding (Walmsley, R. S., Ayres, R. C., Pounder, R. E. & Allan, R. N. A simple clinical colitis activity index. Gut 43, 29–32 (1998)). Endoscopic response was defined as a decrease in total Mayo score by at least 3 points post-VDZ in the last three segments of the intestinal tract. Mucosal healing was recognized when a maximum one segment of the intestinal tract received a maximum Mayo score of 1 during post-VDZ (week 14) endoscopy. Since SCCAI scores showed high heterogeneity, and week 14 is generally a too early time point to confidently call endoscopic response or mucosal healing, patients were stratified into responders and non-responders to VDZ based on PGA for all downstream analyses. Cell hashing Cells were labeled with barcoded antibodies (“cell hashing”) using TotalSeq A oligo- conjugated hashtag antibodies (Biolegend) according to the manufacturer's protocol to overcome the challenge of batch effects (Stoeckius, M. et al. Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics. Genome Biol 19, 224 156 WBD (US) 4854-8046-9185v2 (2018)). In short, cells were incubated for 30 min at 4°C with hashtag antibodies, and then washed twice with PBS supplemented with 0.4% BSA to remove redundant hashtags. Viability assessment and cell counting Cell viability was assessed using trypan blue staining reagent (Sigma, T6146) 1:1, and counted on a hemocytometer. Cell viability percentage was calculated as the live cell count divided by the total cell count and then multiplied by 100%. 10x library preparation and sequencing The scRNA-seq libraries were prepared using the following Single Cell 3ʹ Reagent Kits v3. Samples were pooled per 10x lane, aiming for a total recovery of 12.000 cells per lane. cDNA library prep was done according to the 10x manual CG000185 Rev D, and hashtag and antibody-derived libraries were prepared using the manufacturer's protocol (BioLegend TotalSeq-A Antibodies and Cell Hashing with 10x Single Cell 3' Reagent Kit v3.1 (Dual Index) Protocol) (B). Libraries were indexed using 10x PN-120262 Chromium i7 Multiplex Kit. Sequencing was performed by BGI (Hong Kong) on an MGI2000 sequencer, featuring 100bp paired-end reads. High-dimension flow cytometry staining High-dimension flow cytometry was performed using the CytekTM Aurora machine in the UMCG based on a 40-color flow cytometry-based panel (Park, L. M., Lannigan, J. & Jaimes, M. C. OMIP-069: Forty-Color Full Spectrum Flow Cytometry Panel for Deep Immunophenotyping of Major Cell Subsets in Human Peripheral Blood. Cytometry A 97, 1044– 1051 (2020)). Two panels were designed based on the Cytek Immunomonitoring panel (ref OMIP-069) with adjustments made for our study with support of Cytek. A portion of cells extracted from both peripheral blood and biopsies was visualized using antibodies against cell surface markers with this panel. Data analyses were performed using OMIQ software from Dotmatics. 157 WBD (US) 4854-8046-9185v2 Quantification and Statistical Analyses Data pre-processing Biopsy dissociation, scRNA library generation and sequencing was performed in two batches (Batch 1: 8 samples, Batch 2: 17 samples). Biopsy sequencing files in FastQ format were used as input in Cellranger v.3.1.0, to perform filtering, barcode counting, and alignment. The human GRCh38-3.0.0. reference genome was used for alignment. Souporcell v1 doublet detection was performed on the alignment data (Heaton, H. et al. Souporcell: robust clustering of single-cell RNA-seq data by genotype without reference genotypes. Nat Methods 17, 615–620 (2020)). Once the Seurat object (satijalab.org) was generated, HTO metadata were integrated and the data was filtered based on the HTO assignment (ref G). In cases where the cell was HTO- negative, the Souporcell assignment was used instead. Batch 1 and 2 objects were subsequently merged. The generated data were normalized through the SCTransform method implemented in Seurat and filtered for cells with a fraction of mitochondrial genes expressed (MT) higher than 70%. Next, PCA was performed considering the first 30 components through the RunPCA function in Seurat. Finally, FindNeighbors and FindClusters functions (default parameters) were used to identify cell-based clusters. The Seurat object was subdivided into three different compartments based on epithelial (EPCAM+), immune (CD45+), and stromal (THY1, SOX10, MADCAM1) markers. Because of the usually lower MT content of immune cells, the immune compartment was further filtered for MT content over 20%. The previously described preprocessing steps were then repeated for the three compartments separately. The aforementioned processing steps used in the biopsy data processing were also followed during the processing of PBMCs scRNA-sequencing data. However, for the filtering of MT content a threshold of 15% was used, and there was no division into different compartments. The Azimuth cell type annotation method in Seurat was used to automatically annotate the cell types within each compartment based on a reference single-cell dataset, where cells in the query dataset are annotated by labeling them based on their closest projected reference cell (cell-cell). The training dataset of Smillie et al. was used for the biopsy data and the human PBMCs Azimuth dataset [the human PBMC dataset is available from the NIH Human Biomolecular Atlas Project (HuBMAP) Azimuth web application] was used for the PBMC data. Furthermore, 158 WBD (US) 4854-8046-9185v2 some biologically relevant cell types originally not present in the biopsy reference dataset were added through selecting cells with the expression of specific marker genes (as described in the Results section) (Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019)). Cell abundances analysis To quantify differential celltype abundances, Bayesian models were used to address the problem of the compositionality of the data and low sample size. Specifically, Pibble (fido package, V 1.0.2) and scCODA v() were chosen considering results significant at credible intervals over or equal to 75% and FDR no greater than 0.3 respectively (Büttner, M., Ostner, J., Müller, C. L., Theis, F. J. & Schubert, B. scCODA is a Bayesian model for compositional single-cell data analysis. Nat Commun 12, 6876 (2021)). Additionally, the non-parametric Mann-Whitney test was performed on the proportions of each cell type in different comparisons. DE analysis and pathway analysis The Seurat implementation of MAST was used to perform differential gene expression analysis at a single-cell level. The statistically significant identified features were divided into positive and negative genes and used as input for enrichment pathway analysis. The Enrichr V 3.1 function that based its GO terms identification on the “GO_Biological_Process_2018” database was used to identify enrichment of specific pathways. Cell-cell interaction analysis Cell-cell communication analysis was performed through the integration of two different cell- cell communication methods. Data was first interrogated using the R package Cellchat (1.4.0), a public database containing information on ligand-receptor interactions and able to provide a first overview of the single cell interaction per specific condition. The investigation was focused on cell-cell communication in responders and non-responders at baseline and after treatment. Further cell-cell communication analysis was performed using NicheNet through the R package nichenetr (1.1.0). NicheNet analysis provides an in-depth understanding of intercellular interactions by using a background set of differentially expressed (DE) genes, which allowed prediction of potential ligand-receptor interactions and determination if specific cell-cell 159 WBD (US) 4854-8046-9185v2 interactions resulted in variations in downstream gene expression. The DE genes selection was performed based on the gene presence in at least 10% of the specific cell types, an absolute LFC of 0.25, and a Bonferroni p-value adjusted of 0.05. During Nichenet analysis, the focus was on specific target cells (inflammatory monocytes, inflammatory fibroblasts, and Tregs) that were treated separately as receiver and sender cells (see Tables 3 and 4, which identify non- overlapping subsets of ligand-receptor pairs (i.e., ligand-receptor pairs that are unique to responders or nonresponders) and Tables 5 and 6, which identify non-overlapping subsets of markers for cell communication in responders and non-responders, respectively, prior to vedolizumab treatment (pre-VDZ)). Furthermore, Nichenet pairwise analysis was performed on a previously selected group of interesting cell-types, which comprises inflammatory monocytes, Tregs, inflammatory fibroblasts, Tc17 cells, IgG+ plasma cells, NKs, DCs M cells and activated endothelial cells. 160 WBD (US) 4854-8046-9185v2 Table 3. Network of selected cell types using CellChat and NicheNet in responders prior to vedolizumab treatment (pre-VDZ) (subset showing ligand-receptor pairs that are unique to responders) Receiver cell Receptor Ligand Sender cell IgG ICAM1 ITGB2 Inflammatory monocytes IgG PECAM1 PECAM1 Inflammatory monocytes IgG CD74_CXCR4 MIF Inflammatory fibroblasts IgG CD74_CD44 MIF Inflammatory fibroblasts IgG PTPRC LGALS9 M Cells IgG ITGAE CDH1 M Cells Inflammatory IL10RA IL22 CD8pos_IL17pos monocytes Inflammatory TNFRSF1A TNF Inflammatory monocytes; Tregs monocytes Inflammatory TNFRSF1B TNF Inflammatory monocytes; Tregs monocytes Inflammatory ITGA5_ITGB1 NAMPT Inflammatory monocytes monocytes Inflammatory HAVCR2 LGALS9 Inflammatory monocytes; DC; monocytes Post_capillary_Venules; M_cells Inflammatory CD36 THBS1 Inflammatory monocytes; monocytes Inflammatory fibroblasts; Post_capillary_Venules Inflammatory CD36 THBS2 Inflammatory fibroblasts monocytes Inflammatory PILRA CD99 Inflammatory monocytes; Tregs; monocytes Inflammatory fibroblasts; CD8pos_IL17pos; DC; NKs; Post_capillary_Venules; M_cells 161 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell Inflammatory LILRB1 HLA-F Inflammatory monocytes; Tregs; monocytes M_cells Inflammatory NECTIN2 TIGIT Tregs; CD8pos_IL17pos monocytes Inflammatory PLXNB2 SEMA4D Tregs; IgG monocytes Inflammatory CD74_CXCR4 MIF Inflammatory fibroblasts monocytes Inflammatory CD74_CD44 MIF Inflammatory fibroblasts monocytes Inflammatory TLR4 ANGPTL Inflammatory fibroblasts monocytes 2 Inflammatory ITGA4_ITGB1 FN1 Inflammatory fibroblasts monocytes Inflammatory CD44 LAMA2 Inflammatory fibroblasts monocytes Inflammatory CD44 LAMB2 Inflammatory fibroblasts monocytes Inflammatory CD36 THBS1 Inflammatory monocytes; monocytes Inflammatory fibroblasts; Post_capillary_Venules Inflammatory CD36 THBS2 Inflammatory fibroblasts monocytes Inflammatory CD47 THBS1 Inflammatory monocytes; monocytes Inflammatory fibroblasts; Post_capillary_Venules Inflammatory CD47 THBS2 Inflammatory fibroblasts monocytes Inflammatory NOTCH2 DLL1 Inflammatory fibroblasts 162 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell monocytes Inflammatory NOTCH2 JAG1 Post-capillary venules; M_cells monocytes Inflammatory NOTCH2 JAG2 Post-capillary venules monocytes Inflammatory IL7R TSLP Inflammatory fibroblasts monocytes Inflammatory CD40 CD40LG CD8pos_IL17pos monocytes Inflammatory TGFBR2 TGFB1 IgG monocytes Inflammatory TGFBR2 TGFB3 Post-capillary venules monocytes Inflammatory NRP2 VEGFC Post-capillary venules monocytes Inflammatory FLT1 PGF Post-capillary venules monocytes Tregs CD40LG CD40 Inflammatory fibroblasts Tregs IL18R1 IL18 M_cells Tregs IL10RA IL10 Inflammatory monocytes Tregs IL10RA IL22 CD8pos_IL17pos Tregs IL7R TSLP Inflammatory fibroblasts Tregs TNFRSF14 BTLA Tregs Tregs TNFRSF1B TNF Inflammatory monocytes; Tregs; CD8pos_IL17pos; NKs; M_cells Tregs CD99 CD99 Inflammatory monocytes; Tregs; Inflammatory fibroblasts; CD8pos_IL17pos; DC; Post_capillary_Venules; M_cells 163 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell Tregs TIGIT NECTIN2 Inflammatory monocytes; Inflammatory fibroblasts; DC Tregs IL6ST IL11 Inflammatory fibroblasts Tregs TGFB2 TGFB1 IgG Tregs GLG1 SELE Post-capillary venules Tregs NOTCH1 DLL1 Post-capillary venules Tregs TGFBR2 TGFB3 Post-capillary venules Tregs CD74 APP M_cells Tregs TNFRSF25 TNFSF15 M_cells Inflammatory TNFRSF1A TNF Inflammatory monocytes fibroblasts Inflammatory CD47 THBS1 Inflammatory monocytes fibroblasts Inflammatory CD55 ADGRE5 Inflammatory monocytes fibroblasts Inflammatory ITGA4_ITGB1 VCAM1 Inflammatory monocytes fibroblasts Inflammatory NRP1 VEGFA Inflammatory monocytes; fibroblasts Inflammatory fibroblasts Inflammatory NRP1 PGF Post-capillary venules fibroblasts Inflammatory NRP2 VEGFA Inflammatory monocytes; fibroblasts Inflammatory fibroblasts Inflammatory NRP1_NRP2 VEGFA M_cells fibroblasts Inflammatory ICAM1 ITGB2 Tregs; CD8pos_IL17pos; DC; NKs fibroblasts Inflammatory ICAM1 ITGAL Tregs; CD8pos_IL17pos fibroblasts 164 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell Inflammatory ICAM1 ITGAM DC; M_cells fibroblasts Inflammatory NECTIN2 TIGIT Tregs; CD8pos_IL17pos fibroblasts Inflammatory PLXNB2 SEMA4D Tregs; CD8pos_IL17pos fibroblasts Inflammatory TNFRSF14 BTLA Tregs fibroblasts Inflammatory FGFR1 FGF2 Inflammatory fibroblasts fibroblasts Inflammatory CD74_CD44 MIF Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB5 POSTN Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB8 FN1 Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB8 LAMA2 Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB8 LAMA4 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 LAMA5 Post-capillary venules fibroblasts Inflammatory ITGAV_ITGB8 LAMB1 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 LAMB2 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 LAMB3 M_cells fibroblasts Inflammatory ITGAV_ITGB8 LAMC1 Inflammatory fibroblasts; 165 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 COL1A1 Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB8 COL1A2 Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB8 COL4A1 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 COL4A2 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 COL6A1 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGAV_ITGB8 COL6A1 Inflammatory fibroblasts fibroblasts Inflammatory ITGAV_ITGB8 COL6A3 Inflammatory fibroblasts fibroblasts Inflammatory CD44 LAMA2 Inflammatory fibroblasts fibroblasts Inflammatory CD44 LAMB2 Inflammatory fibroblasts fibroblasts Inflammatory CD47 THBS1 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory CD47 THBS2 Inflammatory fibroblasts fibroblasts Inflammatory JAM3 JAM3 Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory JAM3 F11R M_cells fibroblasts Inflammatory JAM2 JAM3 Post-capillary venules fibroblasts 166 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell Inflammatory F11R JAM3 Post-capillary venules fibroblasts Inflammatory PTPRM PTPRM Inflammatory fibroblasts; fibroblasts Post_capillary_Venules Inflammatory ITGA8 TNC Inflammatory fibroblasts fibroblasts Inflammatory ITGAV TNC Inflammatory fibroblasts fibroblasts Inflammatory IL6ST IL11 Inflammatory fibroblasts fibroblasts Inflammatory ACVR1 BMP7 Inflammatory fibroblasts fibroblasts Inflammatory BMPR2 BMP7 Inflammatory fibroblasts fibroblasts Inflammatory F2R GZMA CD8pos_IL17pos fibroblasts Inflammatory F2R PRSS3 M_cells fibroblasts Inflammatory CD55 ADGRE5 CD8pos_IL17pos; DC; NKs; ILCs fibroblasts Inflammatory TGFBR1_TGFBR2_ACVR TGFB3 Post-capillary venules fibroblasts L1 Inflammatory LRP1 SERPING Post-capillary venules fibroblasts 1 Inflammatory BMPR2_ACVR1 BMP7 M_cells fibroblasts Inflammatory EDNRB EDN1 M_cells fibroblasts Inflammatory EDNRB EDN3 M_cells 167 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell fibroblasts Inflammatory CD74 APP M_cells fibroblasts Table 4. Network of selected cell types using CellChat and NicheNet in non-responders prior to vedolizumab treatment (pre-VDZ) (subset showing ligand-receptor pairs that are unique to non-responders) Receiver cell Receptor Ligand Sender cell IgG CD44/SDC1 COL1A1 Inflammatory fibroblasts IgG CD40 LTB CD8pos_IL17pos IgG GLG1 SELE Post_capillary_Venules IgG ITGA6 LAMB1 Post_capillary_Venules Inflammatory ALOX5 ALOXA5A Tregs monocytes P Inflammatory CD4 HLA.DRA IgG monocytes Inflammatory CEACAM5 CD1D DC monocytes Inflammatory ITGAX_ITGB2 ICAM1 NKs monocytes Inflammatory TNFRSF10B_TNFRSF10 TNFSF10 NKs monocytes D Inflammatory CD99 CD99 ILCs monocytes Inflammatory CSF3R CSF3 Post_capillary_Venules monocytes Inflammatory CSF1R/CSF3R CSF3 Post_capillary_Venules monocytes 168 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell Inflammatory LILRB3 ANGPTL2 Post_capillary_Venules monocytes Inflammatory ITGAV VWF Post_capillary_Venules monocytes Inflammatory FPR3/FPR2 ANXA1 Post_capillary_Venules monocytes Inflammatory IL6ST LIF M_cells monocytes Tregs CXCR4 CXCL12 Inflammatory fibroblasts Tregs ITGB1 ADAM12 CD8pos_IL17pos Tregs CD28 CD80 DC Tregs CTLA4 CD80 DC Tregs CD28_CTLA4 CD80 DC Tregs CD4 HLA.DRA IgG Tregs CD4 HLA-DQB1 Post_capillary_Venules Tregs IGF2R GZMB NKs Tregs ITGAL_ITGB2 ICAM1 NKs Tregs RPSA LAMB2 Post_capillary_Venules Tregs CCR6 CCL20 M_cells Inflammatory MYLK CALM2 Tregs; CD8pos_IL17pos; fibroblasts IgG Inflammatory ITGA1 COL4A1 Inflammatory fibroblasts fibroblasts Inflammatory ITGB8 COL4A1 Inflammatory fibroblasts fibroblasts Inflammatory SDC4_ITGB1 ADAM12 CD8pos_IL17pos fibroblasts Inflammatory RPSA LAMB2 Post_capillary_Venules fibroblasts 169 WBD (US) 4854-8046-9185v2 Receiver cell Receptor Ligand Sender cell Inflammatory IL6ST/LIFR LIF M_cells fibroblasts Table 5. Subset of markers for cell communication in responders prior to vedolizumab treatment (pre-VDZ) (subset showing ligands or receptors that are unique to responders) Cell type Sender cell or receiver cell Marker Inflammatory monocytes Sender cell ANXA1 Inflammatory monocytes Sender cell AREG Inflammatory monocytes Sender cell CCL2 Inflammatory monocytes Sender cell CCL3 Inflammatory monocytes Sender cell CCL4 Inflammatory monocytes Sender cell CD46 Inflammatory monocytes Sender cell CXCL10 Inflammatory monocytes Sender cell CXCL3 Inflammatory monocytes Sender cell HBEGF Inflammatory monocytes Sender cell HLA-DRB1 Inflammatory monocytes Sender cell ICAM1 Inflammatory monocytes Sender cell IL10 Inflammatory monocytes Sender cell IL1A Inflammatory monocytes Sender cell IL1B Inflammatory monocytes Sender cell IL1RN Inflammatory monocytes Sender cell SELL Inflammatory monocytes Sender cell TNF Inflammatory monocytes Sender cell TNFSF13B Inflammatory monocytes Receiver cell IL7R Inflammatory monocytes Receiver cell CD47 Inflammatory monocytes Receiver cell PLXNB2 Inflammatory monocytes Receiver cell ITGA5 170 WBD (US) 4854-8046-9185v2 Cell type Sender cell or receiver cell Marker Inflammatory monocytes Receiver cell CXCR4 Inflammatory monocytes Receiver cell CD74 Inflammatory monocytes Receiver cell IL6ST Inflammatory monocytes Receiver cell CD4 Inflammatory monocytes Receiver cell ITGA4 Inflammatory monocytes Receiver cell CSF3R Inflammatory monocytes Receiver cell CSF1R Inflammatory monocytes Receiver cell TNFRSF1B Inflammatory monocytes Receiver cell TNFRSF1A Inflammatory monocytes Receiver cell CD36 Inflammatory monocytes Receiver cell IL1RAP Inflammatory monocytes Receiver cell FPR2 Inflammatory monocytes Receiver cell IL1R1 Inflammatory monocytes Receiver cell ITGB1 Inflammatory fibroblasts Sender cell ANXA1 Inflammatory fibroblasts Sender cell BMP7 Inflammatory fibroblasts Sender cell CD40 Inflammatory fibroblasts Sender cell CD46 Inflammatory fibroblasts Sender cell COL18A1 Inflammatory fibroblasts Sender cell CSF1 Inflammatory fibroblasts Sender cell CSF3 Inflammatory fibroblasts Sender cell CTGF Inflammatory fibroblasts Sender cell FGF2 Inflammatory fibroblasts Sender cell HSPG2 Inflammatory fibroblast Sender cell ICAM1 Inflammatory fibroblasts Sender cell IL-11 Inflammatory fibroblasts Sender cell JAM3 Inflammatory fibroblasts Sender cell LAMA2 Inflammatory fibroblasts Sender cell LAMB2 171 WBD (US) 4854-8046-9185v2 Cell type Sender cell or receiver cell Marker Inflammatory fibroblasts Sender cell MIF Inflammatory fibroblasts Sender cell NAMPT Inflammatory fibroblasts Sender cell NECTIN2 Inflammatory fibroblasts Sender cell NRG1 Inflammatory fibroblasts Sender cell TNC Inflammatory fibroblasts Sender cell TSLP Inflammatory fibroblasts Sender cell VEGFA Inflammatory fibroblasts Sender cell WNT5A Inflammatory fibroblasts Receiver cell NRP1 Inflammatory fibroblasts Receiver cell TNFRSF1A Inflammatory fibroblasts Receiver cell PLXNB2 Inflammatory fibroblasts Receiver cell IL6ST Inflammatory fibroblasts Receiver cell FGFR1 Inflammatory fibroblasts Receiver cell LRP6 Inflammatory fibroblasts Receiver cell TNFRSF14 Inflammatory fibroblasts Receiver cell BMPR2 Inflammatory fibroblasts Receiver cell ITGAV Tregs Sender cell BTLA Tregs Sender cell CD28 Tregs Sender cell CD46 Tregs Sender cell ITGA4 Tregs Sender cell ITGB2 Tregs Sender cell LTB Tregs Sender cell SEMA4D Tregs Sender cell TNF Tregs Receiver cell IL7R Tregs Receiver cell TIGIT Tregs Receiver cell CD74 Tregs Receiver cell IL6ST 172 WBD (US) 4854-8046-9185v2 Cell type Sender cell or receiver cell Marker Tregs Receiver cell IL10RA Tregs Receiver cell TNFRSF14 Tregs Receiver cell TNFRSF1B Tregs Receiver cell CD44 Tregs Receiver cell IL1R2 Tregs Receiver cell IL1R1 Table 6. Subset of markers for cell communication in non-responders prior to vedolizumab treatment (pre-VDZ) (subset showing ligands or receptors that are unique to non- responders) Cell type Sender cell or receiver cell Marker Inflammatory monocytes Sender cell ADGRE5 Inflammatory monocytes Sender cell CD99 Inflammatory monocytes Sender cell HLA-E Inflammatory monocytes Sender cell ITGB2 Inflammatory monocytes Receiver cell ALOX5 Inflammatory fibroblasts Sender cell APOE Inflammatory fibroblasts Sender cell CCL2 Inflammatory fibroblasts Sender cell CD99 Inflammatory fibroblasts Sender cell COL1A2 Inflammatory fibroblasts Sender cell COL4A2 Inflammatory fibroblasts Sender cell COL6A1 Inflammatory fibroblasts Sender cell COL6A2 Inflammatory fibroblasts Sender cell COL6A3 Inflammatory fibroblasts Sender cell CXCL12 Inflammatory fibroblasts Sender cell FGF7 Inflammatory fibroblasts Sender cell HLA-E Inflammatory fibroblasts Sender cell IL6 Inflammatory fibroblasts Sender cell LAMA4 173 WBD (US) 4854-8046-9185v2 Cell type Sender cell or receiver cell Marker Inflammatory fibroblasts Sender cell LAMB1 Inflammatory fibroblasts Sender cell LAMC1 Inflammatory fibroblasts Sender cell THBS2 Inflammatory fibroblasts Receiver cell ITGA1 Inflammatory fibroblasts Receiver cell MYLK Tregs Sender cell ALOXA5AP Tregs Sender cell AREG Tregs Sender cell CALM2 Tregs Sender cell HLA-E Tregs Receiver cell CXCR4 High-dimension flow cytometry Cell type annotation Data from the Cytek panels for both PBMCs and biopsies were analyzed using the OMIQ platform following the cytometry analysis tutorial as a guide. FCS files were imported to the OMIQ program. Compensation was performed on the Cytek Aurora, and standard scaling settings were applied to the data. The data were manually gated to exclude doublets, dead cells, aggregates and CD45+ cells or EPCAM+ cells were selected. For biopsies, CD45+ colonic cells were the focus. In PBMCs, files were selected with a target count of 10,000 randomly selected cells per file, leading to 900,000 cells for analyses. One sample was excluded based on a lack of cells. In the biopsy data, all 797,670 cells were selected for downstream analysis. Afterwards, a Uniform Manifold Approximation and Projection (UMAP) algorithm was run to produce two- dimensional embeddings of the data for visualization. UMAP settings were as follows: all files used, all fluorescent parameters were used besides CD45 and Live/Dead, Neighbors = 80, Minimum Distance = 0.7, Components = 2, Metric = Euclidean, Learning Rate = 1, Epochs = 250, Random Seed = 5493, Embedding Initialization = spectral. Data were explored based on disease location, timepoint, anti-TNF exposure, response, processing day, patient, sex and on cell type or integrin specific markers. Data was clustered using FlowSOM. Settings were as follows: all files used, all fluorescent parameters plus umap_1, umap_2 were used besides CD45 and Live/Dead, 625 clusters with xdim = 25 and ydim = 25, rlen = 10, Distance Metric = euclidian, 174 WBD (US) 4854-8046-9185v2 consensus metaclustering with k = 100, Random Seed = 7455. Metaclusters were manually grouped into populations using a combination of surface marker intensity, population location, heatmaps based on cell type defining markers (CD38, CD19, CD27, CD8, CD14, CD56, CD4) and prior manual annotation. Four subsets of PBMCs were identified: myeloid cells, natural killer cells (NKs) and innate lymphoid cells (ILCs), B cells, and T cells. Three subsets of colonic mucosal biopsies were myeloid cells, B cells, and T cells combined with NKs. UMAP and metaclustering were repeated for each subset to obtain the final cell type annotation. To avoid individual user bias, cell type annotation was checked by multiple users. Analyses When possible, cell types were grouped into populations that match the cell type annotation performed in the scRNAseq data. Counts of each cell type population at pre-VDZ and post-VDZ were exported. These counts of different subsets were combined into one dataframe for further analyses. Metadata about time point and PGA response were also exported. Given the compositional aspect of the data, a combined approach of Pibble and Wilcoxon Rank Sum test was used. For analysis, no minimal cell count number was applied. Data were grouped into pre- VDZ and post-VDZ and subsequently in response and non-response. Identifying integrin expression changes To determine the differential expression of integrins on peripheral and colonic immune cells by scRNA-seq, the MAST function as built into the Seurat package was used. All p values were Benjamini-Hochberg corrected for multiple testing. In OMIQ positive populations of cell types expressing individual integrins were selected in both the peripheral blood and colonic immune cells based on blanco staining controls. Median fluorescence intensities of these integrin-expressing cells were compared using a non-parametric Mann-Whitney test between responders and non-responders at two timepoints. Each group of interest consisted of at least 1000 cells. RESULTS 175 WBD (US) 4854-8046-9185v2 Response rates for VDZ in anti-TNFα naive and anti-TNFα exposed patients From a total of 25 UC patients (mean age 41±12.7 years, 52% female, 36% anti-TNFα naive), 15 patients (60%) reached PGA response at week 14. Clinical outcomes showed that patients with no prior use of anti-TNFα were more likely to respond to treatment with VDZ compared to anti- TNFα exposed patients (89% vs 44% response rate, respectively). Single-cell profiling of peripheral blood and colon from UC patients Transcriptome profiles of 95,057 and 159,188 high-quality single cells were generated from PBMCs and biopsies, respectively. In addition, 900,000 PBMCs and 797,670 CD45+ colonic cells were characterized based on their surface proteins using Cytek. Single cell RNA sequencing profiling of biopsies and PBMCs The scRNAseq data of the PBMCs and gut mucosal biopsies of the 25 UC patients were included in the study. Through matching with the Smillie-trained reference dataset, a total of 159,188 cells and 54 high granularity-specific cell types were identified in the biopsy dataset. To obtain the final cell type classification, the original biopsy dataset was subdivided into three different compartments through specific markers. The epithelial compartment was isolated selecting the cells showing an average gene expression of EPCAM>3. Subsequently, the stromal compartment was extracted using THY>0.3 (fibroblasts), SOX10>2 (glia) and MADCAM> 1 (endothelial) as markers. The remaining CD45+ and CD27+ cells were deemed the immune compartment. For the epithelium, a total of 71,547 cells and 16 cell types were identified using Azimuth with the Smillie reference set. In addition to the Azimuth cell types the biologically relevant Paneth-like cells were assigned based on marker expression (LYZ, REG3A, module score > 2). For the immune compartment, a total of 68,809 cells and 25 cell types were identified using Azimuth with the Smillie reference set (ref). Again, specific marker gene expression was used to assign additional biologically relevant cell types. The plasma compartment was further subdivided into IgA (IGHA1> 250), IgG (IGHG1> 80), IgM (IGHM>900), and Ig-negative cell types. Furthermore, plasmacytoid dendritic cells (pDCs) cells were identified (ITM2C, PLD4, SERPINF1, LILRA4, IL3RA, TPM2, MZB1, SPIB, IRF4, SMPD3, module score > 0.6). Finally, a total of 18,832 cells and 13 cell types were identified inside the stromal compartment using 176 WBD (US) 4854-8046-9185v2 Azimuth with the Smillie reference set. Using the same cell type annotation approach, a total of 95.057 PBMCs were profiles and 30 cell types were identified. Single cell profiling of CD45+ cells from biopsies and PBMCs using Cytek Flow cytometry data of the PBMCs of the 25 UC patients were included in the study. Four subsets of PBMCs were identified: myeloid cells, natural killer cells (NKs) and innate lymphoid cells (ILCs), B cells, and T cells. Myeloid cells were subsampled to include all 188.146 cells. An UMAP was generated based on the selection of all files, CD141, ITGB7, CD1d, CD19, CD123, CD11c, CD103, CD14, CD16, CD56, CD4 as features and Neighbors = 80, Minimum Distance = 0.7, Components = 2, Metric = Euclidean, Learning Rate = 1, Epochs = 250, Random Seed = 6045, Embedding Initialization = spectral. Afterwards FlowSOM was run, with the comma- separated k values of 80. Doublets were identified. Metaclusters were appointed to a cell type based on their position in the classical gates.8 myeloid cell types were identified. First monocytes were grouped based on the expression of CD14 and CD16: Non-classical monocytes (CD14+Cd16), intermediate monocytes (CD14+CD16+), classical monocytes (CD14+CD16-) and classical monocytes 2 (CD14dCD16d). DCs were annotated based on CD14-CD16d cells. Next CD123+ pDCs were identified. Left over cells were further subdivided into CD1c+ and CD141+ cells. NKs and ILCs were subsampled to include all 51.459 cells. An UMAP was generated based on the selection of all files, CD57, gdTCR, CD19, CD123, CD8, CD14, CD16, CD20, CD56, CD4, APC-R700-A, BV510-A as features and Neighbors = 80, Minimum Distance = 0.7, Components = 2, Metric = Euclidean, Learning Rate = 1, Epochs = 250, Random Seed = 3666, Embedding Initialization = spectral. Afterwards FlowSOM was run, with the comma-separated k values of 50. Metaclusters with clear expression of CD127+ were grouped as ILCs. All leftover metaclusters were combined and manually gated on concatenated files to identify 8 cell types consisting of CD56bCD16-, early NKs (CD56bCD16d), CD56bCD16b, CD56dCD16-, mature NKs (CD56dCD16b), CD56-CD16- and terminal NKs (CD56-CD16b) and 3 cell type groups (CD56bright, CD56dim, CD56neg). B cells were subsampled to include all 31.774 cells. An UMAP was generated based on the selection of all files, ITGB7, CD38, CD19, CD27, IgD, IgG, IgM, CD103, CD20, CD49d and CD24 as features and Neighbors = 80, Minimum Distance = 0.7, Components = 2, Metric = Euclidean, Learning Rate = 1, Epochs = 250, Random Seed = 7809, Embedding Initialization = spectral. Afterwards FlowSOM was run, 177 WBD (US) 4854-8046-9185v2 with the comma-separated k values of 50. Metaclusters were appointed to a cell type based on their position in the classical gates.4 B cell types were identified. First B cells were subgrouped into Translational B cells (CD27+CD38-), plasmablasts (CD27+CD38+) and CD38- cells. CD38- cells are subgrouped IgD- memory B cells (IgD-) and metaclusters best matching CD27- IgD+ cells were annotated as naive B cells. Metacluster were visually appointed to a cell type based on position in the general gates. IgD- memory B cells (IgD-) were further subclustered based on switched IgD- memory B cells and IgD- non-switched cells (IgM+, also called IgM+ cells). Switched IgD- memory B cells were subannotated as IgG+ when showing a high expression of IgG. Switched IgD- memory B cells combined with IgG+ and IgM+ cells are all memory B cells. A few cells were left unannotated. T cells were subsampled to include all 619.961 cells. An UMAP was generated based on the selection of all files, D57, gdTCR, ITGB7, CD38, CD17, CCR7, CD28, PD-1, CD103, CD8, CD56, CD45RA, CD49d, CD25, CD4, CXCR3, APC-R700-A (CD127) and BV510-A (CD3) as features and Neighbors = 80, Minimum Distance = 0.7, Components = 2, Metric = Euclidean, Learning Rate = 1, Epochs = 250, Random Seed = 3183, Embedding Initialization = spectral. Afterwards FlowSOM was run, with the comma-separated k values of 120.17 or more T cell types were identified. Metacluster were visually appointed to a cell type based on position in the general gates. Metaclusters positive for gdTCR were grouped as gd T cells (CD3+gdTCR+). Metaclusters negative for gdTCR were divided into CD56- and CD56+ cells, the latter group forms the NKT- Like cells. Metacluster negative for CD3- but positive for CD4+ and CD8+ were also annotated. The left over metaclusters are appointed to CD8+, double positive (dp: CD4+CD8+), CD4+ and double negative (dn: CD4-CD8-) based on their position in the general gates. CD4+ metaclusters were divided into Tregs (CD25hiCD127lo) based on their position in the general gates. CD4+ non Treg cell metaclusters were fused and manually clustered based on markers CCR7 and CD45RA. Resulting in CD4+ TEMRA (CCR7-CD45RAb), CD4+ Naive T cells (CCR7+CD45RAb), CD4+ Late TEM (CCR7-CD45RAd), CD4+ Translation TCM (CCR7+CD45RAd), CD4+ TEM (CCR7-CD45RA-) and CD4+ TCM (CCR7-CD45RA-). Effector memory cells were also fused and manually subclustered based on CD27 and CD28, resulting in CD4+ early like TEM (CD27- CD28+), CD4+ early TEM (CD27+CD28+), CD4+ intermediate TEM (CD27+CD28-), CD4+ terminal TEM (CD27-CD28-). CD8+ cell metaclusters were fused and manually clustered based on markers CCR7 and CD45RA. Resulting in CD8+ TEMRA (CCR7-CD45RAb), CD8+ Naive 178 WBD (US) 4854-8046-9185v2 T cells (CCR7+CD45RAb), CD8+ Late TEM (CCR7-CD45RAd), CD8+ Translation TCM (CCR7+CD45RAd), CD8+ TEM (CCR7-CD45RA-) and CD8+ TCM (CCR7+CD45RA-). Effector memory cells were also fused and manually subclustered based on CD27 and CD28, resulting in CD8+ early like TEM (CD27-CD28+), CD8+ early TEM (CD27+CD28+), CD8+ intermediate TEM (CD27+CD28-) and CD8+ terminal TEM (CD27-CD28-). For gut mucosal biopsies a similar cell type annotation approach was used. Gut mucosal biopsies collected from 15 patients were included in the study. Four subsets were identified: epithelial cells, myeloid cells, B cells, and T cells/NKs/ILCs. Compositional analysis reveals changes in cell abundances that take place in the mucosa and peripheral blood of VDZ-treated UC patients To investigate potential differences in cellular composition associated with VDZ treatment, the frequencies of cell types were compared between responders and non-responders both at pre- VDZ and at post-VDZ. The analysis was executed in parallel for single-cell RNA-seq data and Cytek data to allow for the necessary comparisons. Cell composition changes over treatment duration in responders (FIG.3) At post-VDZ compared to pre-VDZ, analysis of cell abundances in scRNAseq data revealed a partial recovery of the epithelial and stromal cell mucosal compartments in responders after treatment. Specifically, the abundance of enterocyte progenitors, BEST4+ enterocytes, immature enterocytes, goblet cells, immature goblet cells, microfold (M) cells, cycling TA cells, secretory TA cells, TA 1 cells, TA 2 cells, stem cells, WNT5B+ 1 fibroblasts, WNT5B+ 2 fibroblasts, WNT2B+ Fos-lo 1 fibroblasts, RSPO3+ fibroblasts increased, while the abundance of inflammatory fibroblasts and Paneth-like cells decreased. In colon mucosa at post-VDZ the scRNA-seq analysis showed that responders had lower frequencies of CD4+ PD1+ T cells, CD4+ Memory T cells, CD4+ activated Fos-lo T cells, CD8+ IL17+T cells, Cycling T cells, GC, IgM plasma cells, NK cells, DC1, DC2, inflammatory monocytes, macrophages, and CD69+ mast cells. The Cytek analysis showed results similar to the scRNA-seq: in responders, CD4+ naive T cells, CD8 naive T cells, CD4+ Memory T cells, B naive cells, DCs, macrophages, ILCs, plasmablasts, and pDCs were decreased at post-VDZ compared to pre-VDZ (FIG.2). In the 179 WBD (US) 4854-8046-9185v2 peripheral blood in responders, both scRNA-seq analysis and Cytek data analysis showed an increase in the presence of certain cell types: The scRNA-seq analysis revealed a significant increase in the percentage of CD4+ Cytotoxic T cells, NK cells, cDC2, and pDC in post-VDZ compared to pre-VDZ in responders. Similarly, at post-VDZ in responders, Cytek data analysis showed an increased presence of NK cells, pDCs, and CD16+ monocytes, and a decrease of CD8+ Naive T cells and CD4-CD8- T cells. Cell composition changes over treatment duration in non-responders (Tables 7-8) At post-VDZ compared to pre-VDZ, colonic biopsies from non-responders to VDZ showed an increase within the stromal compartment including Glia cells, WNT2B+ Fos-lo 1 fibroblasts, RSPO3+ fibroblasts, WNT5B+ 1 fibroblasts, microvascular cells, and myofibroblasts in the scRNA-seq analysis. Cytek analysis at post-VDZ compared to pre-VDZ showed an increase in mucosal CD8+ effector memory T cells (CD8 TEM), CD8+ memory T cells (CD8 CM), CD4+ memory T cells, and γδ-T cells, and a decrease in DC2s, naive B cells, and DCs in non- responders (FIG.2). In the peripheral blood, the scRNA-seq analysis revealed a significant increase of CD4+ naïve T cells and CD4+ TCM and a decrease in NK proliferating cells in non- responders. In the Cytek analysis of the peripheral blood of non-responders between pre-VDZ and post-VDZ an increase in CD4+ naïve T cells, CD4+ transitional TCM, Treg, CD8+ naïve T cells and a decrease in plasmablasts was observed. Tables 7-8 show changes in cell composition of the mucosa and PBMCs in responders and non-responders after 14 weeks of treatment with vedolizumab. Statistical analysis was performed using two methods: the Bayesian multinomial logistic regression (pibble model) with the credible intervals (CI) 75%, 90% and 95%, and the Wilcoxon rank sum test (p value < 0.05). For each cell type, the direction of change post-VDZ is shown in column “change” and level of significance is recorded as CI (for pibble) and p value (for Wilcoxon test), while “–” represents no significant change. Some cell types from the mucosal Cytek dataset were merged to match cell types identified in the mucosal scRNA-seq dataset. Specifically, “CD4+ naive T cells” included CD25– CD4+ naive T cells and CD45RA+CD25dim CD4+ naive T cells, “CD4+ TEM” included CD25dim CD4+ TEM and CD25int CD4+ TEM, and “Tregs” included CD25high memory Tregs and CD25int naive Tregs. PBMCs, peripheral blood mononuclear 180 WBD (US) 4854-8046-9185v2 cells; VDZ, vedolizumab; pre-VDZ, 2 weeks prior to vedolizumab treatment; post-VDZ, 14 weeks after vedolizumab treatment. Table 7. Responders, changes post-VDZ (compared to pre-VDZ) Responders, changes post-VDZ (compared to pre-VDZ) Tissue Compart Cell Change Change CI P value technique ment Mucosa Epitheliu Enterocyte Increase 95% 0.013 scRNAseq m progenitors Mucosa Epitheliu BEST 4+ Increase 95% 0.0002 scRNAseq m enterocytes Mucosa Epitheliu Immature Increase 90% 0.023 scRNA-seq m enterocytes 2 Mucosa Epitheliu Goblet Increase 90% 0.038 scRNA-seq m Mucosa Epitheliu Immature goblet Increase 95% - scRNA-seq m Mucosa Epitheliu M cells Increase 75% - scRNA-seq m Mucosa Epitheliu Cycling TA Increase 95% 0.008 scRNA-seq m Mucosa Epitheliu Secretory TA Increase 95% 0.0001 scRNA-seq m Mucosa Epitheliu TA 1 Increase 95% - scRNA-seq m Mucosa Epitheliu TA 2 Increase 95% 0.004 scRNA-seq m Mucosa Epitheliu Stem Increase 95% 0.0004 scRNA-seq m Mucosa Epitheliu Paneth-like cells Decrease 95% - scRNA-seq m Mucosa Stroma WNT5B+ 1 Increase 95% - scRNA-seq Mucosa Stroma WNT5B+ 2 Increase 95% 0.017 scRNA-seq Mucosa Stroma WNT2B+ Fos-lo 1 Increase 95% 0.043 scRNA-seq Mucosa Stroma WNT2B+Fos-hi Increase 90% - scRNA-seq Mucosa Stroma RSPO3+ Increase 90% - scRNA-seq fibroblasts Mucosa Stroma Myfibroblasts Increase 75% - scRNA-seq Mucosa Stroma Inflammatory Decrease 95% 0.041 scRNA-seq fibroblasts Mucosa Immune CD4+ PD1+ Decrease 95% - scRNA-seq Mucosa Immune CD4+ TCM Decrease 75% - scRNA-seq 181 WBD (US) 4854-8046-9185v2 Responders, changes post-VDZ (compared to pre-VDZ) Tissue Compart Cell Change Change CI P value technique ment Mucosa Immune CD4+ activated Decrease 95% 0.032 scRNA-seq Fos-lo Mucosa Immune CD8+ IL17+ Decrease 95% - scRNA-seq Mucosa Immune Cycling T Decrease 95% - scRNA-seq Mucosa Immune GC Decrease 75% - scRNA-seq Mucosa Immune IgM Decrease 95% - scRNA-seq Mucosa Immune NKs Decrease 95% - scRNA-seq Mucosa Immune DC1 Decrease 75% - scRNA-seq Mucosa Immune DC2 Decrease 95% - scRNA-seq Mucosa Immune Inflammatory Decrease 95% 0.023 scRNA-seq monocytes Mucosa Immune Macrophages Decrease 95% - scRNA-seq Mucosa Immune CD69- mast Decrease 95% - scRNA-seq Mucosa Immune CD4+ TEM Increase 75% - Cytek Mucosa Immune CD4+ naïve Decrease 75% - Cytek Mucosa Immune CD4+ TCM Decrease - 0.034 Cytek Mucosa Immune CD8+ naïve Decrease 95% 0.017 Cytek Mucosa Immune B naïve Decrease 95% 0.027 Cytek Mucosa Immune B non-switch Decrease 75% - Cytek Mucosa Immune DCs Decrease 95% 0.005 Cytek Mucosa Immune CD123+ pDCs Decrease 90% - Cytek Mucosa Immune Macrophages Decrease 75% - Cytek Mucosa Immune ILCs Increase 95% 0.007 Cytek Mucosa Immune Plasmablasts Increase 75% - Cytek PBMCs Immune CD4+ CTL Increase 75% - scRNA-seq PBMCs Immune NKs Increase 90% - scRNA-seq PBMCs Immune cDC2 Increase 75% - scRNA-seq PBMCs Immune pDCs Increase 95% 0.039 scRNA-seq PBMCs Immune Plasmablasts Decrease 95% - scRNA-seq PBMCs Immune CD8+ Naïve Decrease 75% - Cytek PBMCs Immune CD4-CD8- T cells Decrease 95% - Cytek PBMCs Immune NK mature Increase 75% - Cytek PBMCs Immune NK early Increase 75% 0.024 Cytek PBMCs Immune CD123+ pDCs Increase 95% 0.004 Cytek PBMCs Immune CD1c+ DCs Increase - 0.046 Cytek 182 WBD (US) 4854-8046-9185v2 Responders, changes post-VDZ (compared to pre-VDZ) Tissue Compart Cell Change Change CI P value technique ment PBMCs Immune Non-classical Increase 75% - Cytek monocytes PBMCs Immune Plasmablasts Decrease 95% - Cytek Table 8. Non-Responders, changes post-VDZ (compared to pre-VDZ) Non-Responders, changes post-VDZ (compared to pre-VDZ) Tissue Compartment Cell Change Change CI P value technique Mucosa Stroma Glia Increase 95% 0.01 scRNA-seq Mucosa Stroma WNT2B+ Fos-lo 1 Increase 75% - scRNA-seq Mucosa Stroma RSPO3+ Increase 75% 0.026 scRNA-seq fibrbolasts Mucosa Stroma WNT5B+ 1 Increase 75% - scRNA-seq Mucosa Stroma Microvascular Increase 75% - scRNA-seq Mucosa Stroma Myofibroblasts Increase 75% - scRNA-seq Mucosa Immune CD4+ activated Decrease 75% - scRNA-seq Fos-lo Mucosa Immune DC2 Decrease 75% - scRNA-seq Mucosa Immune CD4+ TCM Increase 75% - Cytek Mucosa Immune CD8+ TEM Increase 90% - Cytek Mucosa Immune CD8 TCM Increase 90% - Cytek Mucosa Immune B non-switch Decrease 95% - Cytek Mucosa Immune B naïve Decrease 95% - Cytek Mucosa Immune γδ T Increase 90% - Cytek Mucosa Immune DCs Decrease 95% - Cytek PBMCs Immune CD4+ naïve Increase 75% - scRNA-seq PBMCs Immune CD4+ TCM Increase 75% - scRNA-seq PBMCs Immune NK proliferating Decrease 75% - scRNA-seq PBMCs Immune B intermediate Decrease - 0.011 scRNA-seq PBMCs Immune CD4+ naïve Increase 75% - Cytek PBMCs Immune CD4+ transitional Increase 75% - Cytek TCM PBMCs Immune Tregs Increase 75% - Cytek PBMCs Immune CD8+ naïve Increase 75% - Cytek PBMCs Immune Plasmablasts Decrease 95% 0.004 Cytek Cell composition differences between responders and non-responders at pre-VDZ (Tables 9-10) 183 WBD (US) 4854-8046-9185v2 To analyze whether the initial amount of innate and adaptive immune cells in the peripheral blood and mucosa of UC patients correlated to the outcome of the response to subsequent VDZ therapy, the cell abundances between non-responders and responders prior to the commencement of VDZ therapy were compared. In the scRNA-seq analysis of the colon mucosa at pre-VDZ non-responders had lower initial frequencies of tuft cells and glial cells and higher initial frequencies of enterocyte progenitors than responders. In the scRNA-seq analysis of the colon mucosa at pre-VDZ non-responders had higher baseline abundances of NKs, ILCs, DC2s, inflammatory monocytes, and Ig-negative plasma cells, and lower baseline abundances of CD69- and CD69+ mast cells compared to responders. These observations were largely confirmed in the Cytek analysis, which showed that there was a notable higher level of mucosal NKs, ILCs, DCs, and γδ-T cells and a decrease of macrophages in non-responders compared to responders at baseline (FIG.2). PBMC samples mirrored those in the mucosa: The scRNA-seq analysis revealed a higher level of peripheral blood NKs, NK proliferating cells, and γδ-T cells, and a decrease of CD8+ naive T cells and B memory cells in non-responders compared to responders at pre-treatment. Similarly, in Cytek analysis, a higher number of peripheral blood of NKs, cDC1, γδ-T cells, and a decrease of many CD4+ and CD8+ T cells and B cells (see Tables 9-10) in non- responders compared to responders before the start of VDZ treatment was observed. Tables 9-10 show changes in cell composition of the mucosa and PBMCs in non- responders 2 weeks prior to vedolizumab treatment (pre-VDZ) and 14 weeks after (post-VDZ) compared to responders. Statistical analysis was performed using two methods: the Bayesian multinomial logistic regression (pibble model) with the credible intervals (CI) 75%, 90% and 95%, and the Wilcoxon rank sum test (p value < 0.05). For each cell type, the direction of change post-VDZ is shown in column “change” and level of significance is recorded as CI (for pibble) and p value (for Wilcoxon test), while “–” represents no significant change. Some cell types from the mucosal Cytek dataset were merged to match cell types identified in the mucosal scRNA-seq dataset. Specifically, “CD4+ naive T cells'' included CD25– CD4+ naive T cells and CD45RA+CD25dim CD4+ naive T cells, “CD4+ TEM” included CD25dim CD4+ TEM and CD25int CD4+ TEM, and “Tregs” included CD25high memory Tregs and CD25int naive Tregs. PBMCs, peripheral blood mononuclear cells; VDZ, vedolizumab; pre-VDZ, 2 weeks prior to vedolizumab treatment; post-VDZ, 14 weeks after vedolizumab treatment. 184 WBD (US) 4854-8046-9185v2 Table 9. Pre-VDZ, changes in non-responders (compared to responders) Pre-VDZ, changes in non-responders (compared to responders) Tissue Compartment Cell Change CI P value technique Change Mucosa Epithelium Enterocyte Increase 75% - scRNAseq progenitors Mucosa Epithelium Tuft Decrease 75% 0.034 scRNAseq Mucosa Stroma Glia Decrease 90% - scRNA-seq Mucosa Immune Cycling B Decrease 75% - scRNA-seq Mucosa Immune Ig negative Increase 75% - scRNA-seq Mucosa Immune NKs Increase 75% - scRNA-seq Mucosa Immune ILCs Increase - 0.040 scRNA-seq Mucosa Immune DC2 Increase 95% - scRNA-seq Mucosa Immune Inflammator Increase 75% - scRNA-seq y monocytes Mucosa Immune CD69- mast Decrease 90% - scRNA-seq Mucosa Immune CD69+ mast Decrease 75% - scRNA-seq Mucosa Immune B memory Decrease 75% - Cytek Mucosa Immune Macrophage Decrease 75% - Cytek s Mucosa Immune NKs Increase 90% - Cytek Mucosa Immune ILCs Increase 75% - Cytek Mucosa Immune DCs Increase 90% - Cytek Mucosa Immune γδ T Increase 75% - Cytek PBMCs Immune CD8+ naïve Decrease 75% - scRNA-seq PBMCs Immune B memory Decrease 75% - scRNA-seq PBMCs Immune NKs Increase 95% 0.027 scRNA-seq PBMCs Immune NK Increase - 0.024 scRNA-seq proliferating PBMCs Immune γδ T Increase 90% - scRNA-seq PBMCs Immune CD4+ naïve Decrease 75% 0.035 Cytek PBMCs Immune CD4+ Decrease 95% 0.002 Cytek transitional naïve PBMCs Immune CD4+ late Decrease 90% - Cytek TEM PBMCs Immune CD4+ Decrease 75% - Cytek TEMRA PBMCs Immune CD8+ naïve Decrease 95% - Cytek PBMCs Immune CD8+ TEM Decrease 95% - Cytek PBMCs Immune CD8+ Decrease 75% - Cytek 185 WBD (US) 4854-8046-9185v2 Pre-VDZ, changes in non-responders (compared to responders) Tissue Compartment Cell Change CI P value technique Change TEMRA PBMCs Immune CD4-CD- T Decrease 75% - Cytek cells PBMCs Immune B memory Decrease 95% 0.028 Cytek PBMCs Immune B naïve Decrease 75% - Cytek PBMCs Immune NK mature Increase 95% 0.001 Cytek PBMCs Immune NK terminal Increase 95% 0.006 Cytek PBMCs Immune NK early Increase 95% 0.030 Cytek PBMCs Immune ILCs Decrease 90% - Cytek PBMCs Immune CD1c- Increase - 0.040 Cytek CD141+ DCs PBMCs Immune γδ T Increase 75% - Cytek PBMCs Immune Non- Increase 75% 0.035 Cytek classical monocytes PBMCs Immune Intermediate Increase 75% - Cytek monocytes Table 10. Post-VDZ, changes in non-responders (compared to responders) Post-VDZ, changes in non-responders (compared to responders) Tissue Compartment Cell Change Change CI P value technique Mucosa Epithelium Immature Decrease 75% - scRNA-seq enterocytes 2 Mucosa Epithelium BEST4+ Decrease 75% - scRNA-seq enterocytes Mucosa Epithelium Immature goblet Decrease 95% 0.012 scRNA-seq Mucosa Epithelium Enteroendocrine Decrease 90% - scRNA-seq Mucosa Epithelium M cells Decrease 95% - scRNA-seq Mucosa Epithelium Cycling TA Decrease 95% 0.006 scRNA-seq Mucosa Epithelium Secretory TA Decrease 95% 0.006 scRNA-seq Mucosa Epithelium TA 1 Decrease 75% - scRNA-seq Mucosa Epithelium TA 2 Decrease 90% - scRNA-seq Mucosa Epithelium Stem Decrease 95% 0.011 scRNA-seq Mucosa Epithelium Tuft Decrease 75% - scRNA-seq Mucosa Epithelium Paneth-like cells Increase - 0.014 scRNA-seq Mucosa Stroma Inflammatory Increase 90% - scRNA-seq fibroblasts 186 WBD (US) 4854-8046-9185v2 Post-VDZ, changes in non-responders (compared to responders) Tissue Compartment Cell Change Change CI P value technique Mucosa Stroma Post-capillary Increase 75% - scRNA-seq venules Mucosa Stroma WNT2B+ Fos-lo Increase 75% - scRNA-seq 2 Mucosa Immune NKs Increase 95% - scRNA-seq Mucosa Immune DC1 Increase 75% - scRNA-seq Mucosa Immune DC2 Increase 75% - scRNA-seq Mucosa Immune Inflammatory Increase 95% - scRNA-seq monocytes Mucosa Immune Macrophages Increase 90% - scRNA-seq Mucosa Immune CD8+ IL17+ Increase 95% - scRNA-seq Mucosa Immune Ig negative Increase 95% - scRNA-seq Mucosa Immune IgG Increase 90% - scRNA-seq Mucosa Immune IgM Increase 75% - scRNA-seq Mucosa Immune CD4+ naïve Increase 75% - Cytek Mucosa Immune CD8+ TEM Increase 75% - Cytek Mucosa Immune CD8+ TCM Increase 75% - Cytek Mucosa Immune CD8+ TEMRA Increase 75% - Cytek Mucosa Immune B memory Decrease 75% - Cytek Mucosa Immune B naïve Decrease 75% - Cytek Mucosa Immune B non-switch Decrease 90% - Cytek Mucosa Immune NKs Increase 90% - Cytek Mucosa Immune γδ T Increase 95% - Cytek PBMCs Immune γδ T Increase 75% - scRNA-seq PBMCs Immune pDC Decrease 75% - scRNA-seq PBMCs Immune cDC1 Decrease 75% - scRNA-seq PBMCs Immune ASDC Decrease 75% 0.037 scRNA-seq PBMCs Immune CD4+ TEMRA Decrease 75% - Cytek PBMCs Immune CD8+ TCM Decrease - 0.037 Cytek PBMCs Immune Tregs Increase 75% - Cytek PBMCs Immune CD8+ naïve Increase 75% - Cytek PBMCs Immune NK mature Increase 75% - Cytek PBMCs Immune Classical Increase 75% - Cytek monocytes PBMCs Immune CD123+ pDCs Decrease 90% - Cytek PBMCs Immune Plasmablasts Decrease 75% - Cytek Cell composition differences between responders and non-responders at post-VDZ (Tables 9-10) 187 WBD (US) 4854-8046-9185v2 After 14 weeks of VDZ treatment, non-responders to VDZ were characterized in the mucosal scRNA-seq analysis by an expansion of inflammatory fibroblasts and activated endothelial cells (post-capillary venules), WNT2B+ Fos-lo 2 fibroblasts and depletion of most epithelial subsets including immature enterocytes, BEST4+ enterocytes, immature goblet cells, enteroendocrine cells, M cells, cycling TA cells, secretory TA cells, TA 1 cells, TA 2 cells, stem cells and an decrease of Paneth-like cells compared to responders. Additionally, both scRNA-seq and Cytek analysis of colon mucosa revealed that non-responders still showed active mucosal inflammation, as evidenced by a larger proportion of infiltrating innate and adaptive immune cells compared to responders. In particular, an increase in the abundance of mucosal NKs, DC1 cells, DC2 cells, inflammatory monocytes, macrophages, CD8+ IL17+ T cells, plasma cells in non-responders compared to responders at pre-VDZ was detected based on the single-cell RNA-seq analysis. The results obtained from Cytek analysis in the mucosa were comparable with the scRNA-seq analysis (FIG.2). A higher abundance was observed in the presence of NKs, γδ-T cells, CD4+ naive, CD8+ TEM, CD8+ memory T cells, CD8+CD45RA+ T cells, and a lower abundance of many B-cell lines (see Tables 9-10) in non-responders compared to responders 14 weeks after VDZ treatment. In line with the observation of intestinal inflammation, Cytek analysis showed a significant increase in NKs, CD14+ monocytes, CD8+ naïve T cells, and Tregs in PBMCs in non-responders compared to responders at post-VDZ. In the PBMC scRNAseq data a higher abundance of γδ-T cells and a lower abundance of pDC and cDC1 cells in non-responders vs responders post-VDZ was observed. In the PBMC Cytek data a higher abundance of Tregs, CD8+ naïve T cells, NK cells and classical monocytes and a lower abundance of CD4+ T effector memory cells, CD8+ T central memory cells, CD123+ pDCs, plasmablasts in non- responders vs responders post-VDZ was observed. Impact of prior anti-TNF exposure, anatomical location in the gut and presence of inflammation on differential cell abundance analysis To assess the impact of previous anti-TNFα treatment, the patients were further divided into two subgroups: anti-TNFα experienced and anti-TNFα naïve patients. The differential expression and signaling pathway comparisons between responders and non-responders pre-treatment were then performed in both subgroups. The results indicate that previous anti-TNFα treatment did not introduce a bias, as similar patterns were observed in both anti-TNFα experienced and naïve patient subgroups. 188 WBD (US) 4854-8046-9185v2 Changes in integrin expression and surface presence in mucosal and circulating immune cells in VDZ-treated UC patients To investigate the differential response to VDZ therapy, changes in integrin expression were performed between responders and non-responders in both pre-VDZ and post-VDZ. For the scRNA-seq analysis, the Seurat implementation of MAST was used for the identification of significant differences between responders and non-responders over treatment duration. All adjusted p-values subject to multiple testing have been corrected by a Benjamini-Hochberg adjustment. For the Cytek analysis, the differences between the positive median fluorescence intensity and negative median fluorescence intensity of integrins were analyzed to detect changes in integrin expression. Statistical differences were identified using the Wilcoxon rank-sum test, and p-values less than 0.05 were considered to be statistically significant. Differential expression of α4 and β7 integrins during vedolizumab treatment in PBMCs In both responders and non-responders, the surface presence of α4 and β7 goes down in peripheral blood CD4+ T cells and CD8+ T cells of various phenotypes. No differential decrease of α4 and β7 presence was observed between responders and non-responders. Differential expression of alternative integrins during vedolizumab treatment in PBMCs No differential expression nor surface presence of alternative integrins between responders and non-responders was observed, suggesting these do not play a role in VDZ non-response. Differential expression of α4 and β7 integrins during vedolizumab treatment in colonic mucosa Responders over VDZ treatment duration At post-treatment compared to pre-treatment, in responders, the gene expression of ITGA4 was increased on CD4+ T cells, CD8+ T cells, and plasma with negative Ig, IgA, and IgM. However, a significant decrease in the expression of alpha 4 was observed at the protein level, as shown by Cytek analysis, on CD4+ T cells, CD8+ T cells, and B memory cells. The levels of beta 7 increased on T cells in responders as determined by Cytek analysis. Non-responders over VDZ treatment duration An opposite direction of integrin expression in non-responders over VDZ treatment was observed. At post-treatment compared to pre-treatment, ITGA4 gene expression was found to be 189 WBD (US) 4854-8046-9185v2 lower in Inflammatory Monocytes, CD8+ T cells, Follicular, GC, and IgG plasma in non- responders. In non-responders, the gene expression of ITGA4 and ITGB7 was decreased in IgG plasma (suggesting the effect of VDZ is in peripheral lymph nodes based on the interaction of plasma cells and effector T cells). However, an increase in alpha 4 expressions was detected in CD4+ T cells, CD8+ T cells, and B memory cells, as evidenced by the results of Cytek analysis. Non-responders displayed reduced beta 7 expressions on CD4+ T cells, γδ-T cells, and Plasmablast based on Cytek evaluation. Non-responders vs. responders at pre-treatment At pre-treatment, responders show a lower ITGA4 gene expression compared to non-responders. While it might be considered a sign of minor inflammation severity, the same pattern was not observed in the ITGB7 gene expression. Non-responders vs. responders at post-treatment At post-treatment, the ITGA4 gene was upregulated on Inflammatory Monocytes, CD69+ Mast, DCs, IgA, and IgG plasma in responders compared to non-responders, and the ITGB7 gene was upregulated on Tregs, Follicular, IgA, and IgG plasma (the compensatory mechanism). Differential expression of alternative integrins (α1, α3, αE, αM, αL, αX, β1 and β2) during
Figure imgf000191_0001
Responders over VDZ treatment duration At post-treatment compared to pre-treatment, in responders, the gene expression of alternative integrins such as ITGA1, ITGA3, ITGAE, ITGAL, ITGAX, ITGB1, and ITGB2 was decreased among the B cell subsets including Follicular B cells, GC cells, Ig-negative, IgA, and IgG plasma cells. In the same condition, the expression of ITGAX and ITGB1 was downregulated and that expression of ITGB2 was upregulated in the Inflammatory Monocytes of responders. Cytek analysis showed in responders an increase in alpha E on T cell subsets including CD4+ T cells and CD8+ T cells and a decrease in beta 2 on NKs and pDCs compared to non-responders. Non-responders over VDZ treatment duration At post-VDZ compared to pre-VDZ, non-responders showed a higher gene expression of ITGAL, ITGAM, ITGAX, ITGB1, and ITGB2 on Follicular B cells and GC cells than responders. 190 WBD (US) 4854-8046-9185v2 Furthermore, a significantly elevated ITGAX and ITGB1 gene expression among plasma in the same patients was observed. NK expressed increased ITGB2 in non-responders, and Inflammatory Monocytes exhibited an increased ITGAX and a decreased ITGAL, ITGAM, ITGB1, and ITGB2 gene expression. At the protein level, ITGB2 was downregulated in Macrophages in non-responders compared to responders. Non-responders vs. responders at pre-treatment At pre-treatment, in non-responders, inflammatory monocytes expressed a higher level of ITGAE, ITGAM, and ITGB2 gene expression than responders. ITGB2 gene was highly expressed on GC and plasma with IgA, IgG, and IgM in non-responders compared to responders. The heightened expression of the ITGAE gene was observed on Inflammatory Monocytes, CD4+ T cells, Tregs, and B cell subsets. Tregs of non-responders displayed an elevated ITGAE expression compared to responders, which was supported by protein measurements. Non-responders vs. responders at post-treatment At post-treatment, ITGB2 was upregulated on Inflammatory Monocytes in responders compared to non-responders. Increase of ITGB2 was also observed on Macrophages, NKs, and Plasmablast in responders compared to non-responders at post-treatment through protein analysis. Dysregulated functional state of inflammatory monocytes and Tregs, and a distinct signaling pattern of inflammatory fibroblasts substantiate non-response to vedolizumab Inflammatory monocytes in mucosa of non-responders expressed a set of alternative integrins that was different in responders. Furthermore, the relative abundance of inflammatory monocytes was increased in non-responders before VDZ therapy both in PBMCs and mucosal biopsies compared to responders. To gain large-scale insights into underlying differences in the composition of the transcriptome between responders and non-responders to VDZ on inflammatory monocytes, differential expression and signaling pathways of two cell types in mucosal biopsies between responders and non-responders at baseline was comparatively assessed. When separated from other cells in the dataset, clustering of inflammatory monocytes captured in the mucosa prior to treatment (n=1355) was largely driven by the response outcome, 191 WBD (US) 4854-8046-9185v2 indicating that inflammatory monocytes in non-responders have a distinct transcriptional profile compared to responders. Indeed, differential gene analysis identified 482 genes that distinguished these inflammatory monocytes: 205 genes were significantly upregulated in non- responders and 277 genes in responders (FIG. 1A). Genes indicative of pro-inflammatory macrophage profile (IL1B, IL1RN, CCL3, CCL4, CXCL2 and CXCL3) were upregulated in inflammatory monocytes of responders, while in non-responders they highly expressed S10011A, S100A6, S100A4, LGALS1 and LGALS3. The latter encodes galectin-3, a macrophage-secreted protein that is involved in cell adhesion and chemotaxis. To confirm the macrophage-like identity of inflammatory monocytes, immunohistochemical staining of the UC colonic mucosa was performed and showed a large overlap between CD68+ cells and galectin-3+ cells indicating the accumulation of (inflammatory) monocyte-derived macrophages in the lamina propria. Gene set enrichment analysis (GSEA) was used to infer molecular pathways that underlie the divergent transcriptional profiles of inflammatory monocytes. When analyzing underlying signaling pathways of the differentially expressed genes in Inflammatory Monocytes of responders to therapy, similar pathways among the top 10 pathways were merged based on similar gene signatures. Neutrophil mediated immunity, cellular response to lipopolysaccharide, interferon- gamma-mediated signaling pathway, and cytokine-mediated signaling pathway were among the most significantly regulated pathways in responders, which were suggestive of the specific function of monocytes including presenting antigens, promoting inflammation, and wound repair. In non-responders, many upregulated genes were involved in cellular protein translation and metabolism, like regulation of the T cell apoptotic process, ribosome assembly and biogenesis, and cellular protein metabolic process (FIG. 1A-B). In responders, pathways such as inflammatory response, regulation of lymphocyte mediated immunity, activation of innate immune response and cellular response to cytokine stimulus were significantly upregulated (FIG. 1E). This functional profile suggests that these mucosal monocytes actively participate in mediating the immune responses, fulfilling the role of activated pro-inflammatory monocyte- derived macrophages that have been recruited to the site of inflammation. In contrast, enriched pathways in non-responders were mainly associated with metabolic and cellular component organization processes, e.g., amide metabolic process and cellular component organization or biogenesis (FIG. 1E). Thus, inflammatory monocytes are less active in mucosa of non- responders at baseline. Hence, VDZ non-response is marked by inflammatory monocytes 192 WBD (US) 4854-8046-9185v2 presenting an aberrant functional state, which has been previously described in UC as an overactivated phenotype (Cordes et al. Impaired IFN-γ-dependent STAT3 Activation Is Associated With Dysregulation of Regulatory and Inflammatory Signaling in Monocytes of Ulcerative Colitis Patients. Inflamm Bowel Dis 27, 887–901 (2021)). In line with this, responder inflammatory monocytes upregulated at baseline cytokines that are characteristic of M1 macrophages while non-responder monocytes did not, and responsiveness to VDZ was associated with a switch to a less pro-inflammatory (M2-like) profile at week 14 (FIG. 3B). Interestingly, not only mucosa-resident inflammatory monocytes but also circulating monocytes in non-responders displayed similarly aberrant phenotype prior to treatment (FIG.6). Innate immune cells cannot execute a productive inflammatory response without a well- coordinated action of adaptive immune cells. Among them, Tregs were of particular interest because a recent study reported that responses to VDZ are associated with a distinct behavior of Tregs (Abreu, et al. Transcriptional Behavior of Regulatory T Cells Predicts IBD Patient Responses to Vedolizumab Therapy. Inflamm Bowel Dis 28, 1800–1812 (2022)). Furthermore, the overactivated monocyte phenotype has been described to be unable to induce an adequate Treg reaction (Cordes et al. Impaired IFN-γ-dependent STAT3 Activation Is Associated With Dysregulation of Regulatory and Inflammatory Signaling in Monocytes of Ulcerative Colitis Patients. Inflamm Bowel Dis 27, 887–901 (2021)). Based on the differential gene expression and pathway analyses, it was found that Tregs in non-responders, much like inflammatory monocytes, do not seem to participate in the local inflammatory environment, while in responders they upregulate a spectrum of immune-mediating pathways (FIG.1F). Thus, as seen in inflammatory monocytes, a similar pattern in Tregs in mucosa of non-responders at baseline was observed (i.e., Tregs are less active in mucosa of non-responders at baseline). Non-immune cells are also known to be involved in the immune responses. In this case, the focus is on inflammatory fibroblasts since they have the highest anti-TNFα resistance score in UC among all mucosal cells (Smillie et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019)) and have been implicated in pathogenic cellular module that marks non-response to anti-TNFα in Crohn’s disease (Martin et al. Single- Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated 193 WBD (US) 4854-8046-9185v2 with Resistance to Anti-TNF Therapy. Cell 178, 1493–1508 (2019)). Although similarly abundant in the mucosa of responders and non-responders prior to VDZ treatment, inflammatory fibroblasts exhibited pronounced transcriptional differences illustrated by 1542 differentially expressed genes. The pathway analysis revealed that the extent of involvement of inflammatory fibroblasts in the mucosal inflammatory environment is remarkably stronger in non-responders compared to responders (FIG.1G). Thus, an opposite pattern in inflammatory fibroblasts in mucosa of non-responders at baseline is observed compared to inflammatory monocytes and Tregs. In particular, inflammatory fibroblasts of non-responders highly express a broad spectrum of CXC and CC ligand chemokines, IL-6, CSF2 and CSF3 among others, which enables them to regulate migration and chemotaxis of leukocytes, mononuclear cells and granulocytes. In responders, however, inflammatory fibroblasts highly express TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and WNT2B, which renders them to play less of the inflammation mediation role and more of the typical fibroblast role as illustrated by enriched pathways like wound healing and tissue repair (FIG.1G). Taken together, inflammatory fibroblasts may contribute to the VDZ non-response by actively promoting immune cell functions. Monocyte activation is associated with worsening of colonic inflammation in non- responders To further investigate the relationship between monocytes activation and intestinal inflammation, molecular signatures including cytokines gene signatures, transcription factors gene signatures, lipopolysaccharide (LPS) signatures, immune complexes (IC) signatures, and resident macrophage genes signatures were generated [Uzzan et al 2022, NatMed], and differential expression of cytokines gene signatures and transcript factors gene signatures in all mucosal cells, LPS signatures and IC signatures in mucosal Inflammatory Monocytes, and resident macrophage genes signatures in mucosal Macrophages between responders and non-responders were compared both before and at week 14 of VDZ therapy (FIG.3). At post-VDZ compared to pre-VDZ, the pro-inflammatory cytokines and transcript factors were significantly downregulated in responders. Of note, both LPS signatures and IC signatures were decreased in responders to VDZ, while these signatures were highly enriched in inflammatory monocytes of non-responders. 194 WBD (US) 4854-8046-9185v2 Before VDZ treatment, LPS signatures and IC signatures were upregulated in the Inflammation Monocytes of responders than non-responders before starting VDZ therapy. In contrast, increased expression of two signatures in non-responders compared to responders was observed after VDZ treatment. Pathogenic mucosal inflammatory module with a distinct cell cross-talk marks non- response to vedolizumab at baseline Functionally exhausted inflammatory monocytes, inactive Tregs and reactive inflammatory fibroblasts staging the pre-treatment mucosal inflammation was hypothesized to form a pathogenic inflammatory module with a distinct, rewired cross-talk in VDZ-unresponsive UC patients. A cell-cell interaction analysis was thus conducted in four steps: (1) 10 mucosal cell types of immune, stromal and epithelial origin were nominated that are likely to engage in the cross-talk, (2) intercellular communications were quantitatively inferred using CellChat (Jin et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun 12, 1088 (2021)) based on differentially expressed genes at baseline, (3) active ligand-receptor pairs were identified between a cell type-sender and a cell type-receiver for nominated cell types in a pairwise manner using NicheNet (Browaeys et al. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods 17, 159–162 (2020)), and (4) biological processes that underlie ligand-receptor interactions were interpreted using Enrichr. The following cell types were selected: cells of the identified innate inflammatory signature of non-response – inflammatory monocytes, DCs, NKs and ILCs, adaptive immune cells – Tregs, Tc17 and IgG+ plasma cells, stromal cells – inflammatory fibroblasts and activated endothelial cells, and lastly M cells. Most of these cell types comprise the GIMATS module described by Martin et al. (Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell 178, 1493–1508 (2019)), and the significance of M cells in UC was highlighted by Smillie et al (Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019)). Of note, there were no significant differences in the proportion of IgG or IgA class plasma cells (relative to total plasma cells) in the mucosa of responders and non-responders prior to treatment (FIG.1H). Cell-cell interactions were analyzed for the two VDZ response outcomes separately, and two 195 WBD (US) 4854-8046-9185v2 communication networks were built (FIG. 4A-B) which reflects the most relevant signaling mechanisms that cells within the module employ to drive the mucosal inflammation. Table 11: Extended data on the number of ligand-receptor pairs detected by CellChat where a sender cell is a CD8+ IL17+ T cell, DC, IgG+ plasma cell, NK, ILC, activated endothelial cell or an M cell Number of L-R pairs Sender Receiver VDZ-R VDZ-NR CD8+IL17+ T cells CD8+IL17+ T cells 6 6 CD8+IL17+ T cells DCs 10 4 CD8+IL17+ T cells IgG+ plasma cells 2 1 CD8+IL17+ T cells ILCs 4 4 CD8+IL17+ T cells Inflammatory 7 2 fibroblasts CD8+IL17+ T cells Inflammatory 12 4 monocytes CD8+IL17+ T cells M cells 8 3 CD8+IL17+ T cells NKs 5 7 CD8+IL17+ T cells Activated endothelial 13 6 cells CD8+IL17+ T cells Tregs 4 3 DCs CD8+IL17+ T cells 26 23 DCs DCs 26 22 DCs IgG+ plasma cells 5 5 DCs ILCs 5 6 DCs Inflammatory 7 6 fibroblasts DCs Inflammatory 28 12 monocytes DCs M cells 8 5 196 WBD (US) 4854-8046-9185v2 DCs NKs 7 9 DCs Activated endothelial 15 13 cells DCs Tregs 23 21 IgG+ plasma cells CD8+IL17+ T cells 1 0 IgG+ plasma cells DCs 1 1 IgG+ plasma cells IgG+ plasma cells 2 2 IgG+ plasma cells ILCs 0 0 IgG+ plasma cells Inflammatory 1 0 fibroblasts IgG+ plasma cells Inflammatory 1 0 monocytes IgG+ plasma cells M cells 1 0 IgG+ plasma cells NKs 0 2 IgG+ plasma cells Activated endothelial 1 1 cells IgG+ plasma cells Tregs 1 0 NKs CD8+IL17+ T cells 5 5 NKs DCs 8 5 NKs IgG+ plasma cells 2 1 NKs ILCs 3 5 NKs Inflammatory 6 4 fibroblasts NKs Inflammatory 11 8 monocytes NKs M cells 7 3 NKs NKs 5 7 NKs Activated endothelial 10 6 cells NKs Tregs 4 3 197 WBD (US) 4854-8046-9185v2 ILCs CD8+IL17+ T cells 4 5 ILCs DCs 5 4 ILCs IgG+ plasma cells 2 2 ILCs ILCs 2 3 ILCs Inflammatory 3 4 fibroblasts ILCs Inflammatory 6 6 monocytes ILCs M cells 3 2 ILCs NKs 3 6 ILCs Activated endothelial 4 9 cells ILCs Tregs 3 3 Activated endothelial CD8+IL17+ T cells 28 22 cells Activated endothelial DCs 31 24 cells Activated endothelial IgG+ plasma cells 18 17 cells Activated endothelial ILCs 14 16 cells Activated endothelial Inflammatory 41 28 cells fibroblasts Activated endothelial Inflammatory 33 20 cells monocytes Activated endothelial M cells 60 18 cells Activated endothelial NKs 16 17 cells Activated endothelial Activated endothelial 52 53 198 WBD (US) 4854-8046-9185v2 cells cells Activated endothelial Tregs 26 20 cells M cells CD8+IL17+ T cells 15 8 M cells DCs 14 7 M cells IgG+ plasma cells 4 4 M cells ILCs 6 4 M cells Inflammatory 12 5 fibroblasts M cells Inflammatory 17 6 monocytes M cells M cells 18 6 M cells NKs 6 4 M cells Activated endothelial 26 8 cells M cells Tregs 13 7 Overall, less interactions (i.e. less ligand-receptor pairs) between the cells in non-responders compared to responders were found (FIG.7 and Table 11). As senders, inflammatory fibroblasts and activated endothelial cells involved the highest number of ligand-receptor pairs, and IgG+ plasma cells the lowest. Dissecting the networks further, inflammatory monocytes in the mucosa of responders appear in full function as they are predicted to express MHC-II receptors on their surface, self-regulate via autocrine IL-10 signaling, communicate to Tregs to ensure continuous cytokine production and promote proliferation and migration of inflammatory fibroblasts. Signaling from inflammatory monocytes to other members of the responder module is directed towards regulation of cytokine production by Tc17, B cell proliferation and activation, inciting NK and DC chemotaxis and endothelial cell development (FIG. 4A). In contrast, the overactivated phenotype of inflammatory monocytes in non-responders seem to lose the ability of antigen presentation and IL-10-mediated self-regulation. They no longer communicate to Tregs, inflammatory fibroblasts and most other cells in the network, further confirming the aberrant state (FIG.4B). 199 WBD (US) 4854-8046-9185v2 Tregs also drastically switch their behavior in the context of non-response. In particular, Tregs in the mucosa of responders are actively involved in resolving the inflammation: they engage in cell-cell adhesion, negatively regulate cytotoxicity of leukocytes including inflammatory monocytes, Tc17, NKs and DCs, as well as regulate B cell chemotaxis and leukocyte adhesion to vascular endothelial cells (FIG.4A). In non-responders, however, Tregs which no longer receive inducing signals from inflammatory monocytes, do not communicate back to them nor do they show autocrine signaling. The regulatory function of Tregs towards other cells in the network is reduced to negative regulation of NK-mediated cytotoxicity, regulation of response to oxidative stress by DCs and MCP-1 production by activated endothelial cells in an attempt to promote monocyte migration from the bloodstream into the tissue (FIG.4B). A phenotype switch of inflammatory fibroblasts from immune-mediation in non-responders to restorative wound healing in responders was observed (FIG.1G). These functional differences to an extent have translated to the inferred cell-cell interactions. While inflammatory fibroblasts exerting an active autocrine signaling are predicted to promote macrophage chemotaxis and DC proliferation and migration irrespective of the response outcome, there was an evident switch in signaling mediators. In responders, inflammatory fibroblasts carried out most of their functions via IL-11, CXCL2 and CXCL14, while in non-responders they employed CXCL12, CXCL16 and CCL2. Therefore, responder inflammatory fibroblasts are able to promote Treg extravasation and negatively regulate apoptotic signaling in Tc17, IgG+ plasma cells and NKs, suggesting their attempt for fast resolution of inflammation (FIG. 4A). In non-responders, inflammatory fibroblasts negatively regulate extravasation of Tregs, Tc17 and IgG+ plasma cells, participate in regulation of NK-mediated cytotoxicity and stimulate proliferation of endothelial cells (FIG. 4B). Notably, a major trend in non-responders for cells to direct their signaling towards NKs was observed. While in responders, the activity of NKs is moderately contained by Tregs, in non- responders, the NK-mediated immunity and cytotoxicity is unanimously inhibited by all cells of the module via HLA-E (FIG. 4B). This could result in abrupt inability of NKs to contribute to inflammation resolution, further facilitating VDZ non-response. 200 WBD (US) 4854-8046-9185v2 Taken together, non-response to VDZ is marked by the presence of a pathogenic inflammatory module in the mucosa which employs fundamentally different signaling mechanisms compared to responders. DISCUSSION This study is the largest single-cell analysis analyzing the underlying mechanism of (non)response to a biological in IBD. The transcriptome profiles of 159,188 mucosal high- quality single cells and 95,057 high-quality PBMCs of 25 UC patients treated with VDZ was analyzed. In addition, 797,670 mucosal CD45+ cells and 900,000 PBMC CD45+ cells were immunophenotyped based on multidimensional flow cytometry data. VDZ has been approved for the treatment of UC based on the presumption that it blocks the recruitment of mucosal homing T cells recruitment to the inflamed intestinal mucosa (Danese, S. & Panés, J. Development of drugs to target interactions between leukocytes and endothelial cells and treatment algorithms for inflammatory bowel diseases. Gastroenterology 147, 981–989 (2014); Wyant, T. et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut 64, 77–83 (2015)). Several studies have since shown that this is most likely not the main mechanism of action of VDZ (Zeissig, S. et al. Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut 68, 25–39 (2019); Ungar, B. et al. Association of Vedolizumab Level, Anti-Drug Antibodies, and α4β7 Occupancy With Response in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 16, 697-705.e7 (2018)). In order to gain a comprehensive understanding of the mechanism of action of VDZ, a good start is to identify differences between responders and non-responders to VDZ treatment. A longitudinal analysis of changes in the composition of mucosa and peripheral blood cells and an analysis of the changes in integrin expression in (non)response to VDZ treatment was systematically performed. As also reported in previous studies, no proof was found for decreased migration of T or B lymphocytes to the gut mucosa in response to VDZ, neither in VDZ responders, nor in VDZ non- 201 WBD (US) 4854-8046-9185v2 responders. Further, no indication of alternative integrin pathways mediating non-response to VDZ was found. An association with higher numbers of mucosal innate immune cells, NK cells, ILCs, inflammatory monocytes and macrophages, before the start of VDZ treatment with non- response to VDZ was found. In addition, mucosal inflammatory monocytes of non-responders to VDZ seem to have aberrant phenotypes, which could be a causal factor for non-response to therapy. Response rates for VDZ in anti-TNFα naive and anti-TNFα exposed patients Multiple researchers observed that IBD patients with no prior use of anti-TNFα agents were significantly more likely to respond to VDZ treatment compared to patients who had been previously exposed to anti-TNFα agents (Sands BE, et al., Inflamm Bowel Dis. (2017); Stallmach A, et al., Aliment Pharmacol Therapeut. (2016); Narula N, et al., Am J Gastroenterol. (2018)), which is consistent with this study (Sands, B. E. et al. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis 23, 97–106 (2017); Stallmach, A. et al. Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease – a prospective multicenter observational study. Alimentary Pharmacology & Therapeutics 44, 1199–1212 (2016); Narula, N. et al. Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium. Am J Gastroenterol 113, 1345 (2018)). One possible explanation for this difference in response rates is that the failure of anti-TNFα agents may lead to increased immunogenicity, which might affect the efficacy of a subsequent biological treatment such as VDZ. This theory suggests that choosing the most suitable biological as first line of treatment is crucial in achieving efficient response to treatment. Cell composition changes over treatment duration in responders and non-responders The migration of lymphocytes to the gut mucosa is an important factor in the pathogenesis of IBD (Luzentales-Simpson, M., Pang, Y. C. F., Zhang, A., Sousa, J. A. & Sly, L. M. Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases. Front Cell Dev Biol 9, 612830 (2021)). No direct indication that VDZ prevented CD8+ T and CD4+ T subsets from entering the mucosa was observed, since these cell types were not enriched in PBMCs after treatment in responders. When directly 202 WBD (US) 4854-8046-9185v2 comparing non-responders to responders the first have higher numbers of CD4 and CD8 T cells in their PBMCs after treatment, but this is more likely a result of their more active inflammatory status, just as the lower number of CD4 and CD8 T cells in mucosa of non-responders after treatment is likely a result of resolution of the inflammation. These observations suggest that blocking of migration of lymphocytes to the gut mucosa is not the main mechanism of action of VDZ. This is supported by the study of Zeissig et al., who report that the curative effects of VDZ are not only mediated by adaptive immunity, but also tightly linked alteration of innate immunity (Zeissig, S. et al. Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut 68, 25–39 (2019)). Zeissig et al. provided evidence that the abundance of M1 macrophages was dramatically decreased at week 14 with VDZ therapy in responders (Zeissig, S. et al. Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut 68, 25–39 (2019)). Similarly, a study conducted by Schleier et al. demonstrated that impaired gut homing of non-classical monocytes was associated with the efficacy of VDZ. In responders, a partial recovery of the epithelial and stromal cell mucosal compartments at week 14 was observed. Specifically, BEST4+ enterocytes, goblet, immature goblet, RSPO3+ fibroblasts increased after treatment, whereas inflammatory fibroblasts depleted. In non- responders a further decrease of enterocyte lines, among which BEST4+ enterocytes, is seen, as well as a further decrease of immature goblet cells and M cells, and an increase in inflammatory fibroblasts which shows progression of the inflammation during non-response. Innate cellular signature of non-response to VDZ A higher presence of innate immune cells in the gut mucosa in non-responders vs responders at baseline was observed, namely NK cells, inflammatory monocytes, ILCs and DCs, showing a significant difference between the two groups already before the start of VDZ. This profile is also visible in peripheral blood in which NK cells, monocytes, ILCs and DCs are increased before treatment in non-responders. Thus, an innate inflammatory signature marks non-response to VDZ at baseline. This study reveals that response to VDZ is impacted by the composition and the activity of the innate immune cells in the gut mucosa and the peripheral blood, rather than on 203 WBD (US) 4854-8046-9185v2 the mucosal or peripheral T cells at which the treatment was primarily aimed. These findings are in line with current literature as Zeissig et al reported a higher M1/M2 macrophage ratio in the gut mucosa before start of treatment in non-responders (Zeissig, S. et al. Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut 68, 25–39 (2019)). An increase in mucosal inflammatory monocytes and NK cells was observed in non-response to VDZ, suggesting they exert a role in this condition. The role of NK cells in IBD is unclear, but it has been shown that IBD patients have aberrant NK cell function, with reduced cytotoxicity, a dysregulated pattern of cytokine secretion with reduced IFNγ production and increased TNFα and IL17a production (Zaiatz Bittencourt, V., Jones, F., Tosetto, M., Doherty, G. A. & Ryan, E. J. Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients. J Crohns Colitis 15, 1316–1325 (2021)). In both responder and non-responder UC patients a similar NK phenotype was observed, resembling those in other chronic inflammatory diseases, such as cancer and rheumatoid arthritis (Tschopp, J. Mitochondria: Sovereign of inflammation? European Journal of Immunology 41, 1196–1202 (2011); Poznanski, S. M. & Ashkar, A. A. What Defines NK Cell Functional Fate: Phenotype or Metabolism? Front Immunol 10, 1414 (2019); Fearon, U., Hanlon, M. M., Wade, S. M. & Fletcher, J. M. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. Clinical & Experimental Immunology 197, 170–180 (2019); Riley, J. S. & Tait, S. W. Mitochondrial DNA in inflammation and immunity. EMBO reports 21, e49799 (2020)). The higher number of mucosal NK cells in the non-responder group of patients might be leading to strengthening of the adaptive immune response in the mucosa by attraction of adaptive immune cells by TNFα and IL17a, thereby contributing to non-response to VDZ treatment. Activation of NK cells is related to the NKG2D receptor expression in intestinal mucosa from UC patients, by its ligand MICA in the epithelial compartment, with lower frequency of lamina propria NKG2D+ NK cells in severe UC (Ge, L. Q. et al. Upregulated mRNA expression of major histocompatibility complex class I chain-related gene A in colon and activated natural killer cells of Chinese patients with ulcerative colitis. J Dig Dis 12, 82–89 (2011); Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling - PubMed.Wang et al. Oncotarget.2017 Oct 4;8(52):90132-90143). 204 WBD (US) 4854-8046-9185v2 Interestingly, anti-NKG2D antibody treatment, designed to target NKG2D positive lymphocytes (NK and CD8+ T cells) in the inflamed gut, might adequately target pathological NK cells in IBD (Vadstrup, K. et al. NKG2D ligand expression in Crohn’s disease and NKG2D-dependent stimulation of CD8+ T cell migration. Exp Mol Pathol 103, 56–70 (2017)). Furthermore, although an anti-NKG2D monotherapy failed to achieve the relevant end-points in a phase 2 trial (Allez, Gut 2017), if it could correct the highly abundant NK cells associated to VDZ non- response, combination therapy of anti-NKG2D and VDZ might be rational. Furthermore, this study showed that several cell types appear to play completely different roles in the gut mucosal environment between responders and non-responders even before the start of VDZ, rendering the mucosal inflammatory process between the two completely different. Notably, inflammatory monocytes, while more abundant in non-responders, appear to have little to no role in the local inflammatory process, whereas in responders these cells exert their expected functions such as activation of the adaptive and the innate immune response, but also regulation of said immune responses and of their own activity through IL10 self-signaling. Previous studies demonstrated that in UC monocytes can show a specific dysregulation compared to healthy controls and CD patients, with increased baseline activity of the JAK/STAT pathway, predominantly STAT1 over STAT3, which leads to an overactivated state in which these monocytes no longer adequately respond to stimulation with IFNγ (Cordes, F. et al. Impaired IFN-γ-dependent STAT3 Activation Is Associated With Dysregulation of Regulatory and Inflammatory Signaling in Monocytes of Ulcerative Colitis Patients. Inflamm Bowel Dis 27, 887–901 (2021)). The findings described herein suggest that the non-responder specific inflammatory monocytes correspond to the overactivated phenotype described by Cordes et al. In co-culture studies, these overactivated UC derived monocytes as compared to CD derived monocytes, do not produce regulating factors such as IL10 and CD39, and as a result are unable to activate a Treg response. Remarkably, no significant communication was observed between inflammatory monocytes and Tregs in non-responders and a distinct lack of normal Treg cell function in non-responders pre-VDZ compared to responders. Where in non-responders activity of standard house-keeping pathways was primarily observed pre-VDZ, in responders Tregs are actively involved in activating and regulating both the innate and adaptive immune response. In the absence of control of the inflammatory process through the normal innate immune to 205 WBD (US) 4854-8046-9185v2 adaptive immune channels, a distinctly more active role of inflammatory fibroblasts was observed in the mucosal inflammation in non-responders pre-VDZ compared to responders. While in responders these fibroblasts appear to be involved in restorative processes through wound healing and smooth muscle cell migration pathways, in non-responders inflammatory fibroblasts appear to play a role in inflammation regulation through response to interferon, migration of both innate and adaptive immune cells, and regulation of the inflammatory process pathways. This inflammatory fibroblast phenotype does to an extent correspond to the activated fibroblast phenotype that plays a central role in non-response to anti-TNFα in CD as described by Martin et al. in the GIMATS module (Martin et al. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell 178, 1493–1508 (2019)). While the GIMATS module also includes inflammatory monocytes as an important player in non-response to anti-TNFα, the non-response module that was observed for VDZ is notably different as there appears to be no significant role for the IgG plasma cells and activated T cells in non-response to VDZ as opposed to in non-response to anti- TNFα. Based on their differential abundance, their dysfunctional role in non-responder mucosal inflammation pre-VDZ, and their primary role in response to VDZ, it most likely that these dysfunctional inflammatory monocytes play a central role in non-response to VDZ. Interestingly, further research by the same authors shows that Tofacitinib, which at adequate dosage inhibits STAT1, but not STAT3, can correct this phenotype and shift UC inflammatory monocytes to a more regulatory phenotype (Cordes, F. et al. Tofacitinib Reprograms Human Monocytes of IBD Patients and Healthy Controls Toward a More Regulatory Phenotype. Inflamm Bowel Dis 26, 391–406 (2020)). This provides a rational basis for combination therapy for UC. While VDZ is an attractive choice for maintenance therapy because of its limited effect on the systemic immune system and therefore low long term risk of malignancy, the initial response rate of ~50% and ultimate maintenance rate of ~30% means that only a limited number of patients can reap these long term benefits. Potentially, induction remission with Tofacitinib during the start of treatment with VDZ can improve the inflammatory monocyte phenotype and radically improve response and maintenance rates. This is the largest prospective study using single cell transcriptomic profiling and the analyses of 206 WBD (US) 4854-8046-9185v2 surface markers in both the diseased intestinal tissue and peripheral blood to study the response to biological therapy in UC. It was found that (i) integrins other than VDZ-targeted α4β7 do not sustain lymphocyte trafficking to the mucosa in non-responsive UC patients; (ii) non-response to VDZ is marked by a distinct innate cell signature prior to treatment; and (iii) inactive inflammatory monocytes and regulatory T cells, and reactive inflammatory fibroblasts form a pathogenic mucosal inflammatory module of nonresponse to VDZ. New mechanisms of non- response to VDZ and the cell types involved were uncovered. This study presents a blueprint for similar studies in other treatment modalities since understanding the mechanisms of action of biologicals will enable informed decisions about treatment options, which will ultimately lead to more efficient and effective therapy solutions. Example 2. Determination of the Optimal Treatment Target in Ulcerative Colitis (VERDICT) Disease activity and response to therapy in ulcerative colitis (UC) can be assessed by a range of endpoints including symptoms, endoscopic mucosal activity, histological disease activity, and biomarkers. This study (VERDICT: In actiVE Ulcerative Colitis, a RanDomIzed Controlled Trial for Determination of the Optimal Treatment Target) aims to determine the optimal treatment target, which is a research priority for the management of UC both to inform clinical practice and to help inform regulatory endpoints and targets for drug development. Participants with active UC will be randomized in a 2:3:5 ratio to 1 of 3 groups, each with a different treatment target. Treatment targets will be defined as: Group 1: corticosteroid-free [CSF] symptomatic remission; Group 2: corticosteroid-free [CSF] endoscopic + symptomatic remission; Group 3: corticosteroid-free [CSF] histological + endoscopic + symptomatic remission, also termed disease clearance. Treatment algorithms may include the use of vedolizumab. A key premise is that vedolizumab has a favorable safety profile and can be used to treat subjects who are in symptomatic remission but who have not attained endoscopic or histopathologic remission. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the 207 WBD (US) 4854-8046-9185v2 participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm. Participants who are treatment-naïve at randomization will follow treatment algorithm A. Participants, upon entry into the study, will require standard first-line therapy. Either oral 5-ASA and/or immunosuppressive (with optional oral corticosteroid in combination) will be initiated. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm. Participants who are taking non-biologic UC therapies at randomization will follow treatment algorithm B. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm. Participants who are taking anti-TNF, tofacitinib or ustekinumab therapy at randomization will follow treatment algorithm C. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine if remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm. The primary outcome measure is Difference in Time to UC-related Complication Between Treatment Target Groups 1 and 3 [Time Frame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first] (i.e., time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 3). 208 WBD (US) 4854-8046-9185v2 Secondary outcome measures are Difference in Time to UC-related Complication Compared Between Treatment Target Groups 1 and 2 [Time Frame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first]; Difference in Time to UC-related Complication Compared Between Treatment Target Groups 2 and 3 [Time Frame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first]; Difference in Time to UC-related Complication Compared Between Treatment Target Groups (fast responder sub-group) [Time Frame: From date of treatment target achievement until date of first UC- related complication until end of study (Week 96), whichever came first]; Difference in Time to Achieve Treatment Target [Time Frame: up to 96 weeks]; Fecal Calprotectin Levels [Time Frame: Baseline, weeks 8, 16, 32, 48, and 96]; and C-Reactive Protein Concentration [ Time Frame: Baseline, weeks 8, 16, 32, 48, 64, 80, and 96]. VDZ 300 mg was administered intravenously following a treatment algorithm related to baseline UC treatment until assigned treatment target was reached at week 32, with an escalation step between week 16 and 32 as indicated. CSF symptomatic remission was defined as Mayo rectal bleeding subscore=0, CSF endoscopic remission was defined as Mayo Endoscopic Score [MES]≤1, and CSF histologic remission was defined as Geboes score<2B.0. As of 29 Feb 2024, 612 patients were enrolled with 154, 198, and 260 patients assigned to target Groups 1, 2, and 3, respectively. Baseline age and disease duration were similar amongst groups, with respective percentages of patients having baseline MES=3 given by 60.4%, 61.6%, and 64.2%, and receipt of concomitant corticosteroids given by 42.9%, 40.9%, and 50.4% (median dose 25.4, 25.3, and 23.7 mg). There were 71.4%, 75.3%, and 83.5% of patients who were bionaïve, respectively. At time of analysis, 63.6%, 71.2%, and 80.8% of randomized patients in the groups had completed the week 32 visit. In patients with observed data and a week 16 visit, 64.1% (75/117), 42.2% (73/173), and 40.2% (94/234) in Groups 1, 2, and 3, respectively, achieved CSF remission at week 16. In patients with observed data and a week 32 visit, 81.6% (80/98), 61.7% (87/141), and 53.3% (112/210), respectively, achieved CSF remission by week 32, with higher proportions in bionaïve (83.7%, 209 WBD (US) 4854-8046-9185v2 63.8%, and 55.2%) compared to bio-exposed (66.7%, 52.0%, and 40.7%) (Table 12). In the intention-to-treat population, 48.7%, 36.9%, and 36.2% of patients, respectively, achieved CSF remission at week 16, with higher proportions in patients who were bionaïve (56.4% [62/110], 38.3% [57/149], and 38.2% [83/217]) compared to bio-exposed (29.5% [13/44], 32.7% [16/49], and 25.6% [11/43]). By week 32, 51.9%, 43.9%, and 43.1% of the intention-to-treat population achieved CSF remission, with higher proportions in bionaïve (65.5% [72/110], 49.7% [74/149], and 46.5% [101/217]) compared to bio-exposed (18.2% [8/44], 26.5% [13/49], and 25.6% [11/43]). For patients not achieving target at week 16, treatment escalation occurred in 22.7%, 49.5%, and 53.5% of patients; after escalation, proportions achieving CSF remission by week 32 were 41.9% (13/31), 27.0% (20/74), and 19.0% (23/121), respectively. These interim week 32 results provide evidence of improvement from week 16 to 32 across all endpoints and continue to support the efficacy of VDZ in achieving the stringent endpoint of CSF disease clearance. Table 12. Summary of Target Achievement by Week 32 Group Group Grou Group Group Grou Group Group Grou 1 1 Bio- p 1 2 2 Bio- p 2 3 3 Bio- p 3 Bionaïv expose Total Bionaïv expose Total Bionaïv expose Total e d N=98 e d N=14 e d N=21 N=86 N=12 N=116 N=25 1 N=183 N=27 0 CSF 72 8 80 74 13 87 101 11 112 remissio n, (83.7) (66.7) (81.6) (63.8) (52.0) (61.7) (55.2) (40.7) (53.3) n (%) Non CSF 3 (3.5) 0 (0.0) 3 0 (0.0) 0 (0.0) 0 1 (0.5) 0 (0.0) 1 remissio n, (3.1) (0.0) (0.5) n (%) Remissio 11 3 14 40 12 52 81 16 97 n target not (12.8) (25.0) (14.3) (34.5) (48.0) (36.9) (44.3) (59.3) (46.2) achieved, n (%) Remissio 0 (0.0) 1 (8.3) 1 2 (1.7) 0 (0.0) 2 0 (0.0) 0 (0.0) 0 n target status (1.0) (1.4) (0.0) missing, n (%) 210 WBD (US) 4854-8046-9185v2 Week 32 completer analysis set includes all patients who reached the week 32 visit. Group 1 is defined as CSF symptomatic remission; Group 2 is defined as CSF symptomatic remission + CSF endoscopic remission; and Group 3 is defined as CSF symptomatic remission + CSF endoscopic remission + CSF histologic remission. Remission target status missing includes patients who ended the study before the week 32 visit, those who had not reached the week 32 visit, and those who reached the week 32 visit but had no status, as of 29 FEB 2024. Abbreviation: CSF, corticosteroid-free. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference. 211 WBD (US) 4854-8046-9185v2 SEQUENCE TABLE SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: 1 CDR1 of heavy SYWMH (SEQ ID NO: 1) chain mouse ACT-1 antibody 2 CDR2 of heavy EIDPSESNTNYNQKFKG (SEQ ID NO: 2) chain mouse ACT-1 antibody 3 CDR3 of heavy GGYDGWDYAIDY (SEQ ID NO: 3) chain mouse ACT-1 antibody 4 CDR1 of light RSSQSLAKSYGNTYLS (SEQ ID NO: 4) chain mouse ACT-1 antibody 5 CDR2 of light GISNRFS (SEQ ID NO: 5) chain mouse ACT-1 antibody 6 CDR3 of light LQGTHQPYT (SEQ ID NO: 6) chain mouse ACT-1 antibody 7 Amino acid MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKGSG sequence of YTFTSYWMHWVRQAPGQRLEWIGEIDPSESNTNYNQKFKGRVTL heavy chain of TVDISASTAYMELSSLRSEDTAVYYCARGGYDGWDYAIDYWGQG humanized TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS anti-α4β7 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN immunoglobulin HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 7) 8 Amino acid MGWSCIILFLVATATGVHSDVVMTQSPLSLPVTPGEPASISCRSSQS sequence of LAKSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGT light chain of DFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKVEIKRTVAAPS humanized VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS anti-α4β7 GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL immunoglobulin SSPVTKSFNRGEC (SEQ ID NO: 8) 9 Heavy chain QVQLVQSGAEVKKPGASVKVSCKGSGYTFTSYWMHWVRQAPGQ 212 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: (HC) variable RLEWIGEIDPSESNTNYNQKFKGRVTLTVDISASTAYMELSSLRSED region (amino TAVYYCARGGYDGWDYAIDYWGQGTLVTVSS (SEQ ID NO: 9) acid) 10 Light chain (LC) DVVMTQSPLSLPVTPGEPASISCRSSQSLAKSYGNTYLSWYLQKPG variable region QSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC (amino acid) LQGTHQPYTFGQGTKVEIK (SEQ ID NO: 10) 11 CYP27A1 MAALGCARLRWALRGAGRGLCPHGARAKAAIPAALPSDKATGAP GAGPGVRRRQRSLEEIPRLGQLRFFFQLFVQGYALQLHQLQVLYK AKYGPMWMSYLGPQMHVNLASAPLLEQVMRQEGKYPVRNDME LWKEHRDQHDLTYGPFTTEGHHWYQLRQALNQRLLKPAEAALYT DAFNEVIDDFMTRLDQLRAESASGNQVSDMAQLFYYFALEAICYIL FEKRIGCLQRSIPEDTVTFVRSIGLMFQNSLYATFLPKWTRPVLPFW KRYLDGWNAIFSFGKKLIDEKLEDMEAQLQAAGPDGIQVSGYLHF LLASGQLSPREAMGSLPELLMAGVDTTSNTLTWALYHLSKDPEIQ EALHEEVVGVVPAGQVPQHKDFAHMPLLKAVLKETLRLYPVVPT NSRIIEKEIEVDGFLFPKNTQFVFCHYVVSRDPTAFSEPESFQPHRW LRNSQPATPRIQHPFGSVPFGYGVRACLGRRIAELEMQLLLARLIQ KYKVVLAPETGELKSVARIVLVPNKKVGLQFLQRQC (SEQ ID NO: 11) 12 C4orf3 MEVDAPGVDGRDGLRERRGFSEGGRQNFDVRPQSGANGLPKHSY WLDLWLFILFDVVVFLFVYFLP (SEQ ID NO: 12) 13 IRAK3 MAGNCGARGALSAHTLLFDLPPALLGELCAVLDSCDGALGWRGL AERLSSSWLDVRHIEKYVDQGKSGTRELLWSWAQKNKTIGDLLQ VLQEMGHRRAIHLITNYGAVLSPSEKSYQEGGFPNILFKETANVTV DNVLIPEHNEKGILLKSSISFQNIIEGTRNFHKDFLIGEGEIFEVYRVE IQNLTYAVKLFKQEKKMQCKKHWKRFLSELEVLLLFHHPNILELA AYFTETEKFCLIYPYMRNGTLFDRLQCVGDTAPLPWHIRIGILIGISK AIHYLHNVQPCSVICGSISSANILLDDQFQPKLTDFAMAHFRSHLEH QSCTINMTSSSSKHLWYMPEEYIRQGKLSIKTDVYSFGIVIMEVLTG CRVVLDDPKHIQLRDLLRELMEKRGLDSCLSFLDKKVPPCPRNFSA KLFCLAGRCAATRAKLRPSMDEVLNTLESTQASLYFAEDPPTSLKS FRCPSPLFLENVPSIPVEDDESQNNNLLPSDEGLRIDRMTQKTPFEC SQSEVMFLSLDKKPESKRNEEACNMPSSSCEESWFPKYIVPSQDLR PYKVNIDPSSEAPGHSCRSRPVESSCSSKFSWDEYEQYKKE (SEQ ID NO: 13) 14 CXCL9 MKKSGVLFLLGIILLVLIGVQGTPVVRKGRCSCISTNQGTIHLQSLK DLKQFAPSPSCEKIEIIATLKNGVQTCLNPDSADVKELIKKWEKQVS QKKKQKNGKKHQKKKVLKVRKSQRSRQKKTT (SEQ ID NO: 14) 15 SLCO4A1 MPLHQLGDKPLTFPSPNSAMENGLDHTPPSRRASPGTPLSPGSLRS AAHSPLDTSKQPLCQLWAEKHGARGTHEVRYVSAGQSVACGWW AFAPPCLQVLNTPKGILFFLCAAAFLQGMTVNGFINTVITSLERRYD LHSYQSGLIASSYDIAACLCLTFVSYFGGSGHKPRWLGWGVLLMG TGSLVFALPHFTAGRYEVELDAGVRTCPANPGAVCADSTSGLSRY QLVFMLGQFLHGVGATPLYTLGVTYLDENVKSSCSPVYIAIFYTAA ILGPAAGYLIGGALLNIYTEMGRRTELTTESPLWVGAWWVGFLGS GAAAFFTAVPILGYPRQLPGSQRYAVMRAAEMHQLKDSSRGEASN PDFGKTIRDLPLSIWLLLKNPTFILLCLAGATEATLITGMSTFSPKFL 213 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: ESQFSLSASEAATLFGYLVVPAGGGGTFLGGFFVNKLRLRGSAVIK FCLFCTVVSLLGILVFSLHCPSVPMAGVTASYGGSLLPEGHLNLTA PCNAACSCQPEHYSPVCGSDGLMYFSLCHAGCPAATETNVDGQK VYRDCSCIPQNLSSGFGHATAGKCTSTCQRKPLLLVFIFVVIFFTFLS SIPALTATLRCVRDPQRSFALGIQWIVVRILGGIPGPIAFGWVIDKAC LLWQDQCGQQGSCLVYQNSAMSRYILIMGLLYKVLGVLFFAIACF LYKPLSESSDGLETCLPSQSSAPDSATDSQLQSSV (SEQ ID NO: 15) 16 CLEC4E MNSSKSSETQCTERGCFSSQMFLWTVAGIPILFLSACFITRCVVTFRI FQTCDEKKFQLPENFTELSCYNYGSGSVKNCCPLNWEYFQSSCYFF STDTISWALSLKNCSAMGAHLVVINSQEEQEFLSYKKPKMREFFIG LSDQVVEGQWQWVDGTPLTKSLSFWDVGEPNNIATLEDCATMRD SSNPRQNWNDVTCFLNYFRICEMVGINPLNKGKSL (SEQ ID NO: 16) 17 TREM1 MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYT LEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDY HDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTK GFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTAD VSTPDSEINLTNVTDIIRVPVFNIVILLAGGFLSKSLVFSVLFAVTLRS FVP (SEQ ID NO: 17) 18 IL1B MAEVPELASEMMAYYSGNEDDLFFEADGPKQMKCSFQDLDLCPL DGGIQLRISDHHYSKGFRQAASVVVAMDKLRKMLVPCPQTFQEN DLSTFFPFIFEEEPIFFDTWDNEAYVHDAPVRSLNCTLRDSQQKSLV MSGPYELKALHLQGQDMEQQVVFSMSFVQGEESNDKIPVALGLK EKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFVFNKIEINN KLEFESAQFPNWYISTSQAENMPVFLGGTKGGQDITDFTMQFVSS (SEQ ID NO: 18) 19 FLT1 MVSYWDTGVLLCALLSCLLLTGSSSGSKLKDPELSLKGTQHIMQA GQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGKQFCS TLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVE MYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIW DSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQ ISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASV RRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNT SVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVW LKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNVFK NLTATLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTI KWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESITQRM AIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPN GFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMH YSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEIL QKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWF KNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVES SAYLTVQGTSDKSNLELITLTCTCVAATLFWLLLTLFIRKMKRSSSE IKTDYLSIIMDPDEVPLDEQCERLPYDASKWEFARERLKLGKSLGR GAFGKVVQASAFGIKKSPTCRTVAVKMLKEGATASEYKALMTEL KILTHIGHHLNVVNLLGACTKQGGPLMVIVEYCKYGNLSNYLKSK RDLFFLNKDAALHMEPKKEKMEPGLEQGKKPRLDSVTSSESFASS 214 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GFQEDKSLSDVEEEEDSDGFYKEPITMEDLISYSFQVARGMEFLSSR KCIHRDLAARNILLSENNVVKICDFGLARDIYKNPDYVRKGDTRLP LKWMAPESIFDKIYSTKSDVWSYGVLLWEIFSLGGSPYPGVQMDE DFCSRLREGMRMRAPEYSTPEIYQIMLDCWHRDPKERPRFAELVE KLGDLLQANVQQDGKDYIPINAILTGNSGFTYSTPAFSEDFFKESIS APKFNSGSSDDVRYVNAFKFMSLERIKTFEELLPNATSMFDDYQG DSSTLLASPMLKRFTWTDSKPKASLKIDLRVTSKSKESGLSDVSRPS FCHSSCGHVSEGKRRFTYDHAELERKIACCSPPPDYNSVVLYSTPPI (SEQ ID NO: 19) 20 SOD2 MLSRAVCGTSRQLAPVLGYLGSRQKHSLPDLPYDYGALEPHINAQI MQLHHSKHHAAYVNNLNVTEEKYQEALAKGDVTAQIALQPALKF NGGGHINHSIFWTNLSPNGGGEPKGELLEAIKRDFGSFDKFKEKLT AASVGVQGSGWGWLGFNKERGHLQIAACPNQDPLQGTTGLIPLLG IDVWEHAYYLQYKNVRPDYLKAIWNVINWENVTERYMACKK (SEQ ID NO: 20) 21 HIF1A MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLP LPHNVSSHLDKASVMRLTISYLRVRKLLDAGDLDIEDDMKAQMN CFYLKALDGFVMVLTDDGDMIYISDNVNKYMGLTQFELTGHSVF DFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTS RGRTMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLV LICEPIPHPSNIEIPLDSKTFLSRHSLDMKFSYCDERITELMGYEPEEL LGRSIYEYYHALDSDHLTKTHHDMFTKGQVTTGQYRMLAKRGGY VWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECV LKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAG DTIISLDFGSNDTETDDQQLEEVPLYNDVMLPSPNEKLQNINLAMS PLPTAETPKPLRSSADPALNQEVALKLEPNPESLELSFTMPQIQDQT PSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLFAEDTE AKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPES ASPQSTVTVFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILI ASPSPTHIHKETTSATSSPYRDTQSRTASPNRAGKGVIEQTEKSHPR SPNVLSVALSQRTTVPEEELNPKILALQNAQRKRKMEHDGSLFQA VGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSD LACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALD QVN (SEQ ID NO: 21) 22 GBP2 MAPEINLPGPMSLIDNTKGQLVVNPEALKILSAITQPVVVVAIVGLY RTGKSYLMNKLAGKKNGFSLGSTVKSHTKGIWMWCVPHPKKPEH TLVLLDTEGLGDIEKGDNENDSWIFALAILLSSTFVYNSMGTINQQ AMDQLHYVTELTDRIKANSSPGNNSVDDSADFVSFFPAFVWTLRD FTLELEVDGEPITADDYLELSLKLRKGTDKKSKSFNDPRLCIRKFFP KRKCFVFDWPAPKKYLAHLEQLKEEELNPDFIEQVAEFCSYILSHS NVKTLSGGIPVNGPRLESLVLTYVNAISSGDLPCMENAVLALAQIE NSAAVEKAIAHYEQQMGQKVQLPTETLQELLDLHRDSEREAIEVF MKNSFKDVDQMFQRKLGAQLEARRDDFCKQNSKASSDCCMALL QDIFGPLEEDVKQGTFSKPGGYRLFTQKLQELKNKYYQVPRKGIQ AKEVLKKYLESKEDVADALLQTDQSLSEKEKAIEVERIKAESAEAA KKMLEEIQKKNEEMMEQKEKSYQEHVKQLTEKMERDRAQLMAE QEKTLALKLQEQERLLKEGFENESKRLQKDIWDIQMRSKSLEPICNI 215 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: L (SEQ ID NO: 22) 23 SLAMF1 MDPKGLLSLTFVLFLSLAFGASYGTGGRMMNCPKILRQLGSKVLL PLTYERINKSMNKSIHIVVTMAKSLENSVENKIVSLDPSEAGPPRYL GDRYKFYLENLTLGIRESRKEDEGWYLMTLEKNVSVQRFCLQLRL YEQVSTPEIKVLNKTQENGTCTLILGCTVEKGDHVAYSWSEKAGT HPLNPANSSHLLSLTLGPQHADNIYICTVSNPISNNSQTFSPWPGCR TDPSETKPWAVYAGLLGGVIMILIMVVILQLRRRGKTNHYQTTVE KKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQE TNSITVYASVTLPES (SEQ ID NO: 23) 24 IL1A MAKVPDMFEDLKNCYSENEEDSSSIDHLSLNQKSFYHVSYGPLHE GCMDQSVSLSISETSKTSKLTFKESMVVVATNGKVLKKRRLSLSQS ITDDDLEAIANDSEEEIIKPRSAPFSFLSNVKYNFMRIIKYEFILNDAL NQSIIRANDQYLTAAALHNLDEAVKFDMGAYKSSKDDAKITVILRI SKTQLYVTAQDEDQPVLLKEMPEIPKTITGSETNLLFFWETHGTKN YFTSVAHPNLFIATKQDYWVCLAGGPPSITDFQILENQA (SEQ ID NO: 24) 25 PTGS2 MLARALLLCAVLALSHTANPCCSHPCQNRGVCMSVGFDQYKCDC TRTGFYGENCSTPEFLTRIKLFLKPTPNTVHYILTHFKGFWNVVNNI PFLRNAIMSYVLTSRSHLIDSPPTYNADYGYKSWEAFSNLSYYTRA LPPVPDDCPTPLGVKGKKQLPDSNEIVEKLLLRRKFIPDPQGSNMM FAFFAQHFTHQFFKTDHKRGPAFTNGLGHGVDLNHIYGETLARQR KLRLFKDGKMKYQIIDGEMYPPTVKDTQAEMIYPPQVPEHLRFAV GQEVFGLVPGLMMYATIWLREHNRVCDVLKQEHPEWGDEQLFQT SRLILIGETIKIVIEDYVQHLSGYHFKLKFDPELLFNKQFQYQNRIAA EFNTLYHWHPLLPDTFQIHDQKYNYQQFIYNNSILLEHGITQFVESF TRQIAGRVAGGRNVPPAVQKVSQASIDQSRQMKYQSFNEYRKRF MLKPYESFEELTGEKEMSAELEALYGDIDAVELYPALLVEKPRPDA IFGETMVEVGAPFSLKGLMGNVICSPAYWKPSTFGGEVGFQIINTA SIQSLICNNVKGCPFTSFSVPDPELIKTVTINASSSRSGLDDINPTVLL KERSTEL (SEQ ID NO: 25) 26 BCL2L1 MSQSNRELVVDFLSYKLSQKGYSWSQFSDVEENRTEAPEGTESEM ETPSAINGNPSWHLADSPAVNGATGHSSSLDAREVIPMAAVKQAL REAGDEFELRYRRAFSDLTSQLHITPGTAYQSFEQVVNELFRDGVN WGRIVAFFSFGGALCVESVDKEMQVLVSRIAAWMATYLNDHLEP WIQENGGWDTFVELYGNNAAAESRKGQERFNRWFLTGMTVAGV VLLGSLFSRK (SEQ ID NO: 26) 27 SOCS3 MVTHSKFPAAGMSRPLDTSLRLKTFSSKSEYQLVVNAVRKLQESG FYWSAVTGGEANLLLSAEPAGTFLIRDSSDQRHFFTLSVKTQSGTK NLRIQCEGGSFSLQSDPRSTQPVPRFDCVLKLVHHYMPPPGAPSFPS PPTEPSSEVPEQPSAQPLPGSPPRRAYYIYSGGEKIPLVLSRPLSSNV ATLQHLCRKTVNGHLDSYEKVTQLPGPIREFLDQYDAPL (SEQ ID NO: 27) 28 DUSP7 MKNQLRGPPARAHMSTSGAAAAGGTRAGSEPGAGSGSGAGTGAG AATGAGAMPCKSAEWLQEELEARGGASLLLLDCRPHELFESSHIET AINLAIPGLMLRRLRKGNLPIRSIIPNHADKERFATRCKAATVLLYD EATAEWQPEPGAPASVLGLLLQKLRDDGCQAYYLQGGFNKFQTE YSEHCETNVDSSSSPSSSPPTSVLGLGGLRISSDCSDGESDRELPSSA 216 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: TESDGSPVPSSQPAFPVQILPYLYLGCAKDSTNLDVLGKYGIKYILN VTPNLPNAFEHGGEFTYKQIPISDHWSQNLSQFFPEAISFIDEARSKK CGVLVHCLAGISRSVTVTVAYLMQKMNLSLNDAYDFVKRKKSNIS PNFNFMGQLLDFERTLGLSSPCDNHASSEQLYFSTPTNHNLFPLNT LEST (SEQ ID NO: 28) 29 PLEK MEPKRIREGYLVKKGSVFNTWKPMWVVLLEDGIEFYKKKSDNSP KGMIPLKGSTLTSPCQDFGKRMFVFKITTTKQQDHFFQAAFLEERD AWVRDIKKAIKCIEGGQKFARKSTRRSIRLPETIDLGALYLSMKDT EKGIKELNLEKDKKIFNHCFTGNCVIDWLVSNQSVRNRQEGLMIAS SLLNEGYLQPAGDMSKSAVDGTAENPFLDNPDAFYYFPDSGFFCE ENSSDDDVILKEEFRGVIIKQGCLLKQGHRRKNWKVRKFILREDPA YLHYYDPAGAEDPLGAIHLRGCVVTSVESNSNGRKSEEENLFEIIT ADEVHYFLQAATPKERTEWIRAIQMASRTGK (SEQ ID NO: 29) 30 SPP1 MRIAVICFCLLGITCAIPVKQADSGSSEEKQLYNKYPDAVATWLNP DPSQKQNLLAPQNAVSSEETNDFKQETLPSKSNESHDHMDDMDDE DDDDHVDSQDSIDSNDSDDVDDTDDSHQSDESHHSDESDELVTDF PTDLPATEVFTPVVPTVDTYDGRGDSVVYGLRSKSKKFRRPDIQYP DATDEDITSHMESEELNGAYKAIPVAQDLNAPSDWDSRGKDSYET SQLDDQSAETHSHKQSRLYKRKANDESNEHSDVIDSQELSKVSREF HSHEFHSHEDMLVVDPKSKEEDKHLKFRISHELDSASSEVN (SEQ ID NO: 30) 31 TGM2 MAEELVLERCDLELETNGRDHHTADLCREKLVVRRGQPFWLTLH FEGRNYEASVDSLTFSVVTGPAPSQEAGTKARFPLRDAVEEGDWT ATVVDQQDCTLSLQLTTPANAPIGLYRLSLEASTGYQGSSFVLGHF ILLFNAWCPADAVYLDSEEERQEYVLTQQGFIYQGSAKFIKNIPWN FGQFEDGILDICLILLDVNPKFLKNAGRDCSRRSSPVYVGRVVSGM VNCNDDQGVLLGRWDNNYGDGVSPMSWIGSVDILRRWKNHGCQ RVKYGQCWVFAAVACTVLRCLGIPTRVVTNYNSAHDQNSNLLIEY FRNEFGEIQGDKSEMIWNFHCWVESWMTRPDLQPGYEGWQALDP TPQEKSEGTYCCGPVPVRAIKEGDLSTKYDAPFVFAEVNADVVDW IQQDDGSVHKSINRSLIVGLKISTKSVGRDEREDITHTYKYPEGSSE EREAFTRANHLNKLAEKEETGMAMRIRVGQSMNMGSDFDVFAHI TNNTAEEYVCRLLLCARTVSYNGILGPECGTKYLLNLNLEPFSEKS VPLCILYEKYRDCLTESNLIKVRALLVEPVINSYLLAERDLYLENPEI KIRILGEPKQKRKLVAEVSLQNPLPVALEGCTFTVEGAGLTEEQKT VEIPDPVEAGEEVKVRMDLLPLHMGLHKLVVNFESDKLKAVKGF RNVIIGPA (SEQ ID NO: 31) 32 EGR2 MMTAKAVDKIPVTLSGFVHQLSDNIYPVEDLAATSVTIFPNAELGG PFDQMNGVAGDGMINIDMTGEKRSLDLPYPSSFAPVSAPRNQTFT YMGKFSIDPQYPGASCYPEGIINIVSAGILQGVTSPASTTASSSVTSA SPNPLATGPLGVCTMSQTQPDLDHLYSPPPPPPPYSGCAGDLYQDP SAFLSAATTSTSSSLAYPPPPSYPSPKPATDPGLFPMIPDYPGFFPSQ CQRDLHGTAGPDRKPFPCPLDTLRVPPPLTPLSTIRNFTLGGPSAGV TGPGASGGSEGPRLPGSSSAAAAAAAAAAYNPHHLPLRPILRPRKY PNRPSKTPVHERPYPCPAEGCDRRFSRSDELTRHIRIHTGHKPFQCR ICMRNFSRSDHLTTHIRTHTGEKPFACDYCGRKFARSDERKRHTKI HLRQKERKSSAPSASVPAPSTASCSGGVQPGGTLCSSNSSSLGGGP 217 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: LAPCSSRTRTP (SEQ ID NO: 32) 33 INHBA MPLLWLRGFLLASCWIIVRSSPTPGSEGHSAAPDCPSCALAALPKD VPNSQPEMVEAVKKHILNMLHLKKRPDVTQPVPKAALLNAIRKLH VGKVGENGYVEIEDDIGRRAEMNELMEQTSEIITFAESGTARKTLH FEISKEGSDLSVVERAEVWLFLKVPKANRTRTKVTIRLFQQQKHPQ GSLDTGEEAEEVGLKGERSELLLSEKVVDARKSTWHVFPVSSSIQR LLDQGKSSLDVRIACEQCQESGASLVLLGKKKKKEEEGEGKKKGG GEGGAGADEEKEQSHRPFLMLQARQSEDHPHRRRRRGLECDGKV NICCKKQFFVSFKDIGWNDWIIAPSGYHANYCEGECPSHIAGTSGSS LSFHSTVINHYRMRGHSPFANLKSCCVPTKLRPMSMLYYDDGQNII KKDIQNMIVEECGCS (SEQ ID NO: 33) 34 IL1RN MEICRGLRSHLITLLLFLFHSETICRPSGRKSSKMQAFRIWDVNQKT FYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLS CVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAA CPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE (SEQ ID NO: 34) 35 PLAU MRALLARLLLCVLVVSDSKGSNELHQVPSNCDCLNGGTCVSNKYF SNIHWCNCPKKFGGQHCEIDKSKTCYEGNGHFYRGKASTDTMGRP CLPWNSATVLQQTYHAHRSDALQLGLGKHNYCRNPDNRRRPWC YVQVGLKLLVQECMVHDCADGKKPSSPPEELKFQCGQKTLRPRFK IIGGEFTTIENQPWFAAIYRRHRGGSVTYVCGGSLISPCWVISATHC FIDYPKKEDYIVYLGRSRLNSNTQGEMKFEVENLILHKDYSADTLA HHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDPQFGTSCEITGFG KENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAA DPQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPG VYTRVSHFLPWIRSHTKEENGLAL (SEQ ID NO: 35) 36 SMAD3 MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKKLKKT GQLDELEKAITTQNVNTKCITIPRSLDGRLQVSHRKGLPHVIYCRL WRWPDLHSHHELRAMELCEFAFNMKKDEVCVNPYHYQRVETPV LPPVLVPRHTEIPAEFPPLDDYSHSIPENTNFPAGIEPQSNIPETPPPG YLSEDGETSDHQMNHSMDAGSPNLSPNPMSPAHNNLDLQPVTYC EPAFWCSISYYELNQRVGETFHASQPSMTVDGFTDPSNSERFCLGL LSNVNRNAAVELTRRHIGRGVRLYYIGGEVFAECLSDSAIFVQSPN CNQRYGWHPATVCKIPPGCNLKIFNNQEFAALLAQSVNQGFEAVY QLTRMCTIRMSFVKGWGAEYRRQTVTSTPCWIELHLNGPLQWLD KVLTQMGSPSIRCSSVS (SEQ ID NO: 36) 37 REV3L MFSVRIVTADYYMASPLQGLDTCQSPLTQAPVKKVPVVRVFGATP AGQKTCLHLHGIFPYLYVPYDGYGQQPESYLSQMAFSIDRALNVA LGNPSSTAQHVFKVSLVSGMPFYGYHEKERHFMKIYLYNPTMVKR ICELLQSGAIMNKFYQPHEAHIPYLLQLFIDYNLYGMNLINLAAVK FRKARRKSNTLHATGSCKNHLSGNSLADTLFRWEQDEIPSSLILEG VEPQSTCELEVDAVAADILNRLDIEAQIGGNPGLQAIWEDEKQRRR NRNETSQMSQPESQDHRFVPATESEKKFQKRLQEILKQNDFSVTLS GSVDYSDGSQEFSAELTLHSEVLSPEMLQCTPANMVEVHKDKESS KGHTRHKVEEALINEEAILNLMENSQTFQPLTQRLSESPVFMDSSP DEALVHLLAGLESDGYRGERNRMPSPCRSFGNNKYPQNSDDEENE PQIEKEEMELSLVMSQRWDSNIEEHCAKKRSLCRNTHRSSTEDDDS 218 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: SSGEEMEWSDNSLLLASLSIPQLDGTADENSDNPLNNENSRTHSSVI ATSKLSVKPSIFHKDAATLEPSSSAKITFQCKHTSALSSHVLNKEDLI EDLSQTNKNTEKGLDNSVTSFTNESTYSMKYPGSLSSTVHSENSHK ENSKKEILPVSSCESSIFDYEEDIPSVTRQVPSRKYTNIRKIEKDSPFI HMHRHPNENTLGKNSFNFSDLNHSKNKVSSEGNEKGNSTALSSLF PSSFTENCELLSCSGENRTMVHSLNSTADESGLNKLKIRYEEFQEH KTEKPSLSQQAAHYMFFPSVVLSNCLTRPQKLSPVTYKLQPGNKPS RLKLNKRKLAGHQETSTKSSETGSTKDNFIQNNPCNSNPEKDNAL ASDLTKTTRGAFENKTPTDGFIDCHFGDGTLETEQSFGLYGNKYTL RAKRKVNYETEDSESSFVTHNSKISLPHPMEIGESLDGTLKSRKRR KMSKKLPPVIIKYIIINRFRGRKNMLVKLGKIDSKEKQVILTEEKME LYKKLAPLKDFWPKVPDSPATKYPIYPLTPKKSHRRKSKHKSAKK KTGKQQRTNNENIKRTLSFRKKRSHAILSPPSPSYNAETEDCDLNY SDVMSKLGFLSERSTSPINSSPPRCWSPTDPRAEEIMAAAEKEAMLF KGPNVYKKTVNSRIGKTSRARAQIKKSKAKLANPSIVTKKRNKRN QTNKLVDDGKKKPRAKQKTNEKGTSRKHTTLKDEKIKSQSGAEV KFVLKHQNVSEFASSSGGSQLLFKQKDMPLMGSAVDHPLSASLPT GINAQQKLSGCFSSFLESKKSVDLQTFPSSRDDLHPSVVCNSIGPGV SKINVQRPHNQSAMFTLKESTLIQKNIFDLSNHLSQVAQNTQISSG MSSKIEDNANNIQRNYLSSIGKLSEYRNSLESKLDQAYTPNFLHCK DSQQQIVCIAEQSKHSETCSPGNTASEESQMPNNCFVTSLRSPIKQI AWEQKQRGFILDMSNFKPERVKPRSLSEAISQTKALSQCKNRNVST PSAFGEGQSGLAVLKELLQKRQQKAQNANTTQDPLSNKHQPNKNI SGSLEHNKANKRTRSVTSPRKPRTPRSTKQKEKIPKLLKVDSLNLQ NSSQLDNSVSDDSPIFFSDPGFESCYSLEDSLSPEHNYNFDINTIGQT GFCSFYSGSQFVPADQNLPQKFLSDAVQDLFPGQAIEKNEFLSHDN QKCDEDKHHTTDSASWIRSGTLSPEIFEKSTIDSNENRRHNQWKNS FHPLTTRSNSIMDSFCVQQAEDCLSEKSRLNRSSVSKEVFLSLPQPN NSDWIQGHTRKEMGQSLDSANTSFTAILSSPDGELVDVACEDLELY VSRNNDMLTPTPDSSPRSTSSPSQSKNGSFTPRTANILKPLMSPPSRE EIMATLLDHDLSETIYQEPFCSNPSDVPEKPREIGGRLLMVETRLAN DLAEFEGDFSLEGLRLWKTAFSAMTQNPRPGSPLRSGQGVVNKGS SNSPKMVEDKKIVIMPCKCAPSRQLVQVWLQAKEEYERSKKLPKT KPTGVVKSAENFSSSVNPDDKPVVPPKMDVSPCILPTTAHTKEDVD NSQIALQAPTTGCSQTASESQMLPPVASASDPEKDEDDDDNYYISY SSPDSPVIPPWQQPISPDSKALNGDDRPSSPVEELPSLAFENFLKPIK DGIQKSPCSEPQEPLVISPINTRARTGKCESLCFHSTPIIQRKLLERLP EAPGLSPLSTEPKTQKLSNKKGSNTDTLRRVLLTQAKNQFAAVNTP QKETSQIDGPSLNNTYGFKVSIQNLQEAKALHEIQNLTLISVELHAR TRRDLEPDPEFDPICALFYCISSDTPLPDTEKTELTGVIVIDKDKTVF SQDIRYQTPLLIRSGITGLEVTYAADEKALFHEIANIIKRYDPDILLG YEIQMHSWGYLLQRAAALSIDLCRMISRVPDDKIENRFAAERDEY GSYTMSEINIVGRITLNLWRIMRNEVALTNYTFENVSFHVLHQRFP LFTFRVLSDWFDNKTDLYRWKMVDHYVSRVRGNLQMLEQLDLIG KTSEMARLFGIQFLHVLTRGSQYRVESMMLRIAKPMNYIPVTPSVQ QRSQMRAPQCVPLIMEPESRFYSNSVLVLDFQSLYPSIVIAYNYCFS TCLGHVENLGKYDEFKFGCTSLRVPPDLLYQVRHDITVSPNGVAF 219 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VKPSVRKGVLPRMLEEILKTRFMVKQSMKAYKQDRALSRMLDAR QLGLKLIANVTFGYTSANFSGRMPCIEVGDSIVHKARETLERAIKL VNDTKKWGARVVYGDTDSMFVLLKGATKEQSFKIGQEIAEAVTA TNPKPVKLKFEKVYLPCVLQTKKRYVGYMYETLDQKDPVFDAKG IETVRRDSCPAVSKILERSLKLLFETRDISLIKQYVQRQCMKLLEGK ASIQDFIFAKEYRGSFSYKPGACVPALELTRKMLTYDRRSEPQVGE RVPYVIIYGTPGVPLIQLVRRPVEVLQDPTLRLNATYYITKQILPPLA RIFSLIGIDVFSWYHELPRIHKATSSSRSEPEGRKGTISQYFTTLHCP VCDDLTQHGICSKCRSQPQHVAVILNQEIRELERQQEQLVKICKNC TGCFDRHIPCVSLNCPVLFKLSRVNRELSKAPYLRQLLDQF (SEQ ID NO: 37) 38 HCAR3 MNRHHLQDHFLEIDKKNCCVFRDDFIAKVLPPVLGLEFIFGLLGNG LALWIFCFHLKSWKSSRIFLFNLAVADFLLIICLPFVMDYYVRRSD WKFGDIPCRLVLFMFAMNRQGSIIFLTVVAVDRYFRVVHPHHALN KISNWTAAIISCLLWGITVGLTVHLLKKKLLIQNGTANVCISFSICHT FRWHEAMFLLEFFLPLGIILFCSARIIWSLRQRQMDRHAKIKRAITFI MVVAIVFVICFLPSVVVRIHIFWLLHTSGTQNCEVYRSVDLAFFITL SFTYMNSMLDPVVYYFSSPSFPNFFSTLINRCLQRKITGEPDNNRST SVELTGDPNKTRGAPEALIANSGEPWSPSYLGPTSNNHSKKGHCH QEPASLEKQLGCCIE (SEQ ID NO: 38) 39 TLR8 MENMFLQSSMLTCIFLLISGSCELCAEENFSRSYPCDEKKQNDSVIA ECSNRRLQEVPQTVGKYVTELDLSDNFITHITNESFQGLQNLTKINL NHNPNVQHQNGNPGIQSNGLNITDGAFLNLKNLRELLLEDNQLPQI PSGLPESLTELSLIQNNIYNITKEGISRLINLKNLYLAWNCYFNKVCE KTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPSSLRKLFLSNTQIKY ISEEDFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQ NLTQLRYLNLSSTSLRKINAAWFKNMPHLKVLDLEFNYLVGEIAS GAFLTMLPRLEILDLSFNYIKGSYPQHINISRNFSKLLSLRALHLRGY VFQELREDDFQPLMQLPNLSTINLGINFIKQIDFKLFQNFSNLEIIYLS ENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEFDPHSNFYHFTRP LIKPQCAAYGKALDLSLNSIFFIGPNQFENLPDIACLNLSANSNAQV LSGTEFSAIPHVKYLDLTNNRLDFDNASALTELSDLEVLDLSYNSH YFRIAGVTHHLEFIQNFTNLKVLNLSHNNIYTLTDKYNLESKSLVEL VFSGNRLDILWNDDDNRYISIFKGLKNLTRLDLSLNRLKHIPNEAFL NLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNKLLFLTDS LSDFTSSLRTLLLSHNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKS ALETKTTTKLSMLELHGNPFECTCDIGDFRRWMDEHLNVKIPRLV DVICASPGDQRGKSIVSLELTTCVSDVTAVILFFFTFFITTMVMLAA LAHHLFYWDVWFIYNVCLAKVKGYRSLSTSQTFYDAYISYDTKD ASVTDWVINELRYHLEESRDKNVLLCLEERDWDPGLAIIDNLMQSI NQSKKTVFVLTKKYAKSWNFKTAFYLALQRLMDENMDVIIFILLE PVLQHSQYLRLRQRICKSSILQWPDNPKAEGLFWQTLRNVVLTEN DSRYNNMYVDSIKQY (SEQ ID NO: 39) 40 BMF MEPSQCVEELEDDVFQPEDGEPVTQPGSLLSADLFAQSLLDCPLSR LQLFPLTHCCGPGLRPTSQEDKATQTLSPASPSQGVMLPCGVTEEP QRLFYGNAGYRLPLPASFPAVLPIGEQPPEGQWQHQAEVQIARKL QCIADQFHRLHVQQHQQNQNRVWWQILLFLHNLALNGEENRNGA 220 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GPR (SEQ ID NO: 40) 41 APOL3 MGLGQGWGWEASCFACLIRSCCQVVTFTFPFGFQGISQSLENVSG YYADARLEVGSTQLRTAGSCSHSFKRSFLEKKRFTEEATKYFRERV SPVHLQILLTNNEAWKRFVTAAELPRDEADALYEALKKLRTYAAI EDEYVQQKDEQFREWFLKEFPQVKRKIQESIEKLRALANGIEEVHR GCTISNVVSSSTGAASGIMSLAGLVLAPFTAGTSLALTAAGVGLGA ASAVTGITTSIVEHSYTSSAEAEASRLTATSIDRLKVFKEVMRDITP NLLSLLNNYYEATQTIGSEIRAIRQARARARLPVTTWRISAGSGGQ AERTIAGTTRAVSRGARILSATTSGIFLALDVVNLVYESKHLHEGA KSASAEELRRQAQELEENLMELTQIYQRLNPCHTH (SEQ ID NO: 41) 42 ARHGEF10L MASSNPPPQPAIGDQLVPGVPGPSSEAEDDPGEAFEFDDSDDEEDT SAALGVPSLAPERDTDPPLIHLDSIPVTDPDPAAAPPGTGVPAWVS NGDAADAAFSGARHSSWKRKSSRRIDRFTFPALEEDVIYDDVPCES PDAHQPGAERNLLYEDAHRAGAPRQAEDLGWSSSEFESYSEDSGE EAKPEVEVEPAKHRVSFQPKLSPDLTRLKERYARTKRDILALRVGG RDMQELKHKYDCKMTQLMKAAKSGTKDGLEKTRMAVMRKVSF LHRKDVLGDSEEEDMGLLEVSVSDIKPPAPELGPMPEGLSPQQVVR RHILGSIVQSEGSYVESLKRILQDYRNPLMEMEPKALSARKCQVVF FRVKEILHCHSMFQIALSSRVAEWDSTEKIGDLFVASFSKSMVLDV YSDYVNNFTSAMSIIKKACLTKPAFLEFLKRRQVCSPDRVTLYGLM VKPIQRFPQFILLLQDMLKNTPRGHPDRLSLQLALTELETLAEKLNE QKRLADQVAEIQQLTKSVSDRSSLNKLLTSGQRQLLLCETLTETVY GDRGQLIKSKERRVFLLNDMLVCANINFKPANHRGQLEISSLVPLG PKYVVKWNTALPQVQVVEVGQDGGTYDKDNVLIQHSGAKKASA SGQAQNKVYLGPPRLFQELQDLQKDLAVVEQITLLISTLHGTYQNL NMTVAQDWCLALQRLMRVKEEEIHSANKCRLRLLLPGKPDKSGR PISFMVVFITPNPLSKISWVNRLHLAKIGLREENQPGWLCPDEDKKS KAPFWCPILACCIPAFSSRALSLQLGALVHSPVNCPLLGFSAVSTSL PQGYLWVGGGQEGAGGQVEIFSLNRPSPRTVKSFPLAAPVLCMEY IPELEEEAESRDESPTVADPSATVHPTICLGLQDGSILLYSSVDTGTQ CLVSCRSPGLQPVLCLRHSPFHLLAGLQDGTLAAYPRTSGGVLWD LESPPVCLTVGPGPVRTLLSLEDAVWASCGPRVTVLEATTLQPQQS FEAHQDEAVSVTHMVKAGSGVWMAFSSGTSIRLFHTETLEHLQEI NIATRTTFLLPGQKHLCVTSLLICQGLLWVGTDQGVIVLLPVPRLE GIPKITGKGMVSLNGHCGPVAFLAVATSILAPDILRSDQEEAEGPRA EEDKPDGQAHEPMPDSHVGRELTRKKGILLQYRLRSTAHLPGPLLS MREPAPADGAALEHSEEDGSIYEMADDPDIWVRSRPCARDAHRKE ICSVAIISGGQGYRNFGSALGSSGRQAPCGETDSTLLIWQVPLML (SEQ ID NO: 42) 43 GSDMD MGSAFERVVRRVVQELDHGGEFIPVTSLQSSTGFQPYCLVVRKPSS SWFWKPRYKCVNLSIKDILEPDAAEPDVQRGRSFHFYDAMDGQIQ GSVELAAPGQAKIAGGAAVSDSSSTSMNVYSLSVDPNTWQTLLHE RHLRQPEHKVLQQLRSRGDNVYVVTEVLQTQKEVEVTRTHKREG SGRFSLPGATCLQGEGQGHLSQKKTVTIPSGSTLAFRVAQLVIDSD LDVLLFPDKKQRTFQPPATGHKRSTSEGAWPQLPSGLSMMRCLHN FLTDGVPAEGAFTEDFQGLRAEVETISKELELLDRELCQLLLEGLEG 221 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VLRDQLALRALEEALEQGQSLGPVEPLDGPAGAVLECLVLSSGML VPELAIPVVYLLGALTMLSETQHKLLAEALESQTLLGPLELVGSLL EQSAPWQERSTMSLPPGLLGNSWGEGAPAWVLLDECGLELGEDTP HVCWEPQAQGRMCALYASLALLSGLSQEPH (SEQ ID NO: 43) 44 PDPN MWKVSALLFVLGSASLWVLAEGASTGQPEDDTETTGLEGGVAMP GAEDDVVTPGTSEDRYKSGLTTLVATSVNSVTGIRIEDLPTSESTVH AQEQSPSATASNVATSHSTEKVDGDTQTTVEKDGLSTVTLVGIIVG VLLAIGFIGAIIVVVMRKMSGRYSP (SEQ ID NO: 44) 45 RGS2 MQSAMFLAVQHDCRPMDKSAGSGHKSEEKREKMKRTLLKDWKT RLSYFLQNSSTPGKPKTGKKSKQQAFIKPSPEEAQLWSEAFDELLA SKYGLAAFRAFLKSEFCEENIEFWLACEDFKKTKSPQKLSSKARKI YTDFIEKEAPKEINIDFQTKTLIAQNIQEATSGCFTTAQKRVYSLME NNSYPRFLESEFYQDLCKKPQITTEPHAT (SEQ ID NO: 45) 46 MAFB MAAELSMGPELPTSPLAMEYVNDFDLLKFDVKKEPLGRAERPGRP CTRLQPAGSVSSTPLSTPCSSVPSSPSFSPTEQKTHLEDLYWMASNY QQMNPEALNLTPEDAVEALIGSHPVPQPLQSFDSFRGAHHHHHHH HPHPHHAYPGAGVAHDELGPHAHPHHHHHHQASPPPSSAASPAQ QLPTSHPGPGPHATASATAAGGNGSVEDRFSDDQLVSMSVRELNR HLRGFTKDEVIRLKQKRRTLKNRGYAQSCRYKRVQQKHHLENEK TQLIQQVEQLKQEVSRLARERDAYKVKCEKLANSGFREAGSTSDS PSSPEFFL (SEQ ID NO: 46) 47 CCL2 MKVSAALLCLLLIAATFIPQGLAQPDAINAPVTCCYNFTNRKISVQ RLASYRRITSSKCPKEAVIFKTIVAKEICADPKQKWVQDSMDHLDK QTQTPKT (SEQ ID NO: 47) 48 ANXA1 MAMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPS SDVAALHKAIMVKGVDEATIIDILTKRNNAQRQQIKAAYLQETGKP LDETLKKALTGHLEEVVLALLKTPAQFDADELRAAMKGLGTDED TLIEILASRTNKEIRDINRVYREELKRDLAKDITSDTSGDFRNALLSL AKGDRSEDFGVNEDLADSDARALYEAGERRKGTDVNVFNTILTTR SYPQLRRVFQKYTKYSKHDMNKVLDLELKGDIEKCLTAIVKCATS KPAFFAEKLHQAMKGVGTRHKALIRIMVSRSEIDMNDIKAFYQKM YGISLCQAILDETKGDYEKILVALCGGN (SEQ ID NO: 48) 49 ADAM17 MRQSLLFLTSVVPFVLAPRPPDDPGFGPHQRLEKLDSLLSDYDILSL SNIQQHSVRKRDLQTSTHVETLLTFSALKRHFKLYLTSSTERFSQNF KVVVVDGKNESEYTVKWQDFFTGHVVGEPDSRVLAHIRDDDVIIR INTDGAEYNIEPLWRFVNDTKDKRMLVYKSEDIKNVSRLQSPKVC GYLKVDNEELLPKGLVDREPPEELVHRVKRRADPDPMKNTCKLL VVADHRFYRYMGRGEESTTTNYLIELIDRVDDIYRNTSWDNAGFK GYGIQIEQIRILKSPQEVKPGEKHYNMAKSYPNEEKDAWDVKMLL EQFSFDIAEEASKVCLAHLFTYQDFDMGTLGLAYVGSPRANSHGG VCPKAYYSPVGKKNIYLNSGLTSTKNYGKTILTKEADLVTTHELGH NFGAEHDPDGLAECAPNEDQGGKYVMYPIAVSGDHENNKMFSNC SKQSIYKTIESKAQECFQERSNKVCGNSRVDEGEECDPGIMYLNND TCCNSDCTLKEGVQCSDRNSPCCKNCQFETAQKKCQEAINATCKG VSYCTGNSSECPPPGNAEDDTVCLDLGKCKDGKCIPFCEREQQLES CACNETDNSCKVCCRDLSGRCVPYVDAEQKNLFLRKGKPCTVGF CDMNGKCEKRVQDVIERFWDFIDQLSINTFGKFLADNIVGSVLVFS 222 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: LIFWIPFSILVHCVDKKLDKQYESLSLFHPSNVEMLSSMDSASVRII KPFPAPQTPGRLQPAPVIPSAPAAPKLDHQRMDTIQEDPSTDSHMD EDGFEKDPFPNSSTAAKSFEDLTDHPVTRSEKAASFKLQRQNRVDS KETEC (SEQ ID NO: 49) 50 TNF MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTL FCLLHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVA NPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQV LFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGA EAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGII AL (SEQ ID NO: 50) 51 CCL3 MQVSTAALAVLLCTMALCNQFSASLAADTPTACCFSYTSRQIPQN FIADYFETSSQCSKPGVIFLTKRSRQVCADPSEEWVQKYVSDLELS A (SEQ ID NO: 51) 52 CCL4 MKLCVTVLSLLMLVAAFCSPALSAPMGSDPPTACCFSYTARKLPR NFVVDYYETSSLCSQPAVVFQTKRSKQVCADPSESWVQEYVYDLE LN (SEQ ID NO: 52) 53 CXCL2 MARATLSAAPSNPRLLRVALLLLLLVAASRRAAGAPLATELRCQC LQTLQGIHLKNIQSVKVKSPGPHCAQTEVIATLKNGQKACLNPASP MVKKIIEKMLKNGKSN (SEQ ID NO: 53) 54 CXCL3 MAHATLSAAPSNPRLLRVALLLLLLVAASRRAAGASVVTELRCQC LQTLQGIHLKNIQSVNVRSPGPHCAQTEVIATLKNGKKACLNPASP MVQKIIEKILNKGSTN (SEQ ID NO: 54) 55 S10011A MAKISSPTETERCIESLIAVFQKYAGKDGYNYTLSKTEFLSFMNTEL AAFTKNQKDPGVLDRMMKKLDTNSDGQLDFSEFLNLIGGLAMAC HDSFLKAVPSQKRT (SEQ ID NO: 55) 56 S100A6 MACPLDQAIGLLVAIFHKYSGREGDKHTLSKKELKELIQKELTIGS KLQDAEIARLMEDLDRNKDQEVNFQEYVTFLGALALIYNEALKG (SEQ ID NO: 56) 57 S100A4 MACPLEKALDVMVSTFHKYSGKEGDKFKLNKSELKELLTRELPSF LGKRTDEAAFQKLMSNLDSNRDNEVDFQEYCVFLSCIAMMCNEFF EGFPDKQPRKK (SEQ ID NO: 57) 58 LGALS1 MACGLVASNLNLKPGECLRVRGEVAPDAKSFVLNLGKDSNNLCL HFNPRFNAHGDANTIVCNSKDGGAWGTEQREAVFPFQPGSVAEVC ITFDQANLTVKLPDGYEFKFPNRLNLEAINYMAADGDFKIKCVAFD (SEQ ID NO: 58) 59 LGALS3 MADNFSLHDALSGSGNPNPQGWPGAWGNQPAGAGGYPGASYPG AYPGQAPPGAYPGQAPPGAYPGAPGAYPGAPAPGVYPGPPSGPGA YPSSGQPSATGAYPATGPYGAPAGPLIVPYNLPLPGGVVPRMLITIL GTVKPNANRIALDFQRGNDVAFHFNPRFNENNRRVIVCNTKLDNN WGREERQSVFPFESGKPFKIQVLVEPDHFKVAVNDAHLLQYNHRV KKLNEISKLGISGDIDLTSASYTMI (SEQ ID NO: 59) 60 TIMP3 MTPWLGLIVLLGSWSLGDWGAEACTCSPSHPQDAFCNSDIVIRAK VVGKKLVKEGPFGTLVYTIKQMKMYRGFTKMPHVQYIHTEASESL CGLKLEVNKYQYLLTGRVYDGKMYTGLCNFVERWDQLTLSQRK GLNYRYHLGCNCKIKSCYYLPCFVTSKNECLWTDMLSNFGYPGY QSKHYACIRQKGGYCSWYRGWAPPDKSIINATDP (SEQ ID NO: 60) 61 ADAMDEC1 MLRGISQLPAVATMSWVLLPVLWLIVQTQAIAIKQTPELTLHEIVCP 223 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: KKLHILHKREIKNNQTEKHGKEERYEPEVQYQMILNGEEIILSLQKT KHLLGPDYTETLYSPRGEEITTKPENMEHCYYKGNILNEKNSVASI STCDGLRGYFTHHHQRYQIKPLKSTDEKEHAVFTSNQEEQDPANH TCGVKSTDGKQGPIRISRSLKSPEKEDFLRAQKYIDLYLVLDNAFY KNYNENLTLIRSFVFDVMNLLNVIYNTIDVQVALVGMEIWSDGDKI KVVPSASTTFDNFLRWHSSNLGKKIHDHAQLLSGISFNNRRVGLAA SNSLCSPSSVAVIEAKKKNNVALVGVMSHELGHVLGMPDVPFNTK CPSGSCVMNQYLSSKFPKDFSTSCRAHFERYLLSQKPKCLLQAPIPT NIMTTPVCGNHLLEVGEDCDCGSPKECTNLCCEALTCKLKPGTDC GGDAPNHTTE (SEQ ID NO: 61) 62 CXCL14 MSLLPRRAPPVSMRLLAAALLLLLLALYTARVDGSKCKCSRKGPK IRYSDVKKLEMKPKYPHCEEKMVIITTKSVSRYRGQEHCLHPKLQS TKRFIKWYNAWNEKRRVYEE (SEQ ID NO: 62) 63 AGT MDKDCEMKRTTLDSPLGKLELSGCEQGLHEIKLLGKGTSAADAVE VPAPAAVLGGPEPLMQCTAWLNAYFHQPEAIEEFPVPALHHPVFQ QESFTRQVLWKLLKVVKFGEVISYQQLAALAGNPKAARAVGGAM RGNPVPILIPCHRVVCSSGAVGNYSGGLAVKEWLLAHEGHRLGKP GLGGSSGLAGAWLKGAGATSGSPPAGRN (SEQ ID NO: 63) 64 LAMA4 MALSSAWRSVLPLWLLWSAACSRAASGDDNAFPFDIEGSSAVGRQ DPPETSEPRVALGRLPPAAEKCNAGFFHTLSGECVPCDCNGNSNEC LDGSGYCVHCQRNTTGEHCEKCLDGYIGDSIRGAPQFCQPCPCPLP HLANFAESCYRKNGAVRCICNENYAGPNCERCAPGYYGNPLLIGS TCKKCDCSGNSDPNLIFEDCDEVTGQCRNCLRNTTGFKCERCAPG YYGDARIAKNCAVCNCGGGPCDSVTGECLEEGFEPPTGMDCPTIS CDKCVWDLTDALRLAALSIEEGKSGVLSVSSGAAAHRHVNEINAT IYLLKTKLSERENQYALRKIQINNAENTMKSLLSDVEELVEKENQA SRKGQLVQKESMDTINHASQLVEQAHDMRDKIQEINNKMLYYGE EHELSPKEISEKLVLAQKMLEEIRSRQPFFTQRELVDEEADEAYELL SQAESWQRLHNETRTLFPVVLEQLDDYNAKLSDLQEALDQALNY VRDAEDMNRATAARQRDHEKQQERVREQMEVVNMSLSTSADSL TTPRLTLSELDDIIKNASGIYAEIDGAKSELQVKLSNLSNLSHDLVQ EAIDHAQDLQQEANELSRKLHSSDMNGLVQKALDASNVYENIVN YVSEANETAEFALNTTDRIYDAVSGIDTQIIYHKDESENLLNQAREL QAKAESSSDEAVADTSRRVGGALARKSALKTRLSDAVKQLQAAE RGDAQQRLGQSRLITEEANRTTMEVQQATAPMANNLTNWSQNLQ HFDSSAYNTAVNSARDAVRNLTEVVPQLLDQLRTVEQKRPASNVS ASIQRIRELIAQTRSVASKIQVSMMFDGQSAVEVHSRTSMDDLKAF TSLSLYMKPPVKRPELTETADQFILYLGSKNAKKEYMGLAIKNDN LVYVYNLGTKDVEIPLDSKPVSSWPAYFSIVKIERVGKHGKVFLTV PSLSSTAEEKFIKKGEFSGDDSLLDLDPEDTVFYVGGVPSNFKLPTS LNLPGFVGCLELATLNNDVISLYNFKHIYNMDPSTSVPCARDKLAF TQSRAASYFFDGSGYAVVRDITRRGKFGQVTRFDIEVRTPADNGLI LLMVNGSMFFRLEMRNGYLHVFYDFGFSGGPVHLEDTLKKAQIN DAKYHEISIIYHNDKKMILVVDRRHVKSMDNEKMKIPFTDIYIGGA PPEILQSRALRAHLPLDINFRGCMKGFQFQKKDFNLLEQTETLGVG YGCPEDSLISRRAYFNGQSFIASIQKISFFDGFEGGFNFRTLQPNGLL FYYASGSDVFSISLDNGTVIMDVKGIKVQSVDKQYNDGLSHFVISS 224 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VSPTRYELIVDKSRVGSKNPTKGKIEQTQASEKKFYFGGSPISAQYA NFTGCISNAYFTRVDRDVEVEDFQRYTEKVHTSLYECPIESSPLFLL HKKGKNLSKPKASQNKKGGKSKDAPSWDPVALKLPERNTPRNSH CHLSNSPRAIEHAYQYGGTANSRQEFEHLKGDFGAKSQFSIRLRTR SSHGMIFYVSDQEENDFMTLFLAHGRLVYMFNVGHKKLKIRSQEK YNDGLWHDVIFIRERSSGRLVIDGLRVLEESLPPTEATWKIKGPIYL GGVAPGKAVKNVQINSIYSFSGCLSNLQLNGASITSASQTFSVTPCF EGPMETGTYFSTEGGYVVLDESFNIGLKFEIAFEVRPRSSSGTLVHG HSVNGEYLNVHMKNGQVIVKVNNGIRDFSTSVTPKQSLCDGRWH RITVIRDSNVVQLDVDSEVNHVVGPLNPKPIDHREPVFVGGVPESL LTPRLAPSKPFTGCIRHFVIDGHPVSFSKAALVSGAVSINSCPAA (SEQ ID NO: 64) 65 WNT2B MLRPGGAEEAAQLPLRRASAPVPVPSPAAPDGSRASARLGLACLL LLLLLTLPARVDTSWWYIGALGARVICDNIPGLVSRQRQLCQRYPD IMRSVGEGAREWIRECQHQFRHHRWNCTTLDRDHTVFGRVMLRS SREAAFVYAISSAGVVHAITRACSQGELSVCSCDPYTRGRHHDQR GDFDWGGCSDNIHYGVRFAKAFVDAKEKRLKDARALMNLHNNR CGRTAVRRFLKLECKCHGVSGSCTLRTCWRALSDFRRTGDYLRRR YDGAVQVMATQDGANFTAARQGYRRATRTDLVYFDNSPDYCVL DKAAGSLGTAGRVCSKTSKGTDGCEIMCCGRGYDTTRVTRVTQC ECKFHWCCAVRCKECRNTVDVHTCKAPKKAEWLDQT (SEQ ID NO: 65) 66 CCL5 MKVSAAALAVILIATALCAPASASPYSSDTTPCCFAYIARPLPRAHI KEYFYTSGKCSNPAVVFVTRKNRQVCANPEKKWVREYINSLEMS (SEQ ID NO: 66) 67 CEBPB MQRLVAWDPACLPLPPPPPAFKSMEVANFYYEADCLAAAYGGKA APAAPPAARPGPRPPAGELGSIGDHERAIDFSPYLEPLGAPQAPAPA TATDTFEAAPPAPAPAPASSGQHHDFLSDLFSDDYGGKNCKKPAE YGYVSLGRLGAAKGALHPGCFAPLHPPPPPPPPPAELKAEPGFEPA DCKRKEEAGAPGGGAGMAAGFPYALRAYLGYQAVPSGSSGSLST SSSSSPPGTPSPADAKAPPTACYAGAAPAPSQVKSKAKKTVDKHSD EYKIRRERNNIAVRKSRDKAKMRNLETQHKVLELTAENERLQKKV EQLSRELSTLRNLFKQLPEPLLASSGHC (SEQ ID NO: 67) 68 IL23A MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLA WSAHPLVGHMDLREEGDEETTNDVPHIQCGDGCDPQGLRDNSQF CLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSPVGQLHASLLGLSQLLQ PEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVFAH GAATLSP (SEQ ID NO: 68) 69 DCHS2 MSPCGRKMGEGRQQRRAPVGKLLLLPGRRDTPHGRSGSSGARTQ RSLLWLLVHVWLWAASGSSAQLFNLTLSVDEGLPPDTLVGDIRAG LPAAQQQEGSGFFLSEDSDDSPLLDDFHVHPDTGIIRTARRLDRERR DHYSFVAATLLGAVVQVEIRVNDVNDHSPRFPLDSLQLDVSELSPP GTAFRLPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTP GPLPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPR RTGLLSVELRVLDENDNPPVFEQDEYRAAVREDAQPGAEVCRVRA TDRDLGPNGFVRYSVRARQVPGAGSGGGALGDAAYFAVEELSGV VRVWRPLDREAQAWHQLVVEARDGGAEPEVATVRVSIAVLDVN 225 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: DNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDADGDWEKE DEATGELGVGLGDGSISLSLEGGEGDFALLPGGPPGVFFLCVEGPL DRESRDLYELLLVATDAGSPPLSTEETLLLRVADLNDQPPLFSQQH YKASVSEAAAPGTVVMWVSASDADEAGSDHAWLRYTVVQLSAP CNLGSLQSKMVHTAECGPSFAIDSESGAISTIRTLDREVQEAVELKV VAQDLGEPPLSATCLVSITVDDVNDNEPIFWRQVYNATIAEHAPVG HCFLQVTASDADSGLYGFIEYSLYDGFLSYEAPQAFRIDPHDGQIC VSQDIDRERDPATYDLLVEAKDGGGLSAQAFVRVDLEDVNDNHP VFNPSTYVTSISDETQPGTEIINVLATDQDSGIYGTVAYELIPGNVSS LFTIDSTTGIIYLTLPLSHLESTTLSLMVSAQDGGGLTAVINADVTIH IFQTTLAPAEFERPKYTFLVYEDVPEDSPIGTVKAREPLNSSEPIFYRI SSGDLGGKFSIHPRLGTIRTRKPLDHETQPVVVLTVQAQLGSAPAC SSTEVNITVMDVNDNHPAFLRTSDEIRISQTTPPGTALYLARAEDRD SGRNGLIRYSIASPQPGVFAIDRALGVLFLNGSLGAGEQRELTLTLR AEDQGVHPQAALLVLTVVIEKREHSPSWTFEHLVYQVEVSESLSP MTQMLQTQAHPLGPQRAASPLRYSLEPSVDSAMFGIRPYTGWIYL RRQFDYESTQTYNFRVFAWIPEDGFLQNVSTTVIVRVWDENDNSP TFLHDVLFLKVEESPVPQGVIGKITAIDMDSGKNGQLLYFLLSDGK FFKMNPNTGELINWVALDREHRGHHEMTVLVTDRGSPPRNATMA VYVSVTDINDNRPFFPQCLPGKELHVKVLEGQPVNMLVTTVFAKD PDEGNNAEVTYSVSSEDSSDHFKIDANNGEIRTTTILSYDYRPSYR MSVIATDQGVPPLQGQAVVNIQVIPLSKGRAIMSQNIRHLIIPENLK PTKIMSLIKSSDHLQQHYNGKLHFSIVADDKDGHFEIDSSTGDLFLS KELDYETTSHYLFRVITTDHSKNLSLSSTVFLSIDVEDQNDHSPSFQ DELIVISVEENVPIGTLVYVFNAKDDDGSFLNSRIQYYIESHNPGTN PFLIHPSFGTLVTVSRLDRESIPTVILTVTASDQAVNVTDRRLRSLTA QIVILDVNDHNPTFISFPNAHVKEDVTVGSLVHHITAHDPDEGRNG KVTYSILSGNENMTFMLDESSGLLTTTCPLDYEMKTQHILTVLALD DGTPALSSSQTLTVTVLDVNDEAPVFKQHLYEASVKENQNPGEFV TRVEALDRDSGVNSKLQFEIMPGASFELFEINSDTGEVVTTTILDRE IQEVFTLRVLVRDGGFPSLSSTTTILCTVEDENDHAPEFIVSSYDIEV LENQEPEVVYTVLASDMDAGNNRAVEYHIIDGNTDECFTINEMSG ELSTTRALDREQISNFTLVILCSDLGDPPRSSVIHLQVRVLDANDHS PSFPTLYYQSSVREDAEVGTVVLVLSAVDKDEGLNGQTEYFLTDE ASGAFTIDPMSGTLKTSNTLDREARSQHTFSAVARDCSIQGSRSTT VIIKVYVTDVNDNDPVLEQNPFDVFLSPESPTNQTTVIVRADDLDL GPNGTVVFSFAETQSMFSIDKYTGEIQFQQNPSSEYFPIWLQLKVTD QGIPARTTTGLLVIHMEGEDVKISFSHHLYKGLVTENCEAGTSIVTV KAFAPDSIQDSMKYSIFSGNEDGVLSLCSKSGQLTVKEPKFLDFEV RNEVQLIVLAESSGHRAYCKVAVLIQDENDNSPCFEQSIYQASVSE SQLYNAHVIQVFATDLDSGLNGLIEYSILSGNQEEAFQIDALSGVIT TKAILDYELTSSYSLIVQATDKGMPRLSNTTVIKVQVTDINDNAPA FLPSEAVEITEDSLPGVIVTHVSVHDVDLNSAFIFSFAKESNPGTKFA IDQNTGVVVLVKTLDFEEMTEYELLIQISDSVHYTEGALVVRVLDV NDNPPVFSQDFYQVTVPESIPVGYSVLTLSATDLESNENISYRILSSS KEFSIDPKNGTIFTISPVLLLDTISTTQFLVEASDGGNPDLRALTLVEI GIEDMNNYAPEFTVKSYNLSLSEDALVGSTLVTFSNIDHDWTRENT 226 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: YVEYSIISGNSQNNFHVETKFFHSEYPYKQVGYLVLLHSLDREASA SHELVILASDSGCPPLSSTAVISIQVLDVNDNPPNFSSLSYHTHVKES TPLGSHITVVSANDRDTGSHAEIIYNIISGNEKGHFYLEENTGVLYLI KPLDYEKMTKFTLTVQASDAEKKHFSFAVVFVSVLDDNDHAPQF MFSSFSCIVPENLPISSTICSINALDFDAGPYGELTYSIVSPCFLTHGM SYDHDLFLIDPLTGDIHAKQILDYENGNKYCLTVQAKDKGDATAS LVVWVDIEGIDEFEPIFTQDQYFFTLPEKNKDRQLIGRVEASDADA GIDGVILYSLGTSSPFFSVNKTNGNIYLIRALPLIKSQLNKEDTLEMK IIAHSPKSDSKFASCTVFVNVSFSSEGTPLAVFASSFSISLVVSFLVFL ILICILIVMILRHKQKDTINNYEEKKTSSLDADLRVTRDASVLKAFQ KTDDCSNEVVPVDATPEWLSLISIMEKDIVNLYRHSNSSGHCSVEG ETAEDKEIQRINEHPYRKCSDSALSDHESRVPDSGIPRDSDQLSCLS GETDVMVTAETAEASQTFGEGDQGEGCSTTCAQNNVLPQTVQKR EAKESILADVRKESVFISGDQEVRCAALSTQTTSDHDGKDNYHWN YLLSWEPKFQPLASVFNDIAKLKDEHLHMPGIPKEKKSFVFPPPLIT AVAQPGIKAVPPRMPAVNLGQVPPKHPRSPIPYHLGSLPEGMTPNF SPSLSLLTMQPPALSPLLREGELLGTHISGTCHELKAEDEVQI (SEQ ID NO: 69) 70 SELE MIASQFLSALTLVLLIKESGAWSYNTSTEAMTYDEASAYCQQRYT HLVAIQNKEEIEYLNSILSYSPSYYWIGIRKVNNVWVWVGTQKPLT EEAKNWAPGEPNNRQKDEDCVEIYIKREKDVGMWNDERCSKKKL ALCYTAACTNTSCSGHGECVETINNYTCKCDPGFSGLKCEQIVNCT ALESPEHGSLVCSHPLGNFSYNSSCSISCDRGYLPSSMETMQCMSS GEWSAPIPACNVVECDAVTNPANGFVECFQNPGSFPWNTTCTFDC EEGFELMGAQSLQCTSSGNWDNEKPTCKAVTCRAVRQPQNGSVR CSHSPAGEFTFKSSCNFTCEEGFMLQGPAQVECTTQGQWTQQIPVC EAFQCTALSNPERGYMNCLPSASGSFRYGSSCEFSCEQGFVLKGSK RLQCGPTGEWDNEKPTCEAVRCDAVHQPPKGLVRCAHSPIGEFTY KSSCAFSCEEGFELHGSTQLECTSQGQWTEEVPSCQVVKCSSLAVP GKINMSCSGEPVFGTVCKFACPEGWTLNGSAARTCGATGHWSGL LPTCEAPTESNIPLVAGLSAAGLSLLTLAPFLLWLRKCLRKAKKFV PASSCQSLESDGSYQKPSYIL (SEQ ID NO: 70) 71 LTB MGALGLEGRGGRLQGRGSLLLAVAGATSLVTLLLAVPITVLAVLA LVPQDQGGLVTETADPGAQAQQGLGFQKLPEEEPETDLSPGLPAA HLIGAPLKGQGLGWETTKEQAFLTSGTQFSDAEGLALPQDGLYYL YCLVGYRGRAPPGGGDPQGRSVTLRSSLYRAGGAYGPGTPELLLE GAETVTPVLDPARRQGYGPLWYTSVGFGGLVQLRRGERVYVNISH PDMVDFARGKTFFGAVMVG (SEQ ID NO: 71) 72 OSM MGVLLTQRTLLSLVLALLFPSMASMAAIGSCSKEYRVLLGQLQKQ TDLMQDTSRLLDPYIRIQGLDVPKLREHCRERPGAFPSEETLRGLG RRGFLQTLNATLGCVLHRLADLEQRLPKAQDLERSGLNIEDLEKLQ MARPNILGLRNNIYCMAQLLDNSDTAEPTKAGRGASQPPTPTPASD AFQRKLEGCRFLHGYHRFMHSVGRVFSKWGESPNRSRRHSPHQAL RKGVRRTRPSRKGKRLMTRGQLPR (SEQ ID NO: 72) 73 CXCL10 MNQTAILICCLIFLTLSGIQGVPLSRTVRCTCISISNQPVNPRSLEKLE IIPASQFCPRVEIIATMKKKGEKRCLNPESKAIKNLLKAVSKERSKR SP (SEQ ID NO: 73) 227 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: 74 SEC63 MAGQQFQYDDSGNTFFYFLTSFVGLIVIPATYYLWPRDQNAEQIRL KNIRKVYGRCMWYRLRLLKPQPNIIPTVKKIVLLAGWALFLFLAY KVSKTDREYQEYNPYEVLNLDPGATVAEIKKQYRLLSLKYHPDKG GDEVMFMRIAKAYAALTDEESRKNWEEFGNPDGPQATSFGIALPA WIVDQKNSILVLLVYGLAFMVILPVVVGSWWYRSIRYSGDQILIRT TQIYTYFVYKTRNMDMKRLIMVLAGASEFDPQYNKDATSRPTDNI LIPQLIREIGSINLKKNEPPLTCPYSLKARVLLLSHLARMKIPETLEE DQQFMLKKCPALLQEMVNVICQLIVMARNREEREFRAPTLASLEN CMKLSQMAVQGLQQFKSPLLQLPHIEEDNLRRVSNHKKYKIKTIQ DLVSLKESDRHTLLHFLEDEKYEEVMAVLGSFPYVTMDIKSQVLD DEDSNNITVGSLVTVLVKLTRQTMAEVFEKEQSICAAEEQPAEDG QGETNKNRTKGGWQQKSKGPKKTAKSKKKKPLKKKPTPVLLPQS KQQKQKQANGVVGNEAAVKEDEEEVSDKGSDSEEEETNRDSQSE KDDGSDRDSDREQDEKQNKDDEAEWQELQQSIQRKERALLETKS KITHPVYSLYFPEEKQEWWWLYIADRKEQTLISMPYHVCTLKDTE EVELKFPAPGKPGNYQYTVFLRSDSYMGLDQIKPLKLEVHEAKPV PENHPQWDTAIEGDEDQEDSEGFEDSFEEEEEEEEDDD (SEQ ID NO: 74) 75 TNFRSF17 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASV TNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNT GSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVD SDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR (SEQ ID NO: 75) 76 TNFRSF13C MRRGPRSLRGRDAPAPTPCVPAECFDLLVRHCVACGLLRTPRPKP AGASSPAPRTALQPQESVGAGAGEAALPLPGLLFGAPALLGLALVL ALVLVGLVSWRRRQRRLRGASSAEAPDGDKDAPEPLDKVIILSPGI SDATAPAWPPPGEDPGTTPPGHSVPVPATELGSTELVTTKTAGPEQ Q (SEQ ID NO: 76) 77 SDC1 MRRAALWLWLCALALSLQPALPQIVATNLPPEDQDGSGDDSDNFS GSGAGALQDITLSQQTPSTWKDTQLLTAIPTSPEPTGLEATAASTST LPAGEGPKEGEAVVLPEVEPGLTAREQEATPRPRETTQLPTTHLAS TTTATTAQEPATSHPHRDMQPGHHETSTPAGPSQADLHTPHTEDG GPSATERAAEDGASSQLPAAEGSGEQDFTFETSGENTAVVAVEPD RRNQSPVDQGATGASQGLLDRKEVLGGVIAGGLVGLIFAVCLVGF MLYRMKKKDEGSYSLEEPKQANGGAYQKPTKQEEFYA (SEQ ID NO: 77) 78 ITGB1 MNLQPIFWIGLISSVCCVFAQTDENRCLKANAKSCGECIQAGPNCG WCTNSTFLQEGMPTSARCDDLEALKKKGCPPDDIENPRGSKDIKK NKNVTNRSKGTAEKLKPEDITQIQPQQLVLRLRSGEPQTFTLKFKR AEDYPIDLYYLMDLSYSMKDDLENVKSLGTDLMNEMRRITSDFRI GFGSFVEKTVMPYISTTPAKLRNPCTSEQNCTSPFSYKNVLSLTNK GEVFNELVGKQRISGNLDSPEGGFDAIMQVAVCGSLIGWRNVTRL LVFSTDAGFHFAGDGKLGGIVLPNDGQCHLENNMYTMSHYYDYP SIAHLVQKLSENNIQTIFAVTEEFQPVYKELKNLIPKSAVGTLSANS SNVIQLIIDAYNSLSSEVILENGKLSEGVTISYKSYCKNGVNGTGEN GRKCSNISIGDEVQFEISITSNKCPKKDSDSFKIRPLGFTEEVEVILQY 228 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: ICECECQSEGIPESPKCHEGNGTFECGACRCNEGRVGRHCECSTDE VNSEDMDAYCRKENSSEICSNNGECVCGQCVCRKRDNTNEIYSGK FCECDNFNCDRSNGLICGGNGVCKCRVCECNPNYTGSACDCSLDT STCEASNGQICNGRGICECGVCKCTDPKFQGQTCEMCQTCLGVCA EHKECVQCRAFNKGEKKDTCTQECSYFNITKVESRDKLPQPVQPD PVSHCKEKDVDDCWFYFTYSVNGNNEVMVHVVENPECPTGPDIIP IVAGVVAGIVLIGLALLLIWKLLMIIHDRREFAKFEKEKMNAKWDT GENPIYKSAVTTVVNPKYEGK (SEQ ID NO: 78) 79 IL17RA MGAARSPPSAVPGPLLGLLLLLLGVLAPGGASLRLLDHRALVCSQP GLNCTVKNSTCLDDSWIHPRNLTPSSPKDLQIQLHFAHTQQGDLFP VAHIEWTLQTDASILYLEGAELSVLQLNTNERLCVRFEFLSKLRHH HRRWRFTFSHFVVDPDQEYEVTVHHLPKPIPDGDPNHQSKNFLVP DCEHARMKVTTPCMSSGSLWDPNITVETLEAHQLRVSFTLWNEST HYQILLTSFPHMENHSCFEHMHHIPAPRPEEFHQRSNVTLTLRNLK GCCRHQVQIQPFFSSCLNDCLRHSATVSCPEMPDTPEPIPDYMPLW VYWFITGISILLVGSVILLIVCMTWRLAGPGSEKYSDDTKYTDGLP AADLIPPPLKPRKVWIIYSADHPLYVDVVLKFAQFLLTACGTEVAL DLLEEQAISEAGVMTWVGRQKQEMVESNSKIIVLCSRGTRAKWQ ALLGRGAPVRLRCDHGKPVGDLFTAAMNMILPDFKRPACFGTYV VCYFSEVSCDGDVPDLFGAAPRYPLMDRFEEVYFRIQDLEMFQPG RMHRVGELSGDNYLRSPGGRQLRAALDRFRDWQVRCPDWFECEN LYSADDQDAPSLDEEVFEEPLLPPGTGIVKRAPLVREPGSQACLAID PLVGEEGGAAVAKLEPHLQPRGQPAPQPLHTLVLAAEEGALVAAV EPGPLADGAAVRLALAGEGEACPLLGSPGAGRNSVLFLPVDPEDSP LGSSTPMASPDLLPEDVREHLEGLMLSLFEQSLSCQAQGGCSRPAM VLTDPHTPYEEEQRQSVQSDQGYISRSSPQPPEGLTEMEEEEEEEQD PGKPALPLSPEDLESLRSLQRQLLFRQLQKNSGWDTMGSESEGPSA (SEQ ID NO: 79) 80 IL10RA MLPCLVVLLAALLSLRLGSDAHGTELPSPPSVWFEAEFFHHILHWT PIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHS NGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGF ILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKV KHENFSLLTSGEVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYF TVTNVIIFFAFVLLLSGALAYCLALQLYVRRRKKLPSVLLFKKPSPF IFISQRPSPETQDTIHPLDEEAFLKVSPELKNLDLHGSTDSGFGSTKP SLQTEEPQFLLPDPHPQADRTLGNREPPVLGDSCSSGSSNSTDSGIC LQEPSLSPSTGPTWEQQVGSNSRGQDDSGIDLVQNSEGRAGDTQG GSALGHHSPPEPEVPGEEDPAAVAFQGYLRQTRCAEEKATKTGCL EEESPLTDGLGPKFGRCLVDEAGLHPPALAKGYLKQDPLEMTLAS SGAPTGQWNQPTEEWSLLALSSCSDLGISDWSFAHDLAPLGCVAA PGGLLGSFNSDLVTLPLISSLQSSE (SEQ ID NO: 80) 81 IFNGR1 MALLFLLPLVMQGVSRAEMGTADLGPSSVPTPTNVTIESYNMNPIV YWEYQIMPQVPVFTVEVKNYGVKNSEWIDACINISHHYCNISDHV GDPSNSLWVRVKARVGQKESAYAKSEEFAVCRDGKIGPPKLDIRK EEKQIMIDIFHPSVFVNGDEQEVDYDPETTCYIRVYNVYVRMNGSE IQYKILTQKEDDCDEIQCQLAIPVSSLNSQYCVSAEGVLHVWGVTT EKSKEVCITIFNSSIKGSLWIPVVAALLLFLVLSLVFICFYIKKINPLK 229 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: EKSIILPKSLISVVRSATLETKPESKYVSLITSYQPFSLEKEVVCEEPL SPATVPGMHTEDNPGKVEHTEELSSITEVVTTEENIPDVVPGSHLTP IERESSSPLSSNQSEPGSIALNSYHSRNCSESDHSRNGFDTDSSCLES HSSLSDSEFPPNNKGEIKTEGQELITVIKAPTSFGYDKPHVLVDLLV DDSGKESLIGYRPTEDSKEFS (SEQ ID NO: 81) 82 IFNGR2 MRPTLLWSLLLLLGVFAAAAAAPPDPLSQLPAPQHPKIRLYNAEQ VLSWEPVALSNSTRPVVYQVQFKYTDSKWFTADIMSIGVNCTQIT ATECDFTAASPSAGFPMDFNVTLRLRAELGALHSAWVTMPWFQH YRNVTVGPPENIEVTPGEGSLIIRFSSPFDIADTSTAFFCYYVHYWE KGGIQQVKGPFRSNSISLDNLKPSRVYCLQVQAQLLWNKSNIFRVG HLSNISCYETMADASTELQQVILISVGTFSLLSVLAGACFFLVLKYR GLIKYWFHTPPSIPLQIEEYLKDPTQPILEALDKDSSPKDDVWDSVSI ISFPEKEQEDVLQTL (SEQ ID NO: 82) 83 IL1R1 MKVLLRLICFIALLISSLEADKCKEREEKIILVSSANEIDVRPCPLNP NEHKGTITWYKDDSKTPVSTEQASRIHQHKEKLWFVPAKVEDSGH YYCVVRNSSYCLRIKISAKFVENEPNLCYNAQAIFKQKLPVAGDGG LVCPYMEFFKNENNELPKLQWYKDCKPLLLDNIHFSGVKDRLIVM NVAEKHRGNYTCHASYTYLGKQYPITRVIEFITLEENKPTRPVIVSP ANETMEVDLGSQIQLICNVTGQLSDIAYWKWNGSVIDEDDPVLGE DYYSVENPANKRRSTLITVLNISEIESRFYKHPFTCFAKNTHGIDAA YIQLIYPVTNFQKHMIGICVTLTVIIVCSVFIYKIFKIDIVLWYRDSCY DFLPIKASDGKTYDAYILYPKTVGEGSTSDCDIFVFKVLPEVLEKQC GYKLFIYGRDDYVGEDIVEVINENVKKSRRLIIILVRETSGFSWLGG SSEEQIAMYNALVQDGIKVVLLELEKIQDYEKMPESIKFIKQKHGAI RWSGDFTQGPQSAKTRFWKNVRYHMPVQRRSPSSKHQLLSPATK EKLQREAHVPLG (SEQ ID NO: 83) 84 IL1RAP MTLLWCVVSLYFYGILQSDASERCDDWGLDTMRQIQVFEDEPARI KCPLFEHFLKFNYSTAHSAGLTLIWYWTRQDRDLEEPINFRLPENRI SKEKDVLWFRPTLLNDTGNYTCMLRNTTYCSKVAFPLEVVQKDS CFNSPMKLPVHKLYIEYGIQRITCPNVDGYFPSSVKPTITWYMGCY KIQNFNNVIPEGMNLSFLIALISNNGNYTCVVTYPENGRTFHLTRTL TVKVVGSPKNAVPPVIHSPNDHVVYEKEPGEELLIPCTVYFSFLMD SRNEVWWTIDGKKPDDITIDVTINESISHSRTEDETRTQILSIKKVTS EDLKRSYVCHARSAKGEVAKAAKVKQKVPAPRYTVELACGFGAT VLLVVILIVVYHVYWLEMVLFYRAHFGTDETILDGKEYDIYVSYA RNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQ KSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYK AVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMP VKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 84) 85 TNFRSF1 MGLSTVPDLLLPLVLLELLVGIYPSGVIGLVPHLGDREKRDSVCPQ GKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTAS ENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYW SENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSC SNCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVIFFGLCLLSLLFI GLMYRYQRWKSKLYSIVCGKSTPEKEGELEGTTTKPLAPNPSFSPT PGFTPTLGFSPVPSSTFTSSSTYTPGDCPNFAAPRREVAPPYQGADPI LATALASDPIPNPLQKWEDSAHKPQSLDTDDPATLYAVVENVPPL 230 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: RWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPRR EATLELLGRVLRDMDLLGCLEDIEEALCGPAALPPAPSLLR (SEQ ID NO: 85) 86 CCR6 MSGESMNFSDVFDSSEDYFVSVNTSYYSVDSEMLLCSLQEVRQFS RLFVPIAYSLICVFGLLGNILVVITFAFYKKARSMTDVYLLNMAIAD ILFVLTLPFWAVSHATGAWVFSNATCKLLKGIYAINFNCGMLLLTC ISMDRYIAIVQATKSFRLRSRTLPRSKIICLVVWGLSVIISSSTFVFNQ KYNTQGSDVCEPKYQTVSEPIRWKLLMLGLELLFGFFIPLMFMIFC YTFIVKTLVQAQNSKRHKAIRVIIAVVLVFLACQIPHNMVLLVTAA NLGKMNRSCQSEKLIGYTKTVTEVLAFLHCCLNPVLYAFIGQKFR NYFLKILKDLWCVRRKYKSSGFSCAGRYSENISRQTSETADNDNAS SFTM (SEQ ID NO: 86) 87 CD80 MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEV ATLSCGHNVSVEELAQTRIYWQKEKKMVLTMMSGDMNIWPEYK NRTIFDITNNLSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVT LSVKADFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAI NTTVSQDPETELYAVSSKLDFNMTTNHSFMCLIKYGHLRVNQTFN WNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTYCFAPRCRERRRN ERLRRESVRPV (SEQ ID NO: 87) 88 CD40LG MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLH RRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGF VKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQ WAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREA SSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFEL QPGASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 88) 89 IL2RG MLKPSLPFTSLLFLQLPLLGVGLNTTILTPNGNEDTTADFFLTTMPT DSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYK NSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREP RRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCL EHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRF NPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEAVVISVGSMGLI ISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAE SLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTL KPET (SEQ ID NO: 89) 90 CD40 MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQ KLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLR VQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIAT GVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKT DVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPK QEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQER Q (SEQ ID NO: 90) 91 IL2RB MAAPALSWRLPLLILLLPLATSWASAAVNGTSQFTCFYNSRANISC VWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLIL GAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAP ISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAP LLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPL AFRTKPAALGKDTIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPW 231 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: LKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAP EISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFF HLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSG EDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQ ERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPR EGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV (SEQ ID NO: 91) 92 IL18R1 MNCRELPLTLWVLISVSTAESCTSRPHITVVEGEPFYLKHCSCSLAH EIETTTKSWYKSSGSQEHVELNPRSSSRIALHDCVLEFWPVELNDT GSYFFQMKNYTQKWKLNVIRRNKHSCFTERQVTSKIVEVKKFFQI TCENSYYQTLVNSTSLYKNCKKLLLENNKNPTIKKNAEFEDQGYY SCVHFLHHNGKLFNITKTFNITIVEDRSNIVPVLLGPKLNHVAVELG KNVRLNCSALLNEEDVIYWMFGEENGSDPNIHEEKEMRIMTPEGK WHASKVLRIENIGESNLNVLYNCTVASTGGTDTKSFILVRKADMA DIPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFYRHLTRRD ETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKL CIFERDVVPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGL HEALVERKIKIILIEFTPVTDFTFLPQSLKLLKSHRVLKWKADKSLS YNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES (SEQ ID NO: 92) 93 IL7R MTILGTTFGMVFSLLQVVSGESGYAQNGDLEDAELDDYSFSCYSQ LEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQEIY FIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYR EGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNL SSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTP EINNSSGEMDPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPD HKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL QDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLA GNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPP FSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ (SEQ ID NO: 93) 94 TNFRSF14 MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKED EYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLS KCLQCQMCDPAMGLRASRNCSRTENAVCGCSPGHFCIVQDGDHC AACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFSPNGTLEECQ HQTKCSWLVTKAGAGTSSSHWVWWFLSGSLVIVIVCSTVGLIICV KRRKPRGDVVKVIVSVQRKRQEAEGEATVIEALQAPPDVTTVAVE ETIPSFTGRSPNH (SEQ ID NO: 94) 95 IL12RB MEPLVTWVVPLLFLFLLSRQGAACRTSECCFQDPPYPDADSGSASG PRDLRCYRISSDRYECSWQYEGPTAGVSHFLRCCLSSGRCCYFAAG SATRLQFSDQAGVSVLYTVTLWVESWARNQTEKSPEVTLQLYNSV KYEPPLGDIKVSKLAGQLRMEWETPDNQVGAEVQFRHRTPSSPWK LGDCGPQDDDTESCLCPLEMNVAQEFQLRRRQLGSQGSSWSKWS SPVCVPPENPPQPQVRFSVEQLGQDGRRRLTLKEQPTQLELPEGCQ GLAPGTEVTYRLQLHMLSCPCKAKATRTLHLGKMPYLSGAAYNV AVISSNQFGPGLNQTWHIPADTHTEPVALNISVGTNGTTMYWPAR AQSMTYCIEWQPVGQDGGLATCSLTAPQDPDPAGMATYSWSRES GAMGQEKCYYITIFASAHPEKLTLWSTVLSTYHFGGNASAAGTPH 232 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: HVSVKNHSLDSVSVDWAPSLLSTCPGVLKEYVVRCRDEDSKQVSE HPVQPTETQVTLSGLRAGVAYTVQVRADTAWLRGVWSQPQRFSIE VQVSDWLIFFASLGSFLSILLVGVLGYLGLNRAARHLCPPLPTPCAS SAIEFPGGKETWQWINPVDFQEEASLQEALVVEMSWDKGERTEPL EKTELPEGAPELALDTELSLEDGDRCKAKM (SEQ ID NO: 95) 96 TNFRSF1B MAPVAVWAALAVGLELWAAAHALPAQVAFTPYAPEPGSTCRLRE YYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDSTYTQLWN WVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEG CRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDIC RPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQ HTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDFALPVGLIVGVTALG LLIIGVVNCVIMTQVKKKPLCLQREAKVPHLPADKARGTQGPEQQ HLLITAPSSSSSSLESSASALDRRAPTRNQPQAPGVEASGAGEARAS TGSSDSSPGGHGTQVNVTCIVNVCSSSDHSSQCSSQASSTMGDTDS SPSESPKDEQVPFSKEECAFRSQLETPETLLGSTEEKPLPLGVPDAG MKPS (SEQ ID NO: 96) 97 IL-11 MNCVCRLVLVVLSLWPDTAVAPGPPPGPPRVSPDPRAELDSTVLL TRSLLADTRQLAAQLRDKFPADGDHNLDSLPTLAMSAGALGALQL PGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDR LLRRLQLLMSRLALPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLH LTLDWAVRGLLLLKTRL (SEQ ID NO: 97) 98 CXCL12 MNAKVVVVLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANV KHLKILNTPNCALQIVARLKNNNRQVCIDPKLKWIQEYLEKALNK RFKM (SEQ ID NO: 98) 99 CXCL16 MGRDLRPGSRVLLLLLLLLLVYLTQPGNGNEGSVTGSCYCGKRISS DSPPSVQFMNRLRKHLRAYHRCLYYTRFQLLSWSVCGGNKDPWV QELMSCLDLKECGHAYSGIVAHQKHLLPTSPPISQASEGASSDIHTP AQMLLSTLQSTQRPTLPVGSLSSDKELTRPNETTIHTAGHSLAAGPE AGENQKQPEKNAGPTARTSATVPVLCLLAIIFILTAALSYVLCKRR RGQSPQSSPDLPVHYIPVAPDSNT (SEQ ID NO: 99) 100 ICAM1 MAPSSPRPALPALLVLLGALFPGPGNAQTSVSPSKVILPRGGSVLVT CSTSCDQPKLLGIETPLPKKELLLPGNNRKVYELSNVQEDSQPMCY SNCPDGQSTAKTFLTVYWTPERVELAPLPSWQPVGKNLTLRCQVE GGAPRANLTVVLLRGEKELKREPAVGEPAEVTTTVLVRRDHHGA NFSCRTELDLRPQGLELFENTSAPYQLQTFVLPATPPQLVSPRVLEV DTQGTVVCSLDGLFPVSEAQVHLALGDQRLNPTVTYGNDSFSAKA SVSVTAEDEGTQRLTCAVILGNQSQETLQTVTIYSFPAPNVILTKPE VSEGTEVTVKCEAHPRAKVTLNGVPAQPLGPRAQLLLKATPEDNG RSFSCSATLEVAGQLIHKNQTRELRVLYGPRLDERDCPGNWTWPE NSQQTPMCQAWGNPLPELKCLKDGTFPLPIGESVTVTRDLEGTYL CRARSTQGEVTRKVTVNVLSPRYEIVIITVVAAAVIMGTAGLSTYL YNRQRKIKKYRLQQAQKGTPMKPNTQATPP (SEQ ID NO: 100) 101 PECAM1 MQPRWAQGATMWLGVLLTLLLCSSLEGQENSFTINSVDMKSLPD WTVQNGKNLTLQCFADVSTTSHVKPQHQMLFYKDDVLFYNISSM KSTESYFIPEVRIYDSGTYKCTVIVNNKEKTTAEYQVLVEGVPSPRV TLDKKEAIQGGIVRVNCSVPEEKAPIHFTIEKLELNEKMVKLKREK NSRDQNFVILEFPVEEQDRVLSFRCQARIISGIHMQTSESTKSELVT 233 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VTESFSTPKFHISPTGMIMEGAQLHIKCTIQVTHLAQEFPEIIIQKDK AIVAHNRHGNKAVYSVMAMVEHSGNYTCKVESSRISKVSSIVVNI TELFSKPELESSFTHLDQGERLNLSCSIPGAPPANFTIQKEDTIVSQT QDFTKIASKSDSGTYICTAGIDKVVKKSNTVQIVVCEMLSQPRISYD AQFEVIKGQTIEVRCESISGTLPISYQLLKTSKVLENSTKNSNDPAVF KDNPTEDVEYQCVADNCHSHAKMLSEVLRVKVIAPVDEVQISILSS KVVESGEDIVLQCAVNEGSGPITYKFYREKEGKPFYQMTSNATQA FWTKQKASKEQEGEYYCTAFNRANHASSVPRSKILTVRVILAPWK KGLIAVVIIGVIIALLIIAAKCYFLRKAKAKQMPVEMSRPAVPLLNS NNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQY TEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSL DGT (SEQ ID NO: 101) 102 CXCR4 MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSII FLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPF WAVDAVANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAI VHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEADDRY ICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGH QKRKALKTTVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVH KWISITEALAFFHCCLNPILYAFLGAKFKTSAQHALTSVSRGSSLKI LSKGKRGGHSSVSTESESSSFHSS (SEQ ID NO: 102) 103 CD44 MDKFWWHAAWGLCLVPLSLAQIDLNITCRFAGVFHVEKNGRYSIS RTEAADLCKAFNSTLPTMAQMEKALSIGFETCRYGFIEGHVVIPRIH PNSICAANNTGVYILTSNTSQYDTYCFNASAPPEEDCTSVTDLPNAF DGPITITIVNRDGTRYVQKGEYRTNPEDIYPSNPTDDDVSSGSSSER SSTSGGYIFYTFSTVHPIPDEDSPWITDSTDRIPATTLMSTSATATET ATKRQETWDWFSWLFLPSESKNHLHTTTQMAGTSSNTISAGWEPN EENEDERDRHLSFSGSGIDDDEDFISSTISTTPRAFDHTKQNQDWTQ WNPSHSNPEVLLQTTTRMTDVDRNGTTAYEGNWNPEAHPPLIHHE HHEEEETPHSTSTIQATPSSTTEETATQKEQWFGNRWHEGYRQTPK EDSHSTTGTAAASAHTSHPMQGRTTPSPEDSSWTDFFNPISHPMGR GHQAGRRMDMDSSHSITLQPTANPNTGLVEDLDRTGPLSMTTQQS NSQSFSTSHEGLEEDKDHPTTSTLTSSNRNDVTGGRRDPNHSEGST TLLEGYTSHYPHTKESRTFIPVTSAKTGSFGVTAVTVGDSNSNVNR SLSGDQDTFHPSGGSHTTHGSESDGHSHGSQEGGANTTSGPIRTPQI PEWLIILASLLALALILAVCIAVNSRRRCGQKKKLVINSGNGAVED RKPSGLNGEASKSQEMVHLVNKESSETPDQFMTADETRNLQNVD MKIGV (SEQ ID NO: 103) 104 PTPRC MTMYLWLKLLAFGFAFLDTEVFVTGQSPTPSPTGLTTAKMPSVPL SSDPLPTHTTAFSPASTFERENDFSETTTSLSPDNTSTQVSPDSLDNA SAFNTTGVSSVQTPHLPTHADSQTPSAGTDTQTFSGSAANAKLNPT PGSNAISDVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNT TITANTSDAYLNASETTTLSPSGSAVISTTTIATTPSKPTCDEKYANI TVDYLYNKETKLFTAKLNVNENVECGNNTCTNNEVHNLTECKNA SVSISHNSCTAPDKTLILDVPPGVEKFQLHDCTQVEKADTTICLKW KNIETFTCDTQNITYRFQCGNMIFDNKEIKLENLEPEHEYKCDSEIL YNNHKFTNASKIIKTDFGSPGEPQIIFCRSEAAHQGVITWNPPQRSF HNFTLCYIKETEKDCLNLDKNLIKYDLQNLKPYTKYVLSLHAYIIA 234 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: KVQRNGSAAMCHFTTKSAPPSQVWNMTVSMTSDNSMHVKCRPP RDRNGPHERYHLEVEAGNTLVRNESHKNCDFRVKDLQYSTDYTF KAYFHNGDYPGEPFILHHSTSYNSKALIAFLAFLIIVTSIALLVVLYK IYDLHKKRSCNLDEQQELVERDDEKQLMNVEPIHADILLETYKRKI ADEGRLFLAEFQSIPRVFSKFPIKEARKPFNQNKNRYVDILPYDYNR VELSEINGDAGSNYINASYIDGFKEPRKYIAAQGPRDETVDDFWRM IWEQKATVIVMVTRCEEGNRNKCAEYWPSMEEGTRAFGDVVVKI NQHKRCPDYIIQKLNIVNKKEKATGREVTHIQFTSWPDHGVPEDPH LLLKLRRRVNAFSNFFSGPIVVHCSAGVGRTGTYIGIDAMLEGLEA ENKVDVYGYVVKLRRQRCLMVQVEAQYILIHQALVEYNQFGETE VNLSELHPYLHNMKKRDPPSEPSPLEAEFQRLPSYRSWRTQHIGNQ EENKSKNRNSNVIPYDYNRVPLKHELEMSKESEHDSDESSDDDSDS EEPSKYINASFIMSYWKPEVMIAAQGPLKETIGDFWQMIFQRKVKV IVMLTELKHGDQEICAQYWGEGKQTYGDIEVDLKDTDKSSTYTLR VFELRHSKRKDSRTVYQYQYTNWSVEQLPAEPKELISMIQVVKQK LPQKNSSEGNKHHKSTPLLIHCRDGSQQTGIFCALLNLLESAETEEV VDIFQVVKALRKARPGMVSTFEQYQFLYDVIASTYPAQNGQVKKN NHQEDKIEFDNEVDKVKQDANCVNPLGAPEKLPEAKEQAEGSEPT SGTEGPEHSVNGPASPALNQGS (SEQ ID NO: 104) 105 ITGAE MWLFHTLLCIASLALLAAFNVDVARPWLTPKGGAPFVLSSLLHQD PSTNQTWLLVTSPRTKRTPGPLHRCSLVQDEILCHPVEHVPIPKGRH RGVTVVRSHHGVLICIQVLVRRPHSLSSELTGTCSLLGPDLRPQAQ ANFFDLENLLDPDARVDTGDCYSNKEGGGEDDVNTARQRRALEK EEEEDKEEEEDEEEEEAGTEIAIILDGSGSIDPPDFQRAKDFISNMMR NFYEKCFECNFALVQYGGVIQTEFDLRDSQDVMASLARVQNITQV GSVTKTASAMQHVLDSIFTSSHGSRRKASKVMVVLTDGGIFEDPL NLTTVINSPKMQGVERFAIGVGEEFKSARTARELNLIASDPDETHA FKVTNYMALDGLLSKLRYNIISMEGTVGDALHYQLAQIGFSAQILD ERQVLLGAVGAFDWSGGALLYDTRSRRGRFLNQTAAAAADAEAA QYSYLGYAVAVLHKTCSLSYIAGAPRYKHHGAVFELQKEGREASF LPVLEGEQMGSYFGSELCPVDIDMDGSTDFLLVAAPFYHVHGEEG RVYVYRLSEQDGSFSLARILSGHPGFTNARFGFAMAAMGDLSQDK LTDVAIGAPLEGFGADDGASFGSVYIYNGHWDGLSASPSQRIRAST VAPGLQYFGMSMAGGFDISGDGLADITVGTLGQAVVFRSRPVVRL KVSMAFTPSALPIGFNGVVNVRLCFEISSVTTASESGLREALLNFTL DVDVGKQRRRLQCSDVRSCLGCLREWSSGSQLCEDLLLMPTEGEL CEEDCFSNASVKVSYQLQTPEGQTDHPQPILDRYTEPFAIFQLPYEK ACKNKLFCVAELQLATTVSQQELVVGLTKELTLNINLTNSGEDSY MTSMALNYPRNLQLKRMQKPPSPNIQCDDPQPVASVLIMNCRIGH PVLKRSSAHVSVVWQLEENAFPNRTADITVTVTNSNERRSLANET HTLQFRHGFVAVLSKPSIMYVNTGQGLSHHKEFLFHVHGENLFGA EYQLQICVPTKLRGLQVVAVKKLTRTQASTVCTWSQERACAYSSV QHVEEWHSVSCVIASDKENVTVAAEISWDHSEELLKDVTELQILGE ISFNKSLYEGLNAENHRTKITVVFLKDEKYHSLPIIIKGSVGGLLVLI VILVILFKCGFFKRKYQQLNLESIRKAQLKSENLLEEEN (SEQ ID NO: 105) 106 ITGA5 MGSRTPESPLHAVQLRWGPRRRPPLLPLLLLLLPPPPRVGGFNLDA 235 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: EAPAVLSGPPGSFFGFSVEFYRPGTDGVSVLVGAPKANTSQPGVLQ GGAVYLCPWGASPTQCTPIEFDSKGSRLLESSLSSSEGEEPVEYKSL QWFGATVRAHGSSILACAPLYSWRTEKEPLSDPVGTCYLSTDNFT RILEYAPCRSDFSWAAGQGYCQGGFSAEFTKTGRVVLGGPGSYFW QGQILSATQEQIAESYYPEYLINLVQGQLQTRQASSIYDDSYLGYSV AVGEFSGDDTEDFVAGVPKGNLTYGYVTILNGSDIRSLYNFSGEQ MASYFGYAVAATDVNGDGLDDLLVGAPLLMDRTPDGRPQEVGR VYVYLQHPAGIEPTPTLTLTGHDEFGRFGSSLTPLGDLDQDGYNDV AIGAPFGGETQQGVVFVFPGGPGGLGSKPSQVLQPLWAASHTPDFF GSALRGGRDLDGNGYPDLIVGSFGVDKAVVYRGRPIVSASASLTIF PAMFNPEERSCSLEGNPVACINLSFCLNASGKHVADSIGFTVELQL DWQKQKGGVRRALFLASRQATLTQTLLIQNGAREDCREMKIYLR NESEFRDKLSPIHIALNFSLDPQAPVDSHGLRPALHYQSKSRIEDKA QILLDCGEDNICVPDLQLEVFGEQNHVYLGDKNALNLTFHAQNVG EGGAYEAELRVTAPPEAEYSGLVRHPGNFSSLSCDYFAVNQSRLL VCDLGNPMKAGASLWGGLRFTVPHLRDTKKTIQFDFQILSKNLNN SQSDVVSFRLSVEAQAQVTLNGVSKPEAVLFPVSDWHPRDQPQKE EDLGPAVHHVYELINQGPSSISQGVLELSCPQALEGQQLLYVTRVT GLNCTTNHPINPKGLELDPEGSLHHQQKREAPSRSSASSGPQILKCP EAECFRLRCELGPLHQQESQSLQLHFRVWAKTFLQREHQPFSLQCE AVYKALKMPYRILPRQLPQKERQVATAVQWTKAEGSYGVPLWIII LAILFGLLLLGLLIYILYKLGFFKRSLPYGTAMEKAQLKPPATSDA (SEQ ID NO: 106) 107 HAVCR2 MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPG NLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFR KGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTP APTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANEL RDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHS KEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPN EYYCYVSSRQQPSQPLGCRFAMP (SEQ ID NO: 107) 108 CD36 MGCDRNCGLIAGAVIGAVLAVFGGILMPVGDLLIQKTIKKQVVLEE GTIAFKNWVKTGTEVYRQFWIFDVQNPQEVMMNSSNIQVKQRGP YTYRVRFLAKENVTQDAEDNTVSFLQPNGAIFEPSLSVGTEADNFT VLNLAVAAASHIYQNQFVQMILNSLINKSKSSMFQVRTLRELLWG YRDPFLSLVPYPVTTTVGLFYPYNNTADGVYKVFNGKDNISKVAII DTYKGKRNLSYWESHCDMINGTDAASFPPFVEKSQVLQFFSSDICR SIYAVFESDVNLKGIPVYRFVLPSKAFASPVENPDNYCFCTEKIISK NCTSYGVLDISKCKEGRPVYISLPHFLYASPDVSEPIDGLNPNEEEH RTYLDIEPITGFTLQFAKRLQVNLLVKPSEKIQVLKNLKRNYIVPIL WLNETGTIGDEKANMFRSQVTGKINLLGLIEMILLSVGVVMFVAF MISYCACRSKTIK (SEQ ID NO: 108) 109 PILRA MGRPLLLPLLPLLLPPAFLQPSGSTGSGPSYLYGVTQPKHLSASMG GSVEIPFSFYYPWELATAPDVRISWRRGHFHRQSFYSTRPPSIHKDY VNRLFLNWTEGQKSGFLRISNLQKQDQSVYFCRVELDTRSSGRQQ WQSIEGTKLSITQAVTTTTQRPSSMTTTWRLSSTTTTTGLRVTQGK RRSDSWHISLETAVGVAVAVTVLGIMILGLICLLRWRRRKGQQRT KATTPAREPFQNTEEPYENIRNEGQNTDPKLNPKDDGIVYASLALS 236 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: SSTSPRAPPSHRPLKSPQNETLYSVLKA (SEQ ID NO: 109) 110 LILRB1 MTPILTVLICLGLSLGPRTHVQAGHLPKPTLWAEPGSVITQGSPVTL RCQGGQETQEYRLYREKKTALWITRIPQELVKKGQFPIPSITWEHA GRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGG NVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVG PVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSV QPGPIVAPEETLTLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQA GLSQANFTLGPVSRSYGGQYRCYGAHNLSSEWSAPSDPLDILIAGQ FYDRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDP WRLRSTYQSQKYQAEFPMGPVTSAHAGTYRCYGSQSSKPYLLTHP SDPLELVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRH LGVVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPA GAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDT RSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEE DRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVP SIYATLAIH (SEQ ID NO: 110) 111 NECTIN2 MARAAALLPSRSPPTPLLWPLLLLLLLETGAQDVRVQVLPEVRGQ LGGTVELPCHLLPPVPGLYISLVTWQRPDAPANHQNVAAFHPKMG PSFPSPKPGSERLSFVSAKQSTGQDTEAELQDATLALHGLTVEDEG NYTCEFATFPKGSVRGMTWLRVIAKPKNQAEAQKVTFSQDPTTVA LCISKEGRPPARISWLSSLDWEAKETQVSGTLAGTVTVTSRFTLVPS GRADGVTVTCKVEHESFEEPALIPVTLSVRYPPEVSISGYDDNWYL GRTDATLSCDVRSNPEPTGYDWSTTSGTFPTSAVAQGSQLVIHAV DSLFNTTFVCTVTNAVGMGRAEQVIFVRETPNTAGAGATGGIIGGII AAIIATAVAATGILICRQQRKEQTLQGAEEDEDLEGPPSYKPPTPKA KLEAQEMPSQLFTLGASEHSPLKTPYFDAGASCTEQEMPRYHELPT LEERSGPLHPGATSLGSPIPVPPGPPAVEDVSLDLEDEEGEEEEEYL DKINPIYDALSYSSPSDSYQGKGFVMSRAMYV (SEQ ID NO: 111) 112 PLXNB2 MALQLWALTLLGLLGAGASLRPRKLDFFRSEKELNHLAVDEASGV VYLGAVNALYQLDAKLQLEQQVATGPALDNKKCTPPIEASQCHE AEMTDNVNQLLLLDPPRKRLVECGSLFKGICALRALSNISLRLFYE DGSGEKSFVASNDEGVATVGLVSSTGPGGDRVLFVGKGNGPHDN GIIVSTRLLDRTDSREAFEAYTDHATYKAGYLSTNTQQFVAAFEDG PYVFFVFNQQDKHPARNRTLLARMCREDPNYYSYLEMDLQCRDP DIHAAAFGTCLAASVAAPGSGRVLYAVFSRDSRSSGGPGAGLCLFP LDKVHAKMEANRNACYTGTREARDIFYKPFHGDIQCGGHAPGSSK SFPCGSEHLPYPLGSRDGLRGTAVLQRGGLNLTAVTVAAENNHTV AFLGTSDGRILKVYLTPDGTSSEYDSILVEINKRVKRDLVLSGDLGS LYAMTQDKVFRLPVQECLSYPTCTQCRDSQDPYCGWCVVEGRCT RKAECPRAEEASHWLWSRSKSCVAVTSAQPQNMSRRAQGEVQLT VSPLPALSEEDELLCLFGESPPHPARVEGEAVICNSPSSIPVTPPGQD HVAVTIQLLLRRGNIFLTSYQYPFYDCRQAMSLEENLPCISCVSNR WTCQWDLRYHECREASPNPEDGIVRAHMEDSCPQFLGPSPLVIPM NHETDVNFQGKNLDTVKGSSLHVGSDLLKFMEPVTMQESGTFAFR TPKLSHDANETLPLHLYVKSYGKNIDSKLHVTLYNCSFGRSDCSLC RAANPDYRCAWCGGQSRCVYEALCNTTSECPPPVITRIQPETGPLG GGIRITILGSNLGVQAGDIQRISVAGRNCSFQPERYSVSTRIVCVIEA 237 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: AETPFTGGVEVDVFGKLGRSPPNVQFTFQQPKPLSVEPQQGPQAG GTTLTIHGTHLDTGSQEDVRVTLNGVPCKVTKFGAQLQCVTGPQA TRGQMLLEVSYGGSPVPNPGIFFTYRENPVLRAFEPLRSFASGGRSI NVTGQGFSLIQRFAMVVIAEPLQSWQPPREAESLQPMTVVGTDYV FHNDTKVVFLSPAVPEEPEAYNLTVLIEMDGHRALLRTEAGAFEY VPDPTFENFTGGVKKQVNKLIHARGTNLNKAMTLQEAEAFVGAE RCTMKTLTETDLYCEPPEVQPPPKRRQKRDTTHNLPEFIVKFGSRE WVLGRVEYDTRVSDVPLSLILPLVIVPMVVVIAVSVYCYWRKSQQ AEREYEKIKSQLEGLEESVRDRCKKEFTDLMIEMEDQTNDVHEAGI PVLDYKTYTDRVFFLPSKDGDKDVMITGKLDIPEPRRPVVEQALY QFSNLLNSKSFLINFIHTLENQREFSARAKVYFASLLTVALHGKLEY YTDIMHTLFLELLEQYVVAKNPKLMLRRSETVVERMLSNWMSICL YQYLKDSAGEPLYKLFKAIKHQVEKGPVDAVQKKAKYTLNDTGL LGDDVEYAPLTVSVIVQDEGVDAIPVKVLNCDTISQVKEKIIDQVY RGQPCSCWPRPDSVVLEWRPGSTAQILSDLDLTSQREGRWKRVNT LMHYNVRDGATLILSKVGVSQQPEDSQQDLPGERHALLEEENRV WHLVRPTDEVDEGKSKRGSVKEKERTKAITEIYLTRLLSVKGTLQQ FVDNFFQSVLAPGHAVPPAVKYFFDFLDEQAEKHNIQDEDTIHIWK TNSLPLRFWVNILKNPHFIFDVHVHEVVDASLSVIAQTFMDACTRT EHKLSRDSPSNKLLYAKEISTYKKMVEDYYKGIRQMVQVSDQDM NTHLAEISRAHTDSLNTLVALHQLYQYTQKYYDEIINALEEDPAAQ KMQLAFRLQQIAAALENKVTDL (SEQ ID NO: 112) 113 TLR4 MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELNF YKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTI EDGAYQSLSHLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLAS LENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNKI QSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLR NNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEG LCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDFS YNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDL PSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFL GLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGI FNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSP TAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTS KKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEV ERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAV LVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVK NLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIVVVSQHFI QSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLRQQVELYRLL SRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNW QEATSI (SEQ ID NO: 113) 114 ITGA4 MAWEARREPGPRRAAVRETVMLLLCLGVPTGRPYNVDTESALLY QGPHNTLFGYSVVLHSHGANRWLLVGAPTANWLANASVINPGAI YRCRIGKNPGQTCEQLQLGSPNGEPCGKTCLEERDNQWLGVTLSR QPGENGSIVTCGHRWKNIFYIKNENKLPTGGCYGVPPDLRTELSKR IAPCYQDYVKKFGENFASCQAGISSFYTKDLIVMGAPGSSYWTGSL FVYNITTNKYKAFLDKQNQVKFGSYLGYSVGAGHFRSQHTTEVV 238 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GGAPQHEQIGKAYIFSIDEKELNILHEMKGKKLGSYFGASVCAVDL NADGFSDLLVGAPMQSTIREEGRVFVYINSGSGAVMNAMETNLVG SDKYAARFGESIVNLGDIDNDGFEDVAIGAPQEDDLQGAIYIYNGR ADGISSTFSQRIEGLQISKSLSMFGQSISGQIDADNNGYVDVAVGAF RSDSAVLLRTRPVVIVDASLSHPESVNRTKFDCVENGWPSVCIDLT LCFSYKGKEVPGYIVLFYNMSLDVNRKAESPPRFYFSSNGTSDVIT GSIQVSSREANCRTHQAFMRKDVRDILTPIQIEAAYHLGPHVISKRS TEEFPPLQPILQQKKEKDIMKKTINFARFCAHENCSADLQVSAKIGF LKPHENKTYLAVGSMKTLMLNVSLFNAGDDAYETTLHVKLPVGL YFIKILELEEKQINCEVTDNSGVVQLDCSIGYIYVDHLSRIDISFLLD VSSLSRAEEDLSITVHATCENEEEMDNLKHSRVTVAIPLKYEVKLT VHGFVNPTSFVYGSNDENEPETCMVEKMNLTFHVINTGNSMAPNV SVEIMVPNSFSPQTDKLFNILDVQTTTGECHFENYQRVCALEQQKS AMQTLKGIVRFLSKTDKRLLYCIKADPHCLNFLCNFGKMESGKEA SVHIQLEGRPSILEMDETSALKFEIRATGFPEPNPRVIELNKDENVA HVLLEGLHHQRPKRYFTIVIISSSLLLGLIVLLLISYVMWKAGFFKR QYKSILQEENRRDSWSYINSKSNDD (SEQ ID NO: 114) 115 CD47 MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTN MEAQNTTEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQ LLKGDASLKMDKSDAVSHTGNYTCEVTELTREGETIIELKYRVVS WFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALLVAG LVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAI GLTSFVIAILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALA QLLGLVYMKFVASNQKTIQPPRKAVEEPLNAFKESKGMMNDE (SEQ ID NO: 115) 116 NOTCH2 MPALRPALLWALLALWLCCAAPAHALQCRDGYEPCVNEGMCVT YHNGTGYCKCPEGFLGEYCQHRDPCEKNRCQNGGTCVAQAMLG KATCRCASGFTGEDCQYSTSHPCFVSRPCLNGGTCHMLSRDTYEC TCQVGFTGKECQWTDACLSHPCANGSTCTTVANQFSCKCLTGFTG QKCETDVNECDIPGHCQHGGTCLNLPGSYQCQCPQGFTGQYCDSL YVPCAPSPCVNGGTCRQTGDFTFECNCLPGFEGSTCERNIDDCPNH RCQNGGVCVDGVNTYNCRCPPQWTGQFCTEDVDECLLQPNACQN GGTCANRNGGYGCVCVNGWSGDDCSENIDDCAFASCTPGSTCIDR VASFSCMCPEGKAGLLCHLDDACISNPCHKGALCDTNPLNGQYIC TCPQGYKGADCTEDVDECAMANSNPCEHAGKCVNTDGAFHCECL KGYAGPRCEMDINECHSDPCQNDATCLDKIGGFTCLCMPGFKGVH CELEINECQSNPCVNNGQCVDKVNRFQCLCPPGFTGPVCQIDIDDC SSTPCLNGAKCIDHPNGYECQCATGFTGVLCEENIDNCDPDPCHHG QCQDGIDSYTCICNPGYMGAICSDQIDECYSSPCLNDGRCIDLVNG YQCNCQPGTSGVNCEINFDDCASNPCIHGICMDGINRYSCVCSPGF TGQRCNIDIDECASNPCRKGATCINGVNGFRCICPEGPHHPSCYSQV NECLSNPCIHGNCTGGLSGYKCLCDAGWVGINCEVDKNECLSNPC QNGGTCDNLVNGYRCTCKKGFKGYNCQVNIDECASNPCLNQGTC FDDISGYTCHCVLPYTGKNCQTVLAPCSPNPCENAAVCKESPNFES YTCLCAPGWQGQRCTIDIDECISKPCMNHGLCHNTQGSYMCECPP GFSGMDCEEDIDDCLANPCQNGGSCMDGVNTFSCLCLPGFTGDKC QTDMNECLSEPCKNGGTCSDYVNSYTCKCQAGFDGVHCENNINE 239 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: CTESSCFNGGTCVDGINSFSCLCPVGFTGSFCLHEINECSSHPCLNE GTCVDGLGTYRCSCPLGYTGKNCQTLVNLCSRSPCKNKGTCVQK KAESQCLCPSGWAGAYCDVPNVSCDIAASRRGVLVEHLCQHSGV CINAGNTHYCQCPLGYTGSYCEEQLDECASNPCQHGATCSDFIGG YRCECVPGYQGVNCEYEVDECQNQPCQNGGTCIDLVNHFKCSCPP GTRGLLCEENIDDCARGPHCLNGGQCMDRIGGYSCRCLPGFAGER CEGDINECLSNPCSSEGSLDCIQLTNDYLCVCRSAFTGRHCETFVD VCPQMPCLNGGTCAVASNMPDGFICRCPPGFSGARCQSSCGQVKC RKGEQCVHTASGPRCFCPSPRDCESGCASSPCQHGGSCHPQRQPPY YSCQCAPPFSGSRCELYTAPPSTPPATCLSQYCADKARDGVCDEAC NSHACQWDGGDCSLTMENPWANCSSPLPCWDYINNQCDELCNTV ECLFDNFECQGNSKTCKYDKYCADHFKDNHCDQGCNSEECGWD GLDCAADQPENLAEGTLVIVVLMPPEQLLQDARSFLRALGTLLHT NLRIKRDSQGELMVYPYYGEKSAAMKKQRMTRRSLPGEQEQEVA GSKVFLEIDNRQCVQDSDHCFKNTDAAAALLASHAIQGTLSYPLVS VVSESLTPERTQLLYLLAVAVVIILFIILLGVIMAKRKRKHGSLWLP EGFTLRRDASNHKRREPVGQDAVGLKNLSVQVSEANLIGTGTSEH WVDDEGPQPKKVKAEDEALLSEEDDPIDRRPWTQQHLEAADIRRT PSLALTPPQAEQEVDVLDVNVRGPDGCTPLMLASLRGGSSDLSDE DEDAEDSSANIITDLVYQGASLQAQTDRTGEMALHLAARYSRADA AKRLLDAGADANAQDNMGRCPLHAAVAADAQGVFQILIRNRVTD LDARMNDGTTPLILAARLAVEGMVAELINCQADVNAVDDHGKSA LHWAAAVNNVEATLLLLKNGANRDMQDNKEETPLFLAAREGSYE AAKILLDHFANRDITDHMDRLPRDVARDRMHHDIVRLLDEYNVTP SPPGTVLTSALSPVICGPNRSFLSLKHTPMGKKSRRPSAKSTMPTSL PNLAKEAKDAKGSRRKKSLSEKVQLSESSVTLSPVDSLESPHTYVS DTTSSPMITSPGILQASPNPMLATAAPPAPVHAQHALSFSNLHEMQ PLAHGASTVLPSVSQLLSHHHIVSPGSGSAGSLSRLHPVPVPADWM NRMEVNETQYNEMFGMVLAPAEGTHPGIAPQSRPPEGKHITTPREP LPPIVTFQLIPKGSIAQPAGAPQPQSTCPPAVAGPLPTMYQIPEMAR LPSVAFPTAMMPQQDGQVAQTILPAYHPFPASVGKYPTPPSQHSY ASSNAAERTPSHSGHLQGEHPYLTPSPESPDQWSSSSPHSASDWSD VTTSPTPGGAGGGQRGPGTHMSEPPHNNMQVYA (SEQ ID NO: 116) 117 TGFBR2 MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAV KFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRK NDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMC SCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIF YCYRVNRQQKLSSTWETGKTRKLMEFSEHCAIILEDDRSDISSTCA NNINHNTELLPIELDTLVGKGRFAEVYKAKLKQNTSEQFETVAVKI FPYEEYASWKTEKDIFSDINLKHENILQFLTAEERKTELGKQYWLIT AFHAKGNLQEYLTRHVISWEDLRKLGSSLARGIAHLHSDHTPCGR PKMPIVHRDLKSSNILVKNDLTCCLCDFGLSLRLDPTLSVDDLANS GQVGTARYMAPEVLESRMNLENVESFKQTDVYSMALVLWEMTS RCNAVGEVKDYEPPFGSKVREHPCVESMKDNVLRDRGRPEIPSFW LNHQGIQMVCETLTECWDHDPEARLTAQCVAERFSELEHLDRLSG RSCSEEKIPEDGSLNTTK (SEQ ID NO: 117) 240 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: 118 NRP2 MDMFPLTWVFLALYFSRHQVRGQPDPPCGGRLNSKDAGYITSPGY PQDYPSHQNCEWIVYAPEPNQKIVLNFNPHFEIEKHDCKYDFIEIRD GDSESADLLGKHCGNIAPPTIISSGSMLYIKFTSDYARQGAGFSLRY EIFKTGSEDCSKNFTSPNGTIESPGFPEKYPHNLDCTFTILAKPKMEII LQFLIFDLEHDPLQVGEGDCKYDWLDIWDGIPHVGPLIGKYCGTKT PSELRSSTGILSLTFHTDMAVAKDGFSARYYLVHQEPLENFQCNVP LGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSN KEYLQVDLRFLTMLTAIATQGAISRETQNGYYVKSYKLEVSTNGE DWMVYRHGKNHKVFQANNDATEVVLNKLHAPLLTRFVRIRPQT WHSGIALRLELFGCRVTDAPCSNMLGMLSGLIADSQISASSTQEYL WSPSAARLVSSRSGWFPRIPQAQPGEEWLQVDLGTPKTVKGVIIQG ARGGDSITAVEARAFVRKFKVSYSLNGKDWEYIQDPRTQQPKLFE GNMHYDTPDIRRFDPIPAQYVRVYPERWSPAGIGMRLEVLGCDWT DSKPTVETLGPTVKSEETTTPYPTEEEATECGENCSFEDDKDLQLPS GFNCNFDFLEEPCGWMYDHAKWLRTTWASSSSPNDRTFPDDRNF LRLQSDSQREGQYARLISPPVHLPRSPVCMEFQYQATGGRGVALQ VVREASQESKLLWVIREDQGGEWKHGRIILPSYDMEYQIVFEGVIG KGRSGEIAIDDIRISTDVPLENCMEPISAFAGENFKVDIPEIHEREGY EDEIDDEYEVDWSNSSSATSGSGAPSTDKEKSWLYTLDPILITIIAM SSLGVLLGATCAGLLLYCTCSYSGLSSRSCTTLENYNFELYDGLKH KVKMNHQKCCSEA (SEQ ID NO: 118) 119 CD99 MARGAALALLLFGLLGVLVAAPDGGFDLSDALPDNENKKPTAIPK KPSAGDDFDLGDAVVDGENDDPRPPNPPKPMPNPNPNHPSSSGSFS DADLADGVSGGEGKGGSDGGGSHRKEGEEADAPGVIPGIVGAVV VAVAGAISSFIAYQKKKLCFKENAEQGEVDMESHRNANAEPAVQR TLLEK (SEQ ID NO: 119) 120 TIGIT MRWCLLLIWAQGLRQAPLASGMMTGTIETTGNISAEKGGSIILQCH LSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGL GLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGAR FQIPLLGAMAATLVVICTAVIVVVALTRKKKALRIHSVEGDLRRKS AGQEEWSPSAPSPPGSCVQAEAAPAGLCGEQRGEDCAELHDYFNV LSYRSLGNCSFFTETG (SEQ ID NO: 120) 121 IL6ST MLTLQTWLVQALFIFLTTESTGELLDPCGYISPESPVVQLHSNFTAV CVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTD IASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKK MRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVD YSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVI NSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTAS TRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYED RPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEANGKILDYEVTL TRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVL TIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWC VLSDKAPCITDWQQEDGTVHRTYLRGNLAESKCYLITVTPVYADG PGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQN GFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAY TDEGGKDGPEFTFTTPKFAQGEIEAIVVPVCLAFLLTTLLGVLFCFN KRDLIKKHIWPNVPDPSKSHIAQWSPHTPPRHNFNSKDQMYSDGN 241 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: FTDVSVVEIEANDKKPFPEDLKSLDLFKKEKINTEGHSSGIGGSSCM SSSRPSISSSDENESSQNTSSTVQYSTVVHSGYRHQVPSVQVFSRSE STQPLLDSEERPEDLQLVDHVDGGDGILPRQQYFKQNCSQHESSPD ISHFERSKQVSSVNEEDFVRLKQQISDHISQSCGSGQMKMFQEVSA ADAFGPGTEGQVERFETVGMEAATDEGMPKSYLPQTVRQGGYMP Q (SEQ ID NO: 121) 122 TGFB2 MHYCVLSAFLILHLVTVALSLSTCSTLDMDQFMRKRIEAIRGQILS KLKLTSPPEDYPEPEEVPPEVISIYNSTRDLLQEKASRRAAACERER SDEEYYAKEVYKIDMPPFFPSENAIPPTFYRPYFRIVRFDVSAMEKN ASNLVKAEFRVFRLQNPKARVPEQRIELYQILKSKDLTSPTQRYIDS KVVKTRAEGEWLSFDVTDAVHEWLHHKDRNLGFKISLHCPCCTF VPSNNYIIPNKSEELEARFAGIDGTSTYTSGDQKTIKSTRKKNSGKT PHLLLMLLPSYRLESQQTNRRKKRALDAAYCFRNVQDNCCLRPLY IDFKRDLGWKWIHEPKGYNANFCAGACPYLWSSDTQHSRVLSLY NTINPEASASPCCVSQDLEPLTILYYIGKTPKIEQLSNMIVKSCKCS (SEQ ID NO: 122) 123 CD74 MHRRRSRSCREDQKPVMDDQRDLISNNEQLPMLGRRPGAPESKCS RGALYTGFSILVTLLLAGQATTAYFLYQQQGRLDKLTVTSQNLQL ENLRMKLPKPPKPVSKMRMATPLLMQALPMGALPQGPMQNATK YGNMTEDHVMHLLQNADPLKVYPPLKGSFPENLRHLKNTMETID WKVFESWMHHWLLFEMSRHSLEQKPTDAPPKVLTKCQEEVSHIP AVHPGSFRPKCDENGNYLPLQCYGSIGYCWCVFPNGTEVPNTRSR GHHNCSESLELEDPSSGLGVTKQDLGPVPM (SEQ ID NO: 123) 124 TNFRSF25 MEQRPRGCAAVAAALLLVLLGARAQGGTRSPRCDCAGDFHKKIG LFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENHHNSEC ARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSS SPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVS CPTSTLGSCPERCAAVCGWRQMFWVQVLLAGLVVPLLLGATLTY TYRHCWPHKPLVTADEAGMEALTPPPATHLSPLDSAHTLLAPPDSS EKICTVQLVGNSWTPGYPETQEALCPQVTWSWDQLPSRALGPAAA PTLSPESPAGSPAMMLQPGPQLYDVMDAVPARRWKEFVRTLGLRE AEIEAVEVEIGRFRDQQYEMLKRWRQQQPAGLGAVYAALERMGL DGCVEDLRSRLQRGP (SEQ ID NO: 124) 125 CD55 MTVARPSVPAALPLLGELPRLLLLVLLCLPAVWGDCGLPPDVPNA QPALEGRTSFPEDTVITYKCEESFVKIPGEKDSVICLKGSQWSDIEEF CNRSCEVPTRLNSASLKQPYITQNYFPVGTVVEYECRPGYRREPSL SPKLTCLQNLKWSTAVEFCKKKSCPNPGEIRNGQIDVPGGILFGATI SFSCNTGYKLFGSTSSFCLISGSSVQWSDPLPECREIYCPAPPQIDNG IIQGERDHYGYRQSVTYACNKGFTMIGEHSIYCTVNNDEGEWSGPP PECRGKSLTSKVPPTVQKPTTVNVPTTEVSPTSQKTTTKTTTPNAQ ATRSTPVSRTTKHFHETTPNKGSGTTSGTTRLLSGHTCFTLTGLLGT LVTMGLLT (SEQ ID NO: 125) 126 NRP1 MERGLPLLCAVLALVLAPAGAFRNDKCGDTIKIESPGYLTSPGYPH SYHPSEKCEWLIQAPDPYQRIMINFNPHFDLEDRDCKYDYVEVFDG ENENGHFRGKFCGKIAPPPVVSSGPFLFIKFVSDYETHGAGFSIRYEI FKRGPECSQNYTTPSGVIKSPGFPEKYPNSLECTYIVFVPKMSEIILE FESFDLEPDSNPPGGMFCRYDRLEIWDGFPDVGPHIGRYCGQKTPG 242 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: RIRSSSGILSMVFYTDSAIAKEGFSANYSVLQSSVSEDFKCMEALG MESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWI QVDLGLLRFVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITI KEGNKPVLFQGNTNPTDVVVAVFPKPLITRFVRIKPATWETGISMR FEVYGCKITDYPCSGMLGMVSGLISDSQITSSNQGDRNWMPENIRL VTSRSGWALPPAPHSYINEWLQIDLGEEKIVRGIIIQGGKHRENKVF MRKFKIGYSNNGSDWKMIMDDSKRKAKSFEGNNNYDTPELRTFP ALSTRFIRIYPERATHGGLGLRMELLGCEVEAPTAGPTTPNGNLVD ECDDDQANCHSGTGDDFQLTGGTTVLATEKPTVIDSTIQSEFPTYG FNCEFGWGSHKTFCHWEHDNHVQLKWSVLTSKTGPIQDHTGDGN FIYSQADENQKGKVARLVSPVVYSQNSAHCMTFWYHMSGSHVGT LRVKLRYQKPEEYDQLVWMAIGHQGDHWKEGRVLLHKSLKLYQ VIFEGEIGKGNLGGIAVDDISINNHISQEDCAKPADLDKKNPEIKIDE TGSTPGYEGEGEGDKNISRKPGNVLKTLDPILITIIAMSALGVLLGA VCGVVLYCACWHNGMSERNLSALENYNFELVDGVKLKKDKLNT QSTYSEA (SEQ ID NO: 126) 127 FGFR1 MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFL VHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQ DSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSS SEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCP SSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSD KGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALG SNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGV NTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEA LEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDF HSQMAVHKLAKSIPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGT PMLAGVSEYELPEDPRWELPRDRLVLGKPLGEGCFGQVVLAEAIG LDKDKPNRVTKVAVKMLKSDATEKDLSDLISEMEMMKMIGKHK NIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPS HNPEEQLSSKDLVSCAYQVARGMEYLASKKCIHRDLAARNVLVTE DNVMKIADFGLARDIHHIDYYKKTTNGRLPVKWMAPEALFDRIYT HQSDVWSFGVLLWEIFTLGGSPYPGVPVEELFKLLKEGHRMDKPS NCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYL DLSMPLDQYSPSFPDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQL ANGGLKRR (SEQ ID NO: 127) 128 ITGAV MAFPPRRRLRLGPRGLPLLLSGLLLPLCRAFNLDVDSPAEYSGPEG SYFGFAVDFFVPSASSRMFLLVGAPKANTTQPGIVEGGQVLKCDW SSTRRCQPIEFDATGNRDYAKDDPLEFKSHQWFGASVRSKQDKILA CAPLYHWRTEMKQEREPVGTCFLQDGTKTVEYAPCRSQDIDADG QGFCQGGFSIDFTKADRVLLGGPGSFYWQGQLISDQVAEIVSKYDP NVYSIKYNNQLATRTAQAIFDDSYLGYSVAVGDFNGDGIDDFVSG VPRAARTLGMVYIYDGKNMSSLYNFTGEQMAAYFGFSVAATDIN GDDYADVFIGAPLFMDRGSDGKLQEVGQVSVSLQRASGDFQTTKL NGFEVFARFGSAIAPLGDLDQDGFNDIAIAAPYGGEDKKGIVYIFN GRSTGLNAVPSQILEGQWAARSMPPSFGYSMKGATDIDKNGYPDL IVGAFGVDRAILYRARPVITVNAGLEVYPSILNQDNKTCSLPGTAL KVSCFNVRFCLKADGKGVLPRKLNFQVELLLDKLKQKGAIRRALF 243 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: LYSRSPSHSKNMTISRGGLMQCEELIAYLRDESEFRDKLTPITIFME YRLDYRTAADTTGLQPILNQFTPANISRQAHILLDCGEDNVCKPKL EVSVDSDQKKIYIGDDNPLTLIVKAQNQGEGAYEAELIVSIPLQADF IGVVRNNEALARLSCAFKTENQTRQVVCDLGNPMKAGTQLLAGL RFSVHQQSEMDTSVKFDLQIQSSNLFDKVSPVVSHKVDLAVLAAV EIRGVSSPDHVFLPIPNWEHKENPETEEDVGPVVQHIYELRNNGPSS FSKAMLHLQWPYKYNNNTLLYILHYDIDGPMNCTSDMEINPLRIKI SSLQTTEKNDTVAGQGERDHLITKRDLALSEGDIHTLGCGVAQCL KIVCQVGRLDRGKSAILYVKSLLWTETFMNKENQNHSYSLKSSAS FNVIEFPYKNLPIEDITNSTLVTTNVTWGIQPAPMPVPVWVIILAVL AGLLLLAVLVFVMYRMGFFKRVRPPQEEQEREQLQPHENGEGNSE T (SEQ ID NO: 128) 129 JAM3 MALRRPPRLRLCARLPDFFLLLLFRGCLIGAVNLKSSNRTPVVQEF ESVELSCIITDSQTSDPRIEWKKIQDEQTTYVFFDNKIQGDLAGRAEI LGKTSLKIWNVTRRDSALYRCEVVARNDRKEIDEIVIELTVQVKPV TPVCRVPKAVPVGKMATLHCQESEGHPRPHYSWYRNDVPLPTDS RANPRFRNSSFHLNSETGTLVFTAVHKDDSGQYYCIASNDAGSAR CEEQEMEVYDLNIGGIIGGVLVVLAVLALITLGICCAYRRGYFINNK QDGESYKNPGKPDGVNYIRTDEEGDFRHKSSFVI (SEQ ID NO: 129) 130 JAM2 MARRSRHRLLLLLLRYLVVALGYHKAYGFSAPKDQQVVTAVEYQ EAILACKTPKKTVSSRLEWKKLGRSVSFVYYQQTLQGDFKNRAEM IDFNIRIKNVTRSDAGKYRCEVSAPSEQGQNLEEDTVTLEVLVAPA VPSCEVPSSALSGTVVELRCQDKEGNPAPEYTWFKDGIRLLENPRL GSQSTNSSYTMNTKTGTLQFNTVSKLDTGEYSCEARNSVGYRRCP GKRMQVDDLNISGIIAAVVVVALVISVCGLGVCYAQRKGYFSKET SFQKSNSSSKATTMSENDFKHTKSFII (SEQ ID NO: 130) 131 F11R MGTKAQVERKLLCLFILAILLCSLALGSVTVHSSEPEVRIPENNPVK LSCAYSGFSSPRVEWKFDQGDTTRLVCYNNKITASYEDRVTFLPTG ITFKSVTREDTGTYTCMVSEEGGNSYGEVKVKLIVLVPPSKPTVNIP SSATIGNRAVLTCSEQDGSPPSEYTWFKDGIVMPTNPKSTRAFSNSS YVLNPTTGELVFDPLSASDTGEYSCEARNGYGTPMTSNAVRMEAV ERNVGVIVAAVLVTLILLGILVFGIWFAYSRGHFDRTKKGTSSKKVI YSQPSARSEGEFKQTSSFLV (SEQ ID NO: 131) 132 PTPRM MRGLGTCLATLAGLLLTAAGETFSGGCLFDEPYSTCGYSQSEGDD FNWEQVNTLTKPTSDPWMPSGSFMLVNASGRPEGQRAHLLLPQL KENDTHCIDFHYFVSSKSNSPPGLLNVYVKVNNGPLGNPIWNISGD PTRTWNRAELAISTFWPNFYQVIFEVITSGHQGYLAIDEVKVLGHP CTRTPHFLRIQNVEVNAGQFATFQCSAIGRTVAGDRLWLQGIDVR DAPLKEIKVTSSRRFIASFNVVNTTKRDAGKYRCMIRTEGGVGISN YAELVVKEPPVPIAPPQLASVGATYLWIQLNANSINGDGPIVAREV EYCTASGSWNDRQPVDSTSYKIGHLDPDTEYEISVLLTRPGEGGTG SPGPALRTRTKCADPMRGPRKLEVVEVKSRQITIRWEPFGYNVTRC HSYNLTVHYCYQVGGQEQVREEVSWDTENSHPQHTITNLSPYTNV SVKLILMNPEGRKESQELIVQTDEDLPGAVPTESIQGSTFEEKIFLQ WREPTQTYGVITLYEITYKAVSSFDPEIDLSNQSGRVSKLGNETHFL FFGLYPGTTYSFTIRASTAKGFGPPATNQFTTKISAPSMPAYELETPL NQTDNTVTVMLKPAHSRGAPVSVYQIVVEEERPRRTKKTTEILKC 244 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: YPVPIHFQNASLLNSQYYFAAEFPADSLQAAQPFTIGDNKTYNGY WNTPLLPYKSYRIYFQAASRANGETKIDCVQVATKGAATPKPVPE PEKQTDHTVKIAGVIAGILLFVIIFLGVVLVMKKRKLAKKRKETMS STRQEMTVMVNSMDKSYAEQGTNCDEAFSFMDTHNLNGRSVSSP SSFTMKTNTLSTSVPNSYYPDETHTMASDTSSLVQSHTYKKREPAD VPYQTGQLHPAIRVADLLQHITQMKCAEGYGFKEEYESFFEGQSAP WDSAKKDENRMKNRYGNIIAYDHSRVRLQTIEGDTNSDYINGNYI DGYHRPNHYIATQGPMQETIYDFWRMVWHENTASIIMVTNLVEV GRVKCCKYWPDDTEIYKDIKVTLIETELLAEYVIRTFAVEKRGVHE IREIRQFHFTGWPDHGVPYHATGLLGFVRQVKSKSPPSAGPLVVHC SAGAGRTGCFIVIDIMLDMAEREGVVDIYNCVRELRSRRVNMVQT EEQYVFIHDAILEACLCGDTSVPASQVRSLYYDMNKLDPQTNSSQI KEEFRTLNMVTPTLRVEDCSIALLPRNHEKNRCMDILPPDRCLPFLI TIDGESSNYINAALMDSYKQPSAFIVTQHPLPNTVKDFWRLVLDYH CTSVVMLNDVDPAQLCPQYWPENGVHRHGPIQVEFVSADLEEDIIS RIFRIYNAARPQDGYRMVQQFQFLGWPMYRDTPVSKRSFLKLIRQ VDKWQEEYNGGEGRTVVHCLNGGGRSGTFCAISIVCEMLRHQRT VDVFHAVKTLRNNKPNMVDLLDQYKFCYEVALEYLNSG (SEQ ID NO: 132) 133 ITGA8 MSPGASRGPRGSQAPLIAPLCCAAAALGMLLWSPACQAFNLDVEK LTVYSGPKGSYFGYAVDFHIPDARTASVLVGAPKANTSQPDIVEGG AVYYCPWPAEGSAQCRQIPFDTTNNRKIRVNGTKEPIEFKSNQWFG ATVKAHKGKVVACAPLYHWRTLKPTPEKDPVGTCYVAIQNFSAY AEFSPCRNSNADPEGQGYCQAGFSLDFYKNGDLIVGGPGSFYWQG QVITASVADIIANYSFKDILRKLAGEKQTEVAPASYDDSYLGYSVA AGEFTGDSQQELVAGIPRGAQNFGYVSIINSTDMTFIQNFTGEQMA SYFGYTVVVSDVNSDGLDDVLVGAPLFMEREFESNPREVGQIYLY LQVSSLLFRDPQILTGTETFGRFGSAMAHLGDLNQDGYNDIAIGVP FAGKDQRGKVLIYNGNKDGLNTKPSQVLQGVWASHAVPSGFGFT LRGDSDIDKNDYPDLIVGAFGTGKVAVYRARPVVTVDAQLLLHP MIINLENKTCQVPDSMTSAACFSLRVCASVTGQSIANTIVLMAEVQ LDSLKQKGAIKRTLFLDNHQAHRVFPLVIKRQKSHQCQDFIVYLRD ETEFRDKLSPINISLNYSLDESTFKEGLEVKPILNYYRENIVSEQAHI LVDCGEDNLCVPDLKLSARPDKHQVIIGDENHLMLIINARNEGEGA YEAELFVMIPEEADYVGIERNNKGFRPLSCEYKMENVTRMVVCDL GNPMVSGTNYSLGLRFAVPRLEKTNMSINFDLQIRSSNKDNPDSNF VSLQINITAVAQVEIRGVSHPPQIVLPIHNWEPEEEPHKEEEVGPLV EHIYELHNIGPSTISDTILEVGWPFSARDEFLLYIFHIQTLGPLQCQPN PNINPQDIKPAASPEDTPELSAFLRNSTIPHLVRKRDVHVVEFHRQS PAKILNCTNIECLQISCAVGRLEGGESAVLKVRSRLWAHTFLQRKN DPYALASLVSFEVKKMPYTDQPAKLPEGSIVIKTSVIWATPNVSFSI PLWVIILAILLGLLVLAILTLALWKCGFFDRARPPQEDMTDREQLT NDKTPEA (SEQ ID NO: 133) 134 ACVR1 MVDGVMILPVLIMIALPSPSMEDEKPKVNPKLYMCVCEGLSCGNE DHCEGQQCFSSLSINDGFHVYQKGCFQVYEQGKMTCKTPPSPGQA VECCQGDWCNRNITAQLPTKGKSFPGTQNFHLEVGLIILSVVFAVC LLACLLGVALRKFKRRNQERLNPRDVEYGTIEGLITTNVGDSTLAD 245 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: LLDHSCTSGSGSGLPFLVQRTVARQITLLECVGKGRYGEVWRGSW QGENVAVKIFSSRDEKSWFRETELYNTVMLRHENILGFIASDMTSR HSSTQLWLITHYHEMGSLYDYLQLTTLDTVSCLRIVLSIASGLAHL HIEIFGTQGKPAIAHRDLKSKNILVKKNGQCCIADLGLAVMHSQST NQLDVGNNPRVGTKRYMAPEVLDETIQVDCFDSYKRVDIWAFGL VLWEVARRMVSNGIVEDYKPPFYDVVPNDPSFEDMRKVVCVDQQ RPNIPNRWFSDPTLTSLAKLMKECWYQNPSARLTALRIKKTLTKID NSLDKLKTDC (SEQ ID NO: 134) 135 BMPR2 MTSSLQRPWRVPWLPWTILLVSTAAASQNQERLCAFKDPYQQDL GIGESRISHENGTILCSKGSTCYGLWEKSKGDINLVKQGCWSHIGD PQECHYEECVVTTTPPSIQNGTYRFCCCSTDLCNVNFTENFPPPDTT PLSPPHSFNRDETIIIALASVSVLAVLIVALCFGYRMLTGDRKQGLH SMNMMEAAASEPSLDLDNLKLLELIGRGRYGAVYKGSLDERPVA VKVFSFANRQNFINEKNIYRVPLMEHDNIARFIVGDERVTADGRME YLLVMEYYPNGSLCKYLSLHTSDWVSSCRLAHSVTRGLAYLHTEL PRGDHYKPAISHRDLNSRNVLVKNDGTCVISDFGLSMRLTGNRLV RPGEEDNAAISEVGTIRYMAPEVLEGAVNLRDCESALKQVDMYAL GLIYWEIFMRCTDLFPGESVPEYQMAFQTEVGNHPTFEDMQVLVS REKQRPKFPEAWKENSLAVRSLKETIEDCWDQDAEARLTAQCAEE RMAELMMIWERNKSVSPTVNPMSTAMQNERNLSHNRRVPKIGPY PDYSSSSYIEDSIHHTDSIVKNISSEHSMSSTPLTIGEKNRNSINYERQ QAQARIPSPETSVTSLSTNTTTTNTTGLTPSTGMTTISEMPYPDETN LHTTNVAQSIGPTPVCLQLTEEDLETNKLDPKEVDKNLKESSDENL MEHSLKQFSGPDPLSSTSSSLLYPLIKLAVEATGQQDFTQTANGQA CLIPDVLPTQIYPLPKQQNLPKRPTSLPLNTKNSTKEPRLKFGSKHK SNLKQVETGVAKMNTINAAEPHVVTVTMNGVAGRNHSVNSHAA TTQYANGTVLSGQTTNIVTHRAQEMLQNQFIGEDTRLNINSSPDEH EPLLRREQQAGHDEGVLDRLVDRRERPLEGGRTNSNNNNSNPCSE QDVLAQGVPSTAADPGPSKPRRAQRPNSLDLSATNVLDGSSIQIGE STQDGKSGSGEKIKKRVKTPYSLKRWRPSTWVISTESLDCEVNNN GSNRAVHSKSSTAVYLAEGGTATTMVSKDIGMNCL (SEQ ID NO: 135) 136 F2R MGPRRLLLVAACFSLCGPLLSARTRARRPESKATNATLDPRSFLLR NPNDKYEPFWEDEEKNESGLTEYRLVSINKSSPLQKQLPAFISEDAS GYLTSSWLTLFVPSVYTGVFVVSLPLNIMAIVVFILKMKVKKPAVV YMLHLATADVLFVSVLPFKISYYFSGSDWQFGSELCRFVTAAFYC NMYASILLMTVISIDRFLAVVYPMQSLSWRTLGRASFTCLAIWALA IAGVVPLLLKEQTIQVPGLNITTCHDVLNETLLEGYYAYYFSAFSA VFFFVPLIISTVCYVSIIRCLSSSAVANRSKKSRALFLSAAVFCIFIICF GPTNVLLIAHYSFLSHTSTTEAAYFAYLLCVCVSSISCCIDPLIYYYA SSECQRYVYSILCCKESSDPSSYNSSGQLMASKMDTCSSNLNNSIY KKLLT (SEQ ID NO: 136) 137 TGFBR1 MEAAVAAPRPRLLLLVLAAAAAAAAALLPGATALQCFCHLCTKD NFTCVTDGLCFVSVTETTDKVIHNSMCIAEIDLIPRDRPFVCAPSSK TGSVTTTYCCNQDHCNKIELPTTVKSSPGLGPVELAAVIAGPVCFV CISLMLMVYICHNRTVIHHRVPNEEDPSLDRPFISEGTTLKDLIYDM TTSGSGSGLPLLVQRTIARTIVLQESIGKGRFGEVWRGKWRGEEVA 246 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VKIFSSREERSWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQL WLVSDYHEHGSLFDYLNRYTVTVEGMIKLALSTASGLAHLHMEIV GTQGKPAIAHRDLKSKNILVKKNGTCCIADLGLAVRHDSATDTIDI APNHRVGTKRYMAPEVLDDSINMKHFESFKRADIYAMGLVFWEIA RRCSIGGIHEDYQLPYYDLVPSDPSVEEMRKVVCEQKLRPNIPNRW QSCEALRVMAKIMRECWYANGAARLTALRIKKTLSQLSQQEGIK M (SEQ ID NO: 137) 138 LRP1 MLTPPLLLLLPLLSALVAAAIDAPKTCSPKQFACRDQITCISKGWRC DGERDCPDGSDEAPEICPQSKAQRCQPNEHNCLGTELCVPMSRLC NGVQDCMDGSDEGPHCRELQGNCSRLGCQHHCVPTLDGPTCYCN SSFQLQADGKTCKDFDECSVYGTCSQLCTNTDGSFICGCVEGYLLQ PDNRSCKAKNEPVDRPPVLLIANSQNILATYLSGAQVSTITPTSTRQ TTAMDFSYANETVCWVHVGDSAAQTQLKCARMPGLKGFVDEHTI NISLSLHHVEQMAIDWLTGNFYFVDDIDDRIFVCNRNGDTCVTLLD LELYNPKGIALDPAMGKVFFTDYGQIPKVERCDMDGQNRTKLVDS KIVFPHGITLDLVSRLVYWADAYLDYIEVVDYEGKGRQTIIQGILIE HLYGLTVFENYLYATNSDNANAQQKTSVIRVNRFNSTEYQVVTRV DKGGALHIYHQRRQPRVRSHACENDQYGKPGGCSDICLLANSHKA RTCRCRSGFSLGSDGKSCKKPEHELFLVYGKGRPGIIRGMDMGAK VPDEHMIPIENLMNPRALDFHAETGFIYFADTTSYLIGRQKIDGTER ETILKDGIHNVEGVAVDWMGDNLYWTDDGPKKTISVARLEKAAQ TRKTLIEGKMTHPRAIVVDPLNGWMYWTDWEEDPKDSRRGRLER AWMDGSHRDIFVTSKTVLWPNGLSLDIPAGRLYWVDAFYDRIETI LLNGTDRKIVYEGPELNHAFGLCHHGNYLFWTEYRSGSVYRLERG VGGAPPTVTLLRSERPPIFEIRMYDAQQQQVGTNKCRVNNGGCSSL CLATPGSRQCACAEDQVLDADGVTCLANPSYVPPPQCQPGEFACA NSRCIQERWKCDGDNDCLDNSDEAPALCHQHTCPSDRFKCENNRC IPNRWLCDGDNDCGNSEDESNATCSARTCPPNQFSCASGRCIPISW TCDLDDDCGDRSDESASCAYPTCFPLTQFTCNNGRCININWRCDN DNDCGDNSDEAGCSHSCSSTQFKCNSGRCIPEHWTCDGDNDCGD YSDETHANCTNQATRPPGGCHTDEFQCRLDGLCIPLRWRCDGDTD CMDSSDEKSCEGVTHVCDPSVKFGCKDSARCISKAWVCDGDNDC EDNSDEENCESLACRPPSHPCANNTSVCLPPDKLCDGNDDCGDGS DEGELCDQCSLNNGGCSHNCSVAPGEGIVCSCPLGMELGPDNHTC QIQSYCAKHLKCSQKCDQNKFSVKCSCYEGWVLEPDGESCRSLDP FKPFIIFSNRHEIRRIDLHKGDYSVLVPGLRNTIALDFHLSQSALYWT DVVEDKIYRGKLLDNGALTSFEVVIQYGLATPEGLAVDWIAGNIY WVESNLDQIEVAKLDGTLRTTLLAGDIEHPRAIALDPRDGILFWTD WDASLPRIEAASMSGAGRRTVHRETGSGGWPNGLTVDYLEKRIL WIDARSDAIYSARYDGSGHMEVLRGHEFLSHPFAVTLYGGEVYW TDWRTNTLAKANKWTGHNVTVVQRTNTQPFDLQVYHPSRQPMA PNPCEANGGQGPCSHLCLINYNRTVSCACPHLMKLHKDNTTCYEF KKFLLYARQMEIRGVDLDAPYYNYIISFTVPDIDNVTVLDYDAREQ RVYWSDVRTQAIKRAFINGTGVETVVSADLPNAHGLAVDWVSRN LFWTSYDTNKKQINVARLDGSFKNAVVQGLEQPHGLVVHPLRGK LYWTDGDNISMANMDGSNRTLLFSGQKGPVGLAIDFPESKLYWIS SGNHTINRCNLDGSGLEVIDAMRSQLGKATALAIMGDKLWWADQ 247 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VSEKMGTCSKADGSGSVVLRNSTTLVMHMKVYDESIQLDHKGTN PCSVNNGDCSQLCLPTSETTRSCMCTAGYSLRSGQQACEGVGSFLL YSVHEGIRGIPLDPNDKSDALVPVSGTSLAVGIDFHAENDTIYWVD MGLSTISRAKRDQTWREDVVTNGIGRVEGIAVDWIAGNIYWTDQG FDVIEVARLNGSFRYVVISQGLDKPRAITVHPEKGYLFWTEWGQY PRIERSRLDGTERVVLVNVSISWPNGISVDYQDGKLYWCDARTDKI ERIDLETGENREVVLSSNNMDMFSVSVFEDFIYWSDRTHANGSIKR GSKDNATDSVPLRTGIGVQLKDIKVFNRDRQKGTNVCAVANGGC QQLCLYRGRGQRACACAHGMLAEDGASCREYAGYLLYSERTILK SIHLSDERNLNAPVQPFEDPEHMKNVIALAFDYRAGTSPGTPNRIFF SDIHFGNIQQINDDGSRRITIVENVGSVEGLAYHRGWDTLYWTSYT TSTITRHTVDQTRPGAFERETVITMSGDDHPRAFVLDECQNLMFW TNWNEQHPSIMRAALSGANVLTLIEKDIRTPNGLAIDHRAEKLYFS DATLDKIERCEYDGSHRYVILKSEPVHPFGLAVYGEHIFWTDWVR RAVQRANKHVGSNMKLLRVDIPQQPMGIIAVANDTNSCELSPCRI NNGGCQDLCLLTHQGHVNCSCRGGRILQDDLTCRAVNSSCRAQD EFECANGECINFSLTCDGVPHCKDKSDEKPSYCNSRRCKKTFRQCS NGRCVSNMLWCNGADDCGDGSDEIPCNKTACGVGEFRCRDGTCI GNSSRCNQFVDCEDASDEMNCSATDCSSYFRLGVKGVLFQPCERT SLCYAPSWVCDGANDCGDYSDERDCPGVKRPRCPLNYFACPSGR CIPMSWTCDKEDDCEHGEDETHCNKFCSEAQFECQNHRCISKQWL CDGSDDCGDGSDEAAHCEGKTCGPSSFSCPGTHVCVPERWLCDG DKDCADGADESIAAGCLYNSTCDDREFMCQNRQCIPKHFVCDHD RDCADGSDESPECEYPTCGPSEFRCANGRCLSSRQWECDGENDCH DQSDEAPKNPHCTSQEHKCNASSQFLCSSGRCVAEALLCNGQDDC GDSSDERGCHINECLSRKLSGCSQDCEDLKIGFKCRCRPGFRLKDD GRTCADVDECSTTFPCSQRCINTHGSYKCLCVEGYAPRGGDPHSC KAVTDEEPFLIFANRYYLRKLNLDGSNYTLLKQGLNNAVALDFDY REQMIYWTDVTTQGSMIRRMHLNGSNVQVLHRTGLSNPDGLAVD WVGGNLYWCDKGRDTIEVSKLNGAYRTVLVSSGLREPRALVVDV QNGYLYWTDWGDHSLIGRIGMDGSSRSVIVDTKITWPNGLTLDYV TERIYWADAREDYIEFASLDGSNRHVVLSQDIPHIFALTLFEDYVY WTDWETKSINRAHKTTGTNKTLLISTLHRPMDLHVFHALRQPDVP NHPCKVNNGGCSNLCLLSPGGGHKCACPTNFYLGSDGRTCVSNCT ASQFVCKNDKCIPFWWKCDTEDDCGDHSDEPPDCPEFKCRPGQFQ CSTGICTNPAFICDGDNDCQDNSDEANCDIHVCLPSQFKCTNTNRCI PGIFRCNGQDNCGDGEDERDCPEVTCAPNQFQCSITKRCIPRVWVC DRDNDCVDGSDEPANCTQMTCGVDEFRCKDSGRCIPARWKCDGE DDCGDGSDEPKEECDERTCEPYQFRCKNNRCVPGRWQCDYDNDC GDNSDEESCTPRPCSESEFSCANGRCIAGRWKCDGDHDCADGSDE KDCTPRCDMDQFQCKSGHCIPLRWRCDADADCMDGSDEEACGTG VRTCPLDEFQCNNTLCKPLAWKCDGEDDCGDNSDENPEECARFV CPPNRPFRCKNDRVCLWIGRQCDGTDNCGDGTDEEDCEPPTAHTT HCKDKKEFLCRNQRCLSSSLRCNMFDDCGDGSDEEDCSIDPKLTSC ATNASICGDEARCVRTEKAAYCACRSGFHTVPGQPGCQDINECLR FGTCSQLCNNTKGGHLCSCARNFMKTHNTCKAEGSEYQVLYIAD DNEIRSLFPGHPHSAYEQAFQGDESVRIDAMDVHVKAGRVYWTN 248 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: WHTGTISYRSLPPAAPPTTSNRHRRQIDRGVTHLNISGLKMPRGIAI DWVAGNVYWTDSGRDVIEVAQMKGENRKTLISGMIDEPHAIVVD PLRGTMYWSDWGNHPKIETAAMDGTLRETLVQDNIQWPTGLAVD YHNERLYWADAKLSVIGSIRLNGTDPIVAADSKRGLSHPFSIDVFE DYIYGVTYINNRVFKIHKFGHSPLVNLTGGLSHASDVVLYHQHKQ PEVTNPCDRKKCEWLCLLSPSGPVCTCPNGKRLDNGTCVPVPSPTP PPDAPRPGTCNLQCFNGGSCFLNARRQPKCRCQPRYTGDKCELDQ CWEHCRNGGTCAASPSGMPTCRCPTGFTGPKCTQQVCAGYCANN STCTVNQGNQPQCRCLPGFLGDRCQYRQCSGYCENFGTCQMAAD GSRQCRCTAYFEGSRCEVNKCSRCLEGACVVNKQSGDVTCNCTD GRVAPSCLTCVGHCSNGGSCTMNSKMMPECQCPPHMTGPRCEEH VFSQQQPGHIASILIPLLLLLLLVLVAGVVFWYKRRVQGAKGFQHQ RMTNGAMNVEIGNPTYKMYEGGEPDDVGGLLDADFALDPDKPTN FTNPVYATLYMGGHGSRHSLASTDEKRELLGRGPEDEIGDPLA (SEQ ID NO: 138) 139 EDNRB MQPPPSLCGRALVALVLACGLSRIWGEERGFPPDRATPLLQTAEIM TPPTKTLWPKGSNASLARSLAPAEVPKGDRTAGSPPRTISPPPCQGP IEIKETFKYINTVVSCLVFVLGIIGNSTLLRIIYKNKCMRNGPNILIAS LALGDLLHIVIDIPINVYKLLAEDWPFGAEMCKLVPFIQKASVGITV LSLCALSIDRYRAVASWSRIKGIGVPKWTAVEIVLIWVVSVVLAVP EAIGFDIITMDYKGSYLRICLLHPVQKTAFMQFYKTAKDWWLFSF YFCLPLAITAFFYTLMTCEMLRKKSGMQIALNDHLKQRREVAKTV FCLVLVFALCWLPLHLSRILKLTLYNQNDPNRCELLSFLLVLDYIGI NMASLNSCINPIALYLVSKRFKNCFKSCLCCWCQSFEEKQSLEEKQ SCLKFKANDHGYDNFRSSNKYSSS (SEQ ID NO: 139) 140 ITGB5 MPRAPAPLYACLLGLCALLPRLAGLNICTSGSATSCEECLLIHPKCA WCSKEDFGSPRSITSRCDLRANLVKNGCGGEIESPASSFHVLRSLPL SSKGSGSAGWDVIQMTPQEIAVNLRPGDKTTFQLQVRQVEDYPVD LYYLMDLSLSMKDDLDNIRSLGTKLAEEMRKLTSNFRLGFGSFVD KDISPFSYTAPRYQTNPCIGYKLFPNCVPSFGFRHLLPLTDRVDSFN EEVRKQRVSRNRDAPEGGFDAVLQAAVCKEKIGWRKDALHLLVF TTDDVPHIALDGKLGGLVQPHDGQCHLNEANEYTASNQMDYPSL ALLGEKLAENNINLIFAVTKNHYMLYKNFTALIPGTTVEILDGDSK NIIQLIINAYNSIRSKVELSVWDQPEDLNLFFTATCQDGVSYPGQRK CEGLKIGDTASFEVSLEARSCPSRHTEHVFALRPVGFRDSLEVGVT YNCTCGCSVGLEPNSARCNGSGTYVCGLCECSPGYLGTRCECQDG ENQSVYQNLCREAEGKPLCSGRGDCSCNQCSCFESEFGKIYGPFCE CDNFSCARNKGVLCSGHGECHCGECKCHAGYIGDNCNCSTDISTC RGRDGQICSERGHCLCGQCQCTEPGAFGEMCEKCPTCPDACSTKR DCVECLLLHSGKPDNQTCHSLCRDEVITWVDTIVKDDQEAVLCFY KTAKDCVMMFTYVELPSGKSNLTVLREPECGNTPNAMTILLAVVG SILLVGLALLAIWKLLVTIHDRREFAKFQSERSRARYEMASNPLYR KPISTHTVDFTFNKFNKSYNGTVD (SEQ ID NO: 140) 141 ITGB8 MCGSALAFFTAAFVCLQNDRRGPASFLWAAWVFSLVLGLGQGED NRCASSNAASCARCLALGPECGWCVQEDFISGGSRSERCDIVSNLI SKGCSVDSIEYPSVHVIIPTENEINTQVTPGEVSIQLRPGAEANFMLK VHPLKKYPVDLYYLVDVSASMHNNIEKLNSVGNDLSRKMAFFSR 249 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: DFRLGFGSYVDKTVSPYISIHPERIHNQCSDYNLDCMPPHGYIHVLS LTENITEFEKAVHRQKISGNIDTPEGGFDAMLQAAVCESHIGWRKE AKRLLLVMTDQTSHLALDSKLAGIVVPNDGNCHLKNNVYVKSTT MEHPSLGQLSEKLIDNNINVIFAVQGKQFHWYKDLLPLLPGTIAGEI ESKAANLNNLVVEAYQKLISEVKVQVENQVQGIYFNITAICPDGSR KPGMEGCRNVTSNDEVLFNVTVTMKKCDVTGGKNYAIIKPIGFNE TAKIHIHRNCSCQCEDNRGPKGKCVDETFLDSKCFQCDENKCHFD EDQFSSESCKSHKDQPVCSGRGVCVCGKCSCHKIKLGKVYGKYCE KDDFSCPYHHGNLCAGHGECEAGRCQCFSGWEGDRCQCPSAAAQ HCVNSKGQVCSGRGTCVCGRCECTDPRSIGRFCEHCPTCYTACKE NWNCMQCLHPHNLSQAILDQCKTSCALMEQQHYVDQTSECFSSPS YLRIFFIIFIVTFLIGLLKVLIIRQVILQWNSNKIKSSSDYRVSASKKD KLILQSVCTRAVTYRREKPEEIKMDISKLNAHETFRCNF (SEQ ID NO: 141) 142 ACVRL1 MTLGSPRKGLLMLLMALVTQGDPVKPSRGPLVTCTCESPHCKGPT CRGAWCTVVLVREEGRHPQEHRGCGNLHRELCRGRPTEFVNHYC CDSHLCNHNVSLVLEATQPPSEQPGTDGQLALILGPVLALLALVAL GVLGLWHVRRRQEKQRGLHSELGESSLILKASEQGDSMLGDLLDS DCTTGSGSGLPFLVQRTVARQVALVECVGKGRYGEVWRGLWHG ESVAVKIFSSRDEQSWFRETEIYNTVLLRHDNILGFIASDMTSRNSS TQLWLITHYHEHGSLYDFLQRQTLEPHLALRLAVSAACGLAHLHV EIFGTQGKPAIAHRDFKSRNVLVKSNLQCCIADLGLAVMHSQGSD YLDIGNNPRVGTKRYMAPEVLDEQIRTDCFESYKWTDIWAFGLVL WEIARRTIVNGIVEDYRPPFYDVVPNDPSFEDMKKVVCVDQQTPTI PNRLAADPVLSGLAQMMRECWYPNPSARLTALRIKKTLQKISNSP EKPKVIQ (SEQ ID NO: 142) 143 GLG1 MAACGRVRRMFRLSAALHLLLLFAAGAEKLPGQGVHSQGQGPGA NFVSFVGQAGGGGPAGQQLPQLPQSSQLQQQQQQQQQQQQPQPP QPPFPAGGPPARRGGAGAGGGWKLAEEESCREDVTRVCPKHTWS NNLAVLECLQDVREPENEISSDCNHLLWNYKLNLTTDPKFESVAR EVCKSTITEIKECADEPVGKGYMVSCLVDHRGNITEYQCHQYITK MTAIIFSDYRLICGFMDDCKNDINILKCGSIRLGEKDAHSQGEVVSC LEKGLVKEAEEREPKIQVSELCKKAILRVAELSSDDFHLDRHLYFA CRDDRERFCENTQAGEGRVYKCLFNHKFEESMSEKCREALTTRQK LIAQDYKVSYSLAKSCKSDLKKYRCNVENLPRSREARLSYLLMCL ESAVHRGRQVSSECQGEMLDYRRMLMEDFSLSPEIILSCRGEIEHH CSGLHRKGRTLHCLMKVVRGEKGNLGMNCQQALQTLIQETDPGA DYRIDRALNEACESVIQTACKHIRSGDPMILSCLMEHLYTEKMVED CEHRLLELQYFISRDWKLDPVLYRKCQGDASRLCHTHGWNETSEF MPQGAVFSCLYRHAYRTEEQGRRLSRECRAEVQRILHQRAMDVK LDPALQDKCLIDLGKWCSEKTETGQELECLQDHLDDLVVECRDIV GNLTELESEDIQIEALLMRACEPIIQNFCHDVADNQIDSGDLMECLI QNKHQKDMNEKCAIGVTHFQLVQMKDFRFSYKFKMACKEDVLK LCPNIKKKVDVVICLSTTVRNDTLQEAKEHRVSLKCRRQLRVEELE MTEDIRLEPDLYEACKSDIKNFCSAVQYGNAQIIECLKENKKQLST RCHQKVFKLQETEMMDPELDYTLMRVCKQMIKRFCPEADSKTML QCLKQNKNSELMDPKCKQMITKRQITQNTDYRLNPMLRKACKAD 250 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: IPKFCHGILTKAKDDSELEGQVISCLKLRYADQRLSSDCEDQIRIIIQ ESALDYRLDPQLQLHCSDEISSLCAEEAAAQEQTGQVEECLKVNLL KIKTELCKKEVLNMLKESKADIFVDPVLHTACALDIKHHCAAITPG RGRQMSCLMEALEDKRVRLQPECKKRLNDRIEMWSYAAKVAPA DGFSDLAMQVMTSPSKNYILSVISGSICILFLIGLMCGRITKRVTREL KDR (SEQ ID NO: 143) 144 ITGA6 MAAAGQLCLLYLSAGLLSRLGAAFNLDTREDNVIRKYGDPGSLFG FSLAMHWQLQPEDKRLLLVGAPRAEALPLQRANRTGGLYSCDITA RGPCTRIEFDNDADPTSESKEDQWMGVTVQSQGPGGKVVTCAHR YEKRQHVNTKQESRDIFGRCYVLSQNLRIEDDMDGGDWSFCDGR LRGHEKFGSCQQGVAATFTKDFHYIVFGAPGTYNWKGIVRVEQK NNTFFDMNIFEDGPYEVGGETEHDESLVPVPANSYLGLLFLTSVSY TDPDQFVYKTRPPREQPDTFPDVMMNSYLGFSLDSGKGIVSKDEIT FVSGAPRANHSGAVVLLKRDMKSAHLLPEHIFDGEGLASSFGYDV AVVDLNKDGWQDIVIGAPQYFDRDGEVGGAVYVYMNQQGRWN NVKPIRLNGTKDSMFGIAVKNIGDINQDGYPDIAVGAPYDDLGKVF IYHGSANGINTKPTQVLKGISPYFGYSIAGNMDLDRNSYPDVAVGS LSDSVTIFRSRPVINIQKTITVTPNRIDLRQKTACGAPSGICLQVKSC FEYTANPAGYNPSISIVGTLEAEKERRKSGLSSRVQFRNQGSEPKYT QELTLKRQKQKVCMEETLWLQDNIRDKLRPIPITASVEIQEPSSRRR VNSLPEVLPILNSDEPKTAHIDVHFLKEGCGDDNVCNSNLKLEYKF CTREGNQDKFSYLPIQKGVPELVLKDQKDIALEITVTNSPSNPRNPT KDGDDAHEAKLIATFPDTLTYSAYRELRAFPEKQLSCVANQNGSQ ADCELGNPFKRNSNVTFYLVLSTTEVTFDTPDLDINLKLETTSNQD NLAPITAKAKVVIELLLSVSGVAKPSQVYFGGTVVGEQAMKSEDE VGSLIEYEFRVINLGKPLTNLGTATLNIQWPKEISNGKWLLYLVKV ESKGLEKVTCEPQKEINSLNLTESHNSRKKREITEKQIDDNRKFSLF AERKYQTLNCSVNVNCVNIRCPLRGLDSKASLILRSRLWNSTFLEE YSKLNYLDILMRAFIDVTAAAENIRLPNAGTQVRVTVFPSKTVAQY SGVPWWIILVAILAGILMLALLVFILWKCGFFKRSRYDDSVPRYHA VRIRKEEREIKDEKYIDNLEKKQWITKWNENESYS (SEQ ID NO: 144) 145 ALOX5 MPSYTVTVATGSQWFAGTDDYIYLSLVGSAGCSEKHLLDKPFYND FERGAVDSYDVTVDEELGEIQLVRIEKRKYWLNDDWYLKYITLKT PHGDYIEFPCYRWITGDVEVVLRDGRAKLARDDQIHILKQHRRKE LETRQKQYRWMEWNPGFPLSIDAKCHKDLPRDIQFDSEKGVDFVL NYSKAMENLFINRFMHMFQSSWNDFADFEKIFVKISNTISERVMNH WQEDLMFGYQFLNGCNPVLIRRCTELPEKLPVTTEMVECSLERQL SLEQEVQQGNIFIVDFELLDGIDANKTDPCTLQFLAAPICLLYKNLA NKIVPIAIQLNQIPGDENPIFLPSDAKYDWLLAKIWVRSSDFHVHQT ITHLLRTHLVSEVFGIAMYRQLPAVHPIFKLLVAHVRFTIAINTKAR EQLICECGLFDKANATGGGGHVQMVQRAMKDLTYASLCFPEAIK ARGMESKEDIPYYFYRDDGLLVWEAIRTFTAEVVDIYYEGDQVVE EDPELQDFVNDVYVYGMRGRKSSGFPKSVKSREQLSEYLTVVIFT ASAQHAAVNFGQYDWCSWIPNAPPTMRAPPPTAKGVVTIEQIVDT LPDRGRSCWHLGAVWALSQFQENELFLGMYPEEHFIEKPVKEAM ARFRKNLEAIVSVIAERNKKKQLPYYYLSPDRIPNSVAI (SEQ ID 251 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: NO: 145) 146 CD4 MNRGVPFRHLLLVLQLALLPAATQGKKVVLGKKGDTVELTCTAS QKKSIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRADSRRSLWDQ GNFPLIIKNLKIEDSDTYICEVEDQKEEVQLLVFGLTANSDTHLLQG QSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWT CTVLQNQKKVEFKIDIVVLAFQKASSIVYKKEGEQVEFSFPLAFTV EKLTGSGELWWQAERASSSKSWITFDLKNKEVSVKRVTQDPKLQ MGKKLPLHLTLPQALPQYAGSGNLTLALEAKTGKLHQEVNLVVM RATQLQKNLTCEVWGPTSPKLMLSLKLENKEAKVSKREKAVWVL NPEAGMWQCLLSDSGQVLLESNIKVLPTWSTPVQPMALIVLGGVA GLLLFIGLGIFFCVRCRHRRRQAERMSQIKRLLSEKKTCQCPHRFQ KTCSPI (SEQ ID NO: 146) 147 CEACAM5 MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAE GKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQQATPG PAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLVNEEATGQFRV YPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSL PVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVIL NVLYGPDAPTISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTF QQSTQELFIPNITVNNSGSYTCQAHNSDTGLNRTTVTTITVYAEPPK PFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQ LSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPD DPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELF ISNITEKNSGLYTCQANNSASGHSRTTVKTITVSAELPKPSISSNNSK PVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRT LTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPD SSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNN NGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAGATVGIMIGVL VGVALI (SEQ ID NO: 147) 148 ITGAX MTRTRAALLLFTALATSLGFNLDTEELTAFRVDSAGFGDSVVQYA NSWVVVGAPQKITAANQTGGLYQCGYSTGACEPIGLQVPPEAVN MSLGLSLASTTSPSQLLACGPTVHHECGRNMYLTGLCFLLGPTQLT QRLPVSRQECPRQEQDIVFLIDGSGSISSRNFATMMNFVRAVISQFQ RPSTQFSLMQFSNKFQTHFTFEEFRRSSNPLSLLASVHQLQGFTYTA TAIQNVVHRLFHASYGARRDAAKILIVITDGKKEGDSLDYKDVIPM ADAAGIIRYAIGVGLAFQNRNSWKELNDIASKPSQEHIFKVEDFDA LKDIQNQLKEKIFAIEGTETTSSSSFELEMAQEGFSAVFTPDGPVLG AVGSFTWSGGAFLYPPNMSPTFINMSQENVDMRDSYLGYSTELAL WKGVQSLVLGAPRYQHTGKAVIFTQVSRQWRMKAEVTGTQIGSY FGASLCSVDVDSDGSTDLVLIGAPHYYEQTRGGQVSVCPLPRGWR RWWCDAVLYGEQGHPWGRFGAALTVLGDVNGDKLTDVVIGAPG EEENRGAVYLFHGVLGPSISPSHSQRIAGSQLSSRLQYFGQALSGG QDLTQDGLVDLAVGARGQVLLLRTRPVLWVGVSMQFIPAEIPRSA FECREQVVSEQTLVQSNICLYIDKRSKNLLGSRDLQSSVTLDLALD PGRLSPRATFQETKNRSLSRVRVLGLKAHCENFNLLLPSCVEDSVT PITLRLNFTLVGKPLLAFRNLRPMLAADAQRYFTASLPFEKNCGAD HICQDNLGISFSFPGLKSLLVGSNLELNAEVMVWNDGEDSYGTTIT FSHPAGLSYRYVAEGQKQGQLRSLHLTCDSAPVGSQGTWSTSCRI 252 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: NHLIFRGGAQITFLATFDVSPKAVLGDRLLLTANVSSENNTPRTSKT TFQLELPVKYAVYTVVSSHEQFTKYLNFSESEEKESHVAMHRYQV NNLGQRDLPVSINFWVPVELNQEAVWMDVEVSHPQNPSLRCSSEK IAPPASDFLAHIQKNPVLDCSIAGCLRFRCDVPSFSVQEELDFTLKG NLSFGWVRQILQKKVSVVSVAEITFDTSVYSQLPGQEAFMRAQTT TVLEKYKVHNPTPLIVGSSIGGLLLLALITAVLYKVGFFKRQYKEM MEEANGQIAPENGTQTPSPPSEK (SEQ ID NO: 148) 149 TNFRSF10B MEQRGQNAPAASGARKRHGPGPREARGARPGPRVPKTLVLVVAA VLLLVSAESALITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDG RDCISCKYGQDYSTHWNDLLFCLRCTRCDSGEVELSPCTTTRNTV CQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSDIECVHK ESGTKHSGEVPAVEETVTSSPGTPASPCSLSGIIIGVTVAAVVLIVAV FVCKSLLWKKVLPYLKGICSGGGGDPERVDRSSQRPGAEDNVLNE IVSILQPTQVPEQEMEVQEPAEPTGVNMLSPGESEHLLEPAEAERSQ RRRLLVPANEGDPTETLRQCFDDFADLVPFDSWEPLMRKLGLMDN EIKVAKAEAAGHRDTLYTMLIKWVNKTGRDASVHTLLDALETLG ERLAKQKIEDHLLSSGKFMYLEGNADSAMS (SEQ ID NO: 149) 150 CSF3R MARLGNCSLTWAALIILLLPGSLEECGHISVSAPIVHLGDPITASCII KQNCSHLDPEPQILWRLGAELQPGGRQQRLSDGTQESIITLPHLNH TQAFLSCCLNWGNSLQILDQVELRAGYPPAIPHNLSCLMNLTTSSLI CQWEPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPKDGQSHCC IPRKHLLLYQNMGIWVQAENALGTSMSPQLCLDPMDVVKLEPPM LRTMDPSPEAAPPQAGCLQLCWEPWQPGLHINQKCELRHKPQRGE ASWALVGPLPLEALQYELCGLLPATAYTLQIRCIRWPLPGHWSDW SPSLELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVPLEEDSG RIQGYVVSWRPSGQAGAILPLCNTTELSCTFHLPSEAQEVALVAYN SAGTSRPTPVVFSESRGPALTRLHAMARDPHSLWVGWEPPNPWPQ GYVIEWGLGPPSASNSNKTWRMEQNGRATGFLLKENIRPFQLYEII VTPLYQDTMGPSQHVYAYSQEMAPSHAPELHLKHIGKTWAQLEW VPEPPELGKSPLTHYTIFWTNAQNQSFSAILNASSRGFVLHGLEPAS LYHIHLMAASQAGATNSTVLTLMTLTPEGSELHIILGLFGLLLLLTC LCGTAWLCCSPNRKNPLWPSVPDPAHSSLGSWVPTIMEEDAFQLP GLGTPPITKLTVLEEDEKKPVPWESHNSSETCGLPTLVQTYVLQGD PRAVSTQPQSQSGTSDQVLYGQLLGSPTSPGPGHYLRCDSTQPLLA GLTPSPKSYENLWFQASPLGTLVTPAPSQEDDCVFGPLLNFPLLQGI RVHGMEALGSF (SEQ ID NO: 150) 151 CSF1R MGPGVLLLLLVATAWHGQGIPVIEPSVPELVVKPGATVTLRCVGN GSVEWDGPPSPHWTLYSDGSSSILSTNNATFQNTGTYRCTEPGDPL GGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLTDPVLEA GVSLVRVRGRPLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSALM GGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIVCSASS VDVNFDVFLQHNNTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQH AGNYSCVASNVQGKHSTSMFFRVVESAYLNLSSEQNLIQEVTVGE GLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTYR HTFTLSLPRLKPSEAGRYSFLARNPGGWRALTFELTLRYPPEVSVI WTFINGSGTLLCAASGYPQPNVTWLQCSGHTDRCDEAQVLQVWD DPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSW 253 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: AFIPISAGAHTHPPDEFLFTPVVVACMSIMALLLLLLLLLLYKYKQK PKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLG AGAFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMS ELKIMSHLGQHENIVNLLGACTHGGPVLVITEYCCYGDLLNFLRRK AEAMLGPSLSPGQDPEGGVDYKNIHLEKKYVRRDSGFSSQGVDTY VEMRPVSTSSNDSFSEQDLDKEDGRPLELRDLLHFSSQVAQGMAF LASKNCIHRDVAARNVLLTNGHVAKIGDFGLARDIMNDSNYIVKG NARLPVKWMAPESIFDCVYTVQSDVWSYGILLWEIFSLGLNPYPGI LVNSKFYKLVKDGYQMAQPAFAPKNIYSIMQACWALEPTHRPTFQ QICSFLQEQAQEDRRERDYTNLPSSSRSGGSGSSSSELEEESSSEHLT CCEQGDIAQPLLQPNNYQFC (SEQ ID NO: 151) 152 LILRB3 MTPALTALLCLGLSLGPRTRVQAGPFPKPTLWAEPGSVISWGSPVT IWCQGSLEAQEYQLDKEGSPEPLDRNNPLEPKNKARFSIPSMTQHH AGRYRCHYYSSAGWSEPSDPLELVMTGFYNKPTLSALPSPVVASG GNMTLRCGSQKGYHHFVLMKEGEHQLPRTLDSQQLHSGGFQALF PVGPVTPSHRWRFTCYYYYTNTPRVWSHPSDPLEILPSGVSRKPSL LTLQGPVLAPGQSLTLQCGSDVGYDRFVLYKEGERDFLQRPGQQP QAGLSQANFTLGPVSPSHGGQYRCYGAHNLSSEWSAPSDPLNILM AGQIYDTVSLSAQPGPTVASGENVTLLCQSRGYFDTFLLTKEGAAH PPLRLRSMYGAHKYQAEFPMSPVTSAHAGTYRCYGSYSSNPHLLS FPSEPLELMVSGHSGGSSLPPTGPPSTPASHAKDYTVENLIRMGMA GLVLVFLGILLFEAQHSQRNPQDAAGR (SEQ ID NO: 152) 153 FPR3 METNFSIPLNETEEVLPEPAGHTVLWIFSLLVHGVTFVFGVLGNGL VIWVAGFRMTRTVNTICYLNLALADFSFSAILPFRMVSVAMREKW PFGSFLCKLVHVMIDINLFVSVYLITIIALDRCICVLHPAWAQNHRT MSLAKRVMTGLWIFTIVLTLPNFIFWTTISTTNGDTYCIFNFAFWGD TAVERLNVFITMAKVFLILHFIIGFSVPMSIITVCYGIIAAKIHRNHMI KSSRPLRVFAAVVASFFICWFPYELIGILMAVWLKEMLLNGKYKII LVLINPTSSLAFFNSCLNPILYVFMGRNFQERLIRSLPTSLERALTEV PDSAQTSNTDTTSASPPEETELQAM (SEQ ID NO: 153) 154 CD28 MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYN LFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKL GNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVK GKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSK RSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 154) 155 CTLA4 MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAV VLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYM MGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMY PPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFLLTA VSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ ID NO: 155) 156 IGF2R MGAAAGRSPHLGPAPARRPQRSLLLLQLLLLVAAPGSTQAQAAPF PELCSYTWEAVDTKNNVLYKINICGSVDIVQCGPSSAVCMHDLKT RTYHSVGDSVLRSATRSLLEFNTTVSCDQQGTNHRVQSSIAFLCGK TLGTPEFVTATECVHYFEWRTTAACKKDIFKANKEVPCYVFDEEL RKHDLNPLIKLSGAYLVDDSDPDTSLFINVCRDIDTLRDPGSQLRA 254 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: CPPGTAACLVRGHQAFDVGQPRDGLKLVRKDRLVLSYVREEAGK LDFCDGHSPAVTITFVCPSERREGTIPKLTAKSNCRYEIEWITEYAC HRDYLESKTCSLSGEQQDVSIDLTPLAQSGGSSYISDGKEYLFYLN VCGETEIQFCNKKQAAVCQVKKSDTSQVKAAGRYHNQTLRYSDG DLTLIYFGGDECSSGFQRMSVINFECNKTAGNDGKGTPVFTGEVDC TYFFTWDTEYACVKEKEDLLCGATDGKKRYDLSALVRHAEPEQN WEAVDGSQTETEKKHFFINICHRVLQEGKARGCPEDAAVCAVDK NGSKNLGKFISSPMKEKGNIQLSYSDGDDCGHGKKIKTNITLVCKP GDLESAPVLRTSGEGGCFYEFEWHTAAACVLSKTEGENCTVFDSQ AGFSFDLSPLTKKNGAYKVETKKYDFYINVCGPVSVSPCQPDSGA CQVAKSDEKTWNLGLSNAKLSYYDGMIQLNYRGGTPYNNERHTP RATLITFLCDRDAGVGFPEYQEEDNSTYNFRWYTSYACPEEPLECV VTDPSTLEQYDLSSLAKSEGGLGGNWYAMDNSGEHVTWRKYYIN VCRPLNPVPGCNRYASACQMKYEKDQGSFTEVVSISNLGMAKTGP VVEDSGSLLLEYVNGSACTTSDGRQTTYTTRIHLVCSRGRLNSHPIF SLNWECVVSFLWNTEAACPIQTTTDTDQACSIRDPNSGFVFNLNPL NSSQGYNVSGIGKIFMFNVCGTMPVCGTILGKPASGCEAETQTEEL KNWKPARPVGIEKSLQLSTEGFITLTYKGPLSAKGTADAFIVRFVC NDDVYSGPLKFLHQDIDSGQGIRNTYFEFETALACVPSPVDCQVTD LAGNEYDLTGLSTVRKPWTAVDTSVDGRKRTFYLSVCNPLPYIPG CQGSAVGSCLVSEGNSWNLGVVQMSPQAAANGSLSIMYVNGDKC GNQRFSTRITFECAQISGSPAFQLQDGCEYVFIWRTVEACPVVRVE GDNCEVKDPRHGNLYDLKPLGLNDTIVSAGEYTYYFRVCGKLSSD VCPTSDKSKVVSSCQEKREPQGFHKVAGLLTQKLTYENGLLKMNF TGGDTCHKVYQRSTAIFFYCDRGTQRPVFLKETSDCSYLFEWRTQ YACPPFDLTECSFKDGAGNSFDLSSLSRYSDNWEAITGTGDPEHYL INVCKSLAPQAGTEPCPPEAAACLLGGSKPVNLGRVRDGPQWRDG IIVLKYVDGDLCPDGIRKKSTTIRFTCSESQVNSRPMFISAVEDCEYT FAWPTATACPMKSNEHDDCQVTNPSTGHLFDLSSLSGRAGFTAAY SEKGLVYMSICGENENCPPGVGACFGQTRISVGKANKRLRYVDQV LQLVYKDGSPCPSKSGLSYKSVISFVCRPEARPTNRPMLISLDKQTC TLFFSWHTPLACEQATECSVRNGSSIVDLSPLIHRTGGYEAYDESED DASDTNPDFYINICQPLNPMHGVPCPAGAAVCKVPIDGPPIDIGRVA GPPILNPIANEIYLNFESSTPCLADKHFNYTSLIAFHCKRGVSMGTP KLLRTSECDFVFEWETPVVCPDEVRMDGCTLTDEQLLYSFNLSSLS TSTFKVTRDSRTYSVGVCTFAVGPEQGGCKDGGVCLLSGTKGASF GRLQSMKLDYRHQDEAVVLSYVNGDRCPPETDDGVPCVFPFIFNG KSYEECIIESRAKLWCSTTADYDRDHEWGFCRHSNSYRTSSIIFKCD EDEDIGRPQVFSEVRGCDVTFEWKTKVVCPPKKLECKFVQKHKTY DLRLLSSLTGSWSLVHNGVSYYINLCQKIYKGPLGCSERASICRRTT TGDVQVLGLVHTQKLGVIGDKVVVTYSKGYPCGGNKTASSVIELT CTKTVGRPAFKRFDIDSCTYYFSWDSRAACAVKPQEVQMVNGTIT NPINGKSFSLGDIYFKLFRASGDMRTNGDNYLYEIQLSSITSSRNPA CSGANICQVKPNDQHFSRKVGTSDKTKYYLQDGDLDVVFASSSKC GKDKTKSVSSTIFFHCDPLVEDGIPEFSHETADCQYLFSWYTSAVCP LGVGFDSENPGDDGQMHKGLSERSQAVGAVLSLLLVALTCCLLAL LLYKKERRETVISKLTTCCRRSSNVSYKYSKVNKEEETDENETEWL 255 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: MEEIQLPPPRQGKEGQENGHITTKSVKALSSLHGDDQDSEDEVLTI PEVKVHSGRGAGAESSHPVRNAQSNALQEREDDRVGLVRGEKAR KGKSSSAQQKTVSSTKLVSFHDDSDEDLLHI (SEQ ID NO: 156) 157 ITGAL MKDSCITVMAMALLSGFFFFAPASSYNLDVRGARSFSPPRAGRHF GYRVLQVGNGVIVGAPGEGNSTGSLYQCQSGTGHCLPVTLRGSNY TSKYLGMTLATDPTDGSILACDPGLSRTCDQNTYLSGLCYLFRQNL QGPMLQGRPGFQECIKGNVDLVFLFDGSMSLQPDEFQKILDFMKD VMKKLSNTSYQFAAVQFSTSYKTEFDFSDYVKRKDPDALLKHVK HMLLLTNTFGAINYVATEVFREELGARPDATKVLIIITDGEATDSGN IDAAKDIIRYIIGIGKHFQTKESQETLHKFASKPASEFVKILDTFEKL KDLFTELQKKIYVIEGTSKQDLTSFNMELSSSGISADLSRGHAVVG AVGAKDWAGGFLDLKADLQDDTFIGNEPLTPEVRAGYLGYTVTW LPSRQKTSLLASGAPRYQHMGRVLLFQEPQGGGHWSQVQTIHGTQ IGSYFGGELCGVDVDQDGETELLLIGAPLFYGEQRGGRVFIYQRRQ LGFEEVSELQGDPGYPLGRFGEAITALTDINGDGLVDVAVGAPLEE QGAVYIFNGRHGGLSPQPSQRIEGTQVLSGIQWFGRSIHGVKDLEG DGLADVAVGAESQMIVLSSRPVVDMVTLMSFSPAEIPVHEVECSY STSNKMKEGVNITICFQIKSLIPQFQGRLVANLTYTLQLDGHRTRRR GLFPGGRHELRRNIAVTTSMSCTDFSFHFPVCVQDLISPINVSLNFSL WEEEGTPRDQRAQGKDIPPILRPSLHSETWEIPFEKNCGEDKKCEA NLRVSFSPARSRALRLTAFASLSVELSLSNLEEDAYWVQLDLHFPP GLSFRKVEMLKPHSQIPVSCEELPEESRLLSRALSCNVSSPIFKAGHS VALQMMFNTLVNSSWGDSVELHANVTCNNEDSDLLEDNSATTIIPI LYPINILIQDQEDSTLYVSFTPKGPKIHQVKHMYQVRIQPSIHDHNIP TLEAVVGVPQPPSEGPITHQWSVQMEPPVPCHYEDLERLPDAAEPC LPGALFRCPVVFRQEILVQVIGTLELVGEIEASSMFSLCSSLSISFNSS KHFHLYGSNASLAQVVMKVDVVYEKQMLYLYVLSGIGGLLLLLLI FIVLYKVGFFKRNLKEKMEAGRGVPNGIPAEDSEQLASGQEAGDP GCLKPLHEKDSESGGGKD (SEQ ID NO: 157) 158 RPSA MSGALDVLQMKEEDVLKFLAAGTHLGGTNLDFQMEQYIYKRKSD GIYIINLKRTWEKLLLAARAIVAIENPADVSVISSRNTGQRAVLKFA AATGATPIAGRFTPGTFTNQIQAAFREPRLLVVTDPRADHQPLTEA SYVNLPTIALCNTDSPLRYVDIAIPCNNKGAHSVGLMWWMLAREV LRMRGTISREHPWEVMPDLYFYRDPEEIEKEEQAAAEKAVTKEEF QGEWTAPAPEFTATQPEVADWSEGVQVPSVPIQQFPTEDWSAQPA TEDWSAAPTAQATEWVGATTDWS (SEQ ID NO: 158) 159 MYLK MGDVKLVASSHISKTSLSVDPSRVDSMPLTEAPAFILPPRNLCIKEG ATAKFEGRVRGYPEPQVTWHRNGQPITSGGRFLLDCGIRGTFSLVI HAVHEEDRGKYTCEATNGSGARQVTVELTVEGSFAKQLGQPVVS KTLGDRFSAPAVETRPSIWGECPPKFATKLGRVVVKEGQMGRFSC KITGRPQPQVTWLKGNVPLQPSARVSVSEKNGMQVLEIHGVNQDD VGVYTCLVVNGSGKASMSAELSIQGLDSANRSFVRETKATNSDVR KEVTNVISKESKLDSLEAAAKSKNCSSPQRGGSPPWAANSQPQPPR ESKLESCKDSPRTAPQTPVLQKTSSSITLQAARVQPEPRAPGLGVLS PSGEERKRPAPPRPATFPTRQPGLGSQDVVSKAANRRIPMEGQRDS AFPKFESKPQSQEVKENQTVKFRCEVSGIPKPEVAWFLEGTPVRRQ EGSIEVYEDAGSHYLCLLKARTRDSGTYSCTASNAQGQLSCSWTL 256 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: QVERLAVMEVAPSFSSVLKDCAVIEGQDFVLQCSVRGTPVPRITWL LNGQPIQYARSTCEAGVAELHIQDALPEDHGTYTCLAENALGQVS CSAWVTVHEKKSSRKSEYLLPVAPSKPTAPIFLQGLSDLKVMDGS QVTMTVQVSGNPPPEVIWLHNGNEIQESEDFHFEQRGTQHSLCIQE VFPEDTGTYTCEAWNSAGEVRTQAVLTVQEPHDGTQPWFISKPRS VTASLGQSVLISCAIAGDPFPTVHWLRDGKALCKDTGHFEVLQNE DVFTLVLKKVQPWHAGQYEILLKNRVGECSCQVSLMLQNSSARA LPRGREPASCEDLCGGGVGADGGGSDRYGSLRPGWPARGQGWLE EEDGEDVRGVLKRRVETRQHTEEAIRQQEVEQLDFRDLLGKKVST KTLSEDDLKEIPAEQMDFRANLQRQVKPKTVSEEERKVHSPQQVD FRSVLAKKGTSKTPVPEKVPPPKPATPDFRSVLGGKKKLPAENGSS SAETLNAKAVESSKPLSNAQPSGPLKPVGNAKPAETLKPMGNAKP AETLKPMGNAKPDENLKSASKEELKKDVKNDVNCKRGHAGTTDN EKRSESQGTAPAFKQKLQDVHVAEGKKLLLQCQVSSDPPATIIWTL NGKTLKTTKFIILSQEGSLCSVSIEKALPEDRGLYKCVAKNDAGQA ECSCQVTVDDAPASENTKAPEMKSRRPKSSLPPVLGTESDATVKK KPAPKTPPKAAMPPQIIQFPEDQKVRAGESVELFGKVTGTQPITCT WMKFRKQIQESEHMKVENSENGSKLTILAARQEHCGCYTLLVENK LGSRQAQVNLTVVDKPDPPAGTPCASDIRSSSLTLSWYGSSYDGGS AVQSYSIEIWDSANKTWKELATCRSTSFNVQDLLPDHEYKFRVRAI NVYGTSEPSQESELTTVGEKPEEPKDEVEVSDDDEKEPEVDYRTVT INTEQKVSDFYDIEERLGSGKFGQVFRLVEKKTRKVWAGKFFKAY SAKEKENIRQEISIMNCLHHPKLVQCVDAFEEKANIVMVLEIVSGG ELFERIIDEDFELTERECIKYMRQISEGVEYIHKQGIVHLDLKPENIM CVNKTGTRIKLIDFGLARRLENAGSLKVLFGTPEFVAPEVINYEPIG YATDMWSIGVICYILVSGLSPFMGDNDNETLANVTSATWDFDDEA FDEISDDAKDFISNLLKKDMKNRLDCTQCLQHPWLMKDTKNMEA KKLSKDRMKKYMARRKWQKTGNAVRAIGRLSSMAMISGLSGRK SSTGSPTSPLNAEKLESEEDVSQAFLEAVAEEKPHVKPYFSKTIRDL EVVEGSAARFDCKIEGYPDPEVVWFKDDQSIRESRHFQIDYDEDGN CSLIISDVCGDDDAKYTCKAVNSLGEATCTAELIVETMEEGEGEGE EEEE (SEQ ID NO: 159) 160 ITGA1 MAPRPRARPGVAVACCWLLTVVLRCCVSFNVDVKNSMTFSGPVE DMFGYTVQQYENEEGKWVLIGSPLVGQPKNRTGDVYKCPVGRGE SLPCVKLDLPVNTSIPNVTEVKENMTFGSTLVTNPNGGFLACGPLY AYRCGHLHYTTGICSDVSPTFQVVNSIAPVQECSTQLDIVIVLDGSN SIYPWDSVTAFLNDLLERMDIGPKQTQVGIVQYGENVTHEFNLNK YSSTEEVLVAAKKIVQRGGRQTMTALGIDTARKEAFTEARGARRG VKKVMVIVTDGESHDNHRLKKVIQDCEDENIQRFSIAILGSYNRGN LSTEKFVEEIKSIASEPTEKHFFNVSDELALVTIVKTLGERIFALEAT ADQSAASFEMEMSQTGFSAHYSQDWVMLGAVGAYDWNGTVVM QKASQIIIPRNTTFNVESTKKNEPLASYLGYTVNSATASSGDVLYIA GQPRYNHTGQVIIYRMEDGNIKILQTLSGEQIGSYFGSILTTTDIDKD SNTDILLVGAPMYMGTEKEEQGKVYVYALNQTRFEYQMSLEPIKQ TCCSSRQHNSCTTENKNEPCGARFGTAIAAVKDLNLDGFNDIVIGA PLEDDHGGAVYIYHGSGKTIRKEYAQRIPSGGDGKTLKFFGQSIHG EMDLNGDGLTDVTIGGLGGAALFWSRDVAVVKVTMNFEPNKVNI 257 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: QKKNCHMEGKETVCINATVCFDVKLKSKEDTIYEADLQYRVTLDS LRQISRSFFSGTQERKVQRNITVRKSECTKHSFYMLDKHDFQDSVR ITLDFNLTDPENGPVLDDSLPNSVHEYIPFAKDCGNKEKCISDLSLH VATTEKDLLIVRSQNDKFNVSLTVKNTKDSAYNTRTIVHYSPNLVF SGIEAIQKDSCESNHNITCKVGYPFLRRGEMVTFKILFQFNTSYLME NVTIYLSATSDSEEPPETLSDNVVNISIPVKYEVGLQFYSSASEYHISI AANETVPEVINSTEDIGNEINIFYLIRKSGSFPMPELKLSISFPNMTSN GYPVLYPTGLSSSENANCRPHIFEDPFSINSGKKMTTSTDHLKRGTI LDCNTCKFATITCNLTSSDISQVNVSLILWKPTFIKSYFSSLNLTIRG ELRSENASLVLSSSNQKRELAIQISKDGLPGRVPLWVILLSAFAGLL LLMLLILALWKIGFFKRPLKKKMEK (SEQ ID NO: 160) 161 SDC4 MAPARLFALLLFFVGGVAESIRETEVIDPQDLLEGRYFSGALPDDE DVVGPGQESDDFELSGSGDLDDLEDSMIGPEVVHPLVPLDNHIPER AGSGSQVPTEPKKLEENEVIPKRISPVEESEDVSNKVSMSSTVQGSN IFERTEVLAALIVGGIVGILFAVFLILLLMYRMKKKDEGSYDLGKKP IYKKAPTNEFYA (SEQ ID NO: 161) 162 ITGB2 MLGLRPPLLALVGLLSLGCVLSQECTKFKVSSCRECIESGPGCTWC QKLNFTGPGDPDSIRCDTRPQLLMRGCAADDIMDPTSLAETQEDH NGGQKQLSPQKVTLYLRPGQAAAFNVTFRRAKGYPIDLYYLMDLS YSMLDDLRNVKKLGGDLLRALNEITESGRIGFGSFVDKTVLPFVNT HPDKLRNPCPNKEKECQPPFAFRHVLKLTNNSNQFQTEVGKQLISG NLDAPEGGLDAMMQVAACPEEIGWRNVTRLLVFATDDGFHFAGD GKLGAILTPNDGRCHLEDNLYKRSNEFDYPSVGQLAHKLAENNIQ PIFAVTSRMVKTYEKLTEIIPKSAVGELSEDSSNVVQLIKNAYNKLS SRVFLDHNALPDTLKVTYDSFCSNGVTHRNQPRGDCDGVQINVPIT FQVKVTATECIQEQSFVIRALGFTDIVTVQVLPQCECRCRDQSRDR SLCHGKGFLECGICRCDTGYIGKNCECQTQGRSSQELEGSCRKDNN SIICSGLGDCVCGQCLCHTSDVPGKLIYGQYCECDTINCERYNGQV CGGPGRGLCFCGKCRCHPGFEGSACQCERTTEGCLNPRRVECSGR GRCRCNVCECHSGYQLPLCQECPGCPSPCGKYISCAECLKFEKGPF GKNCSAACPGLQLSNNPVKGRTCKERDSEGCWVAYTLEQQDGM DRYLIYVDESRECVAGPNIAAIVGGTVAGIVLIGILLLVIWKALIHLS DLREYRRFEKEKLKSQWNNDNPLFKSATTTVMNPKFAES (SEQ ID NO: 162) 163 TNFRSF10D MGLWGQSVPTASSARAGRYPGARTASGTRPWLLDPKILKFVVFIV AVLLPVRVDSATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRSE YTGACNPCTEGVDYTIASNNLPSCLLCTVCKSGQTNKSSCTTTRDT VCQCEKGSFQDKNSPEMCRTCRTGCPRGMVKVSNCTPRSDIKCKN ESAASSTGKTPAAEETVTTILGMLASPYHYLIIIVVLVIILAVVVVGF SCRKKFISYLKGICSGGGGGPERVHRVLFRRRSCPSRVPGAEDNAR NETLSNRYLQPTQVSEQEIQGQELAELTGVTVELPEEPQRLLEQAE AEGCQRRRLLVPVNDADSADISTLLDASATLEEGHAKETIQDQLV GSEKLFYEEDEAGSATSCL (SEQ ID NO: 163) 164 FPR2 METNFSTPLNEYEEVSYESAGYTVLRILPLVVLGVTFVLGVLGNGL VIWVAGFRMTRTVTTICYLNLALADFSFTATLPFLIVSMAMGEKW PFGWFLCKLIHIVVDINLFGSVFLIGFIALDRCICVLHPVWAQNHRT VSLAMKVIVGPWILALVLTLPVFLFLTTVTIPNGDTYCTFNFASWG 258 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GTPEERLKVAITMLTARGIIRFVIGFSLPMSIVAICYGLIAAKIHKKG MIKSSRPLRVLTAVVASFFICWFPFQLVALLGTVWLKEMLFYGKY KIIDILVNPTSSLAFFNSCLNPMLYVFVGQDFRERLIHSLPTSLERAL SEDSAPTNDTAANSASPPAETELQAM (SEQ ID NO: 164) 165 LIFR MMDIYVCLKRPSWMVDNKRMRTASNFQWLLSTFILLYLMNQVNS QKKGAPHDLKCVTNNLQVWNCSWKAPSGTGRGTDYEVCIENRSR SCYQLEKTSIKIPALSHGDYEITINSLHDFGSSTSKFTLNEQNVSLIPD TPEILNLSADFSTSTLYLKWNDRGSVFPHRSNVIWEIKVLRKESME LVKLVTHNTTLNGKDTLHHWSWASDMPLECAIHFVEIRCYIDNLH FSGLEEWSDWSPVKNISWIPDSQTKVFPQDKVILVGSDITFCCVSQE KVLSALIGHTNCPLIHLDGENVAIKIRNISVSASSGTNVVFTTEDNIF GTVIFAGYPPDTPQQLNCETHDLKEIICSWNPGRVTALVGPRATSY TLVESFSGKYVRLKRAEAPTNESYQLLFQMLPNQEIYNFTLNAHNP LGRSQSTILVNITEKVYPHTPTSFKVKDINSTAVKLSWHLPGNFAKI NFLCEIEIKKSNSVQEQRNVTIKGVENSSYLVALDKLNPYTLYTFRI RCSTETFWKWSKWSNKKQHLTTEASPSKGPDTWREWSSDGKNLII YWKPLPINEANGKILSYNVSCSSDEETQSLSEIPDPQHKAEIRLDKN DYIISVVAKNSVGSSPPSKIASMEIPNDDLKIEQVVGMGKGILLTWH YDPNMTCDYVIKWCNSSRSEPCLMDWRKVPSNSTETVIESDEFRP GIRYNFFLYGCRNQGYQLLRSMIGYIEELAPIVAPNFTVEDTSADSI LVKWEDIPVEELRGFLRGYLFYFGKGERDTSKMRVLESGRSDIKV KNITDISQKTLRIADLQGKTSYHLVLRAYTDGGVGPEKSMYVVTK ENSVGLIIAILIPVAVAVIVGVVTSILCYRKREWIKETFYPDIPNPEN CKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEI ISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVI YIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAA EEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINS RQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 165) 166 AREG MRAPLLPPAPVVLSLLILGSGHYAAGLDLNDTYSGKREPFSGDHSA DGFEVTSRSEMSSGSEISPVSEMPSSSEPSSGADYDYSEEYDNEPQIP GYIVDDSVRVEQVVKPPQNKTESENTSDKPKRKKKGGKNGKNRR NRKKKNPCNAEFQNFCIHGECKYIEHLEAVTCKCQQEYFGERCGE KSMKTHSMIDSSLSKIALAAIAAFMSAVILTAVAVITVQLRRQYVR KYEGEAEERKKLRQENGNVHAIA (SEQ ID NO: 166) 167 CD46 MEPPGRRECPFPSWRFPGLLLAAMVLLLYSFSDACEEPPTFEAMEL IGKPKPYYEIGERVDYKCKKGYFYIPPLATHTICDRNHTWLPVSDD ACYRETCPYIRDPLNGQAVPANGTYEFGYQMHFICNEGYYLIGEEI LYCELKGSVAIWSGKPPICEKVLCTPPPKIKNGKHTFSEVEVFEYLD AVTYSCDPAPGPDPFSLIGESTIYCGDNSVWSRAAPECKVVKCRFP VVENGKQISGFGKKFYYKATVMFECDKGFYLDGSDTIVCDSNSTW DPPVPKCLKVLPPSSTKPPALSHSVSTSSTTKSPASSASGPRPTYKPP VSNYPGYPKPEEGILDSLDVWVIAVIVIAIVVGVAVICVVPYRYLQ RRKKKGTYLTDETHREVKFTSL (SEQ ID NO: 167) 168 HBEGF MKLLPSVVLKLFLAAVLSALVTGESLERLRRGLAAGTSNPDPPTVS TDQLLPLGGGRDRKVRDLQEADLDLLRVTLSSKPQALATPNKEEH GKRKKKGKGLGKKRDPCLRKYKDFCIHGECKYVKELRAPSCICHP GYHGERCHGLSLPVENRLYTYDHTTILAVVAVVLSSVCLLVIVGLL 259 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: MFRYHRRGGYDVENEEKVKLGMTNSH (SEQ ID NO: 168) 169 HLA-DRB1 MVCLKLPGGSCMTALTVTLMVLSSPLALSGDTRPRFLWQPKRECH FFNGTERVRFLDRYFYNQEESVRFDSDVGEFRAVTELGRPDAEYW NSQKDILEQARAAVDTYCRHNYGVVESFTVQRRVQPKVTVYPSKT QPLQHHNLLVCSVSGFYPGSIEVRWFLNGQEEKAGMVSTGLIQNG DWTFQTLVMLETVPRSGEVYTCQVEHPSVTSPLTVEWRARSESAQ SKMLSGVGGFVLGLLFLGAGLFIYFRNQKGHSGLQPTGFLS (SEQ ID NO: 169) 170 IL10 MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLR DAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFY LEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENK SKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO: 170) 171 SELL MIFPWKCQSTQRDLWNIFKLWGWTMLCCDFLAHHGTDCWTYHY SEKPMNWQRARRFCRDNYTDLVAIQNKAEIEYLEKTLPFSRSYYW IGIRKIGGIWTWVGTNKSLTEEAENWGDGEPNNKKNKEDCVEIYIK RNKDAGKWNDDACHKLKAALCYTASCQPWSCSGHGECVEIINNY TCNCDVGYYGPQCQFVIQCEPLEAPELGTMDCTHPLGNFSFSSQCA FSCSEGTNLTGIEETTCGPFGNWSSPEPTCQVIQCEPLSAPDLGIMN CSHPLASFSFTSACTFICSEGTELIGKKKTICESSGIWSNPSPICQKLD KSFSMIKEGDYNPLFIPVAVMVTAFSGLAFIIWLARRLKKGKKSKR SMNDPY (SEQ ID NO: 171) 172 TNFSF13B MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGK LLAATLLLALLSCCLTVVSFYQVAALQGDLASLRAELQGHHAEKL PAGAGAPKAGLEEAPAVTAGLKIFEPPAPGEGNSSQNSRNKRAVQ GPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSALEEKEN KILVKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVT LFRCIQNMPETLPNNSCYSAGIAKLEEGDELQLAIPRENAQISLDGD VTFFGALKLL (SEQ ID NO: 172) 173 BMP7 MHVRSLRAAAPHSFVALWAPLFLLRSALADFSLDNEVHSSFIHRRL RSQERREMQREILSILGLPHRPRPHLQGKHNSAPMFMLDLYNAMA VEEGGGPGGQGFSYPYKAVFSTQGPPLASLQDSHFLTDADMVMSF VNLVEHDKEFFHPRYHHREFRFDLSKIPEGEAVTAAEFRIYKDYIRE RFDNETFRISVYQVLQEHLGRESDLFLLDSRTLWASEEGWLVFDIT ATSNHWVVNPRHNLGLQLSVETLDGQSINPKLAGLIGRHGPQNKQ PFMVAFFKATEVHFRSIRSTGSKQRSQNRSKTPKNQEALRMANVA ENSSSDQRQACKKHELYVSFRDLGWQDWIIAPEGYAAYYCEGEC AFPLNSYMNATNHAIVQTLVHFINPETVPKPCCAPTQLNAISVLYF DDSSNVILKKYRNMVVRACGCH (SEQ ID NO: 173) 174 COL18A1 MAPYPCGCHILLLLFCCLAAARANLLNLNWLWFNNEDTSHAATTI PEPQGPLPVQPTADTTTHVTPRNGSTEPATAPGSPEPPSELLEDGQD TPTSAESPDAPEENIAGVGAEILNVAKGIRSFVQLWNDTVPTESLAR AETLVLETPVGPLALAGPSSTPQENGTTLWPSRGIPSSPGAHTTEAG TLPAPTPSPPSLGRPWAPLTGPSVPPPSSGRASLSSLLGGAPPWGSL QDPDSQGLSPAAAAPSQQLQRPDVRLRTPLLHPLVMGSLGKHAAP SAFSSGLPGALSQVAVTTLTRDSGAWVSHVANSVGPGLANNSALL GADPEAPAGRCLPLPPSLPVCGHLGISRFWLPNHLHHESGEQVRAG 260 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: ARAWGGLLQTHCHPFLAWFFCLLLVPPCGSVPPPAPPPCCQFCEAL QDACWSRLGGGRLPVACASLPTQEDGYCVLIGPAAERISEEVGLL QLLGDPPPQQVTQTDDPDVGLAYVFGPDANSGQVARYHFPSLFFR DFSLLFHIRPATEGPGVLFAITDSAQAMVLLGVKLSGVQDGHQDIS LLYTEPGAGQTHTAASFRLPAFVGQWTHLALSVAGGFVALYVDC EEFQRMPLARSSRGLELEPGAGLFVAQAGGADPDKFQGVIAELKV RRDPQVSPMHCLDEEGDDSDGASGDSGSGLGDARELLREETGAAL KPRLPAPPPVTTPPLAGGSSTEDSRSEEVEEQTTVASLGAQTLPGSD SVSTWDGSVRTPGGRVKEGGLKGQKGEPGVPGPPGRAGPPGSPCL PGPPGLPCPVSPLGPAGPALQTVPGPQGPPGPPGRDGTPGRDGEPG DPGEDGKPGDTGPQGFPGTPGDVGPKGDKGDPGVGERGPPGPQGP PGPPGPSFRHDKLTFIDMEGSGFGGDLEALRGPRGFPGPPGPPGVPG LPGEPGRFGVNSSDVPGPAGLPGVPGREGPPGFPGLPGPPGPPGRE GPPGRTGQKGSLGEAGAPGHKGSKGAPGPAGARGESGLAGAPGP AGPPGPPGPPGPPGPGLPAGFDDMEGSGGPFWSTARSADGPQGPPG LPGLKGDPGVPGLPGAKGEVGADGVPGFPGLPGREGIAGPQGPKG DRGSRGEKGDPGKDGVGQPGLPGPPGPPGPVVYVSEQDGSVLSVP GPEGRPGFAGFPGPAGPKGNLGSKGERGSPGPKGEKGEPGSIFSPD GGALGPAQKGAKGEPGFRGPPGPYGRPGYKGEIGFPGRPGRPGMN GLKGEKGEPGDASLGFGMRGMPGPPGPPGPPGPPGTPVYDSNVFA ESSRPGPPGLPGNQGPPGPKGAKGEVGPPGPPGQFPFDFLQLEAEM KGEKGDRGDAGQKGERGEPGGGGFFGSSLPGPPGPPGPPGPRGYP GIPGPKGESIRGQPGPPGPQGPPGIGYEGRQGPPGPPGPPGPPSFPGP HRQTISVPGPPGPPGPPGPPGTMGASSGVRLWATRQAMLGQVHEV PEGWLIFVAEQEELYVRVQNGFRKVQLEARTPLPRGTDNEVAALQ PPVVQLHDSNPYPRREHPHPTARPWRADDILASPPRLPEPQPYPGA PHHSSYVHLRPARPTSPPAHSHRDFQPVLHLVALNSPLSGGMRGIR GADFQCFQQARAVGLAGTFRAFLSSRLQDLYSIVRRADRAAVPIV NLKDELLFPSWEALFSGSEGPLKPGARIFSFDGKDVLRHPTWPQKS VWHGSDPNGRRLTESYCETWRTEAPSATGQASSLLGGRLLGQSAA SCHHAYIVLCIENSFMTASK (SEQ ID NO: 174) 175 CSF1 MTAPGAAGRCPPTTWLGSLLLLVCLLASRSITEEVSEYCSHMIGSG HLQSLQRLIDSQMETSCQITFEFVDQEQLKDPVCYLKKAFLLVQDI MEDTMRFRDNTPNAIAIVQLQELSLRLKSCFTKDYEEHDKACVRT FYETPLQLLEKVKNVFNETKNLLDKDWNIFSKNCNNSFAECSSQD VVTKPDCNCLYPKAIPSSDPASVSPHQPLAPSMAPVAGLTWEDSEG TEGSSLLPGEQPLHTVDPGSAKQRPPRSTCQSFEPPETPVVKDSTIG GSPQPRPSVGAFNPGMEDILDSAMGTNWVPEEASGEASEIPVPQGT ELSPSRPGGGSMQTEPARPSNFLSASSPLPASAKGQQPADVTGTAL PRVGPVRPTGQDWNHTPQKTDHPSALLRDPPEPGSPRISSLRPQGL SNPSTLSAQPQLSRSHSSGSVLPLGELEGRRSTRDRRSPAEPEGGPA SEGAARPLPRFNSVPLTDTGHERQSEGSFSPQLQESVFHLLVPSVIL VLLAVGGLLFYRWRRRSHQEPQRADSPLEQPEGSPLTQDDRQVEL PV (SEQ ID NO: 175) 176 CSF3 MAGPATQSPMKLMALQLLLWHSALWTVQEATPLGPASSLPQSFLL KCLEQVRKIQGDGAALQEKLVSECATYKLCHPEELVLLGHSLGIP WAPLSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTL 261 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: DTLQLDVADFATTIWQQMEELGMAPALQPTQGAMPAFASAFQRR AGGVLVASHLQSFLEVSYRVLRHLAQP (SEQ ID NO: 176) 177 CTGF MTAASMGPVRVAFVVLLALCSRPAVGQNCSGPCRCPDEPAPRCPA GVSLVLDGCGCCRVCAKQLGELCTERDPCDPHKGLFCHFGSPANR KIGVCTAKDGAPCIFGGTVYRSGESFQSSCKYQCTCLDGAVGCMP LCSMDVRLPSPDCPFPRRVKLPGKCCEEWVCDEPKDQTVVGPALA AYRLEDTFGPDPTMIRANCLVQTTEWSACSKTCGMGISTRVTNDN ASCRLEKQSRLCMVRPCEADLEENIKKGKKCIRTPKISKPIKFELSG CTSMKTYRAKFCGVCTDGRCCTPHRTTTLPVEFKCPDGEVMKKN MMFIKTCACHYNCPGDNDIFESLYYRKMYGDMA (SEQ ID NO: 177) 178 FGF2 MVGVGGGDVEDVTPRPGGCQISGRGARGCNGIPGAAAWEAALPR RRPRRHPSVNPRSRAAGSPRTRGRRTEERPSGSRLGDRGRGRALPG GRLGGRGRGRAPERVGGRGRGRGTAAPRAAPAARGSRPGPAGTM AAGSITTLPALPEDGGSGAFPPGHFKDPKRLYCKNGGFFLRIHPDG RVDGVREKSDPHIKLQLQAEERGVVSIKGVCANRYLAMKEDGRLL ASKCVTDECFFFERLESNNYNTYRSRKYTSWYVALKRTGQYKLGS KTGPGQKAILFLPMSAKS (SEQ ID NO: 178) 179 HSPG2 MGWRAAGALLLALLLHGRLLAVTHGLRAYDGLSLPEDIETVTASQ MRWTHSYLSDDEDMLADSISGDDLGSGDLGSGDFQMVYFRALVN FTRSIEYSPQLEDAGSREFREVSEAVVDTLESEYLKIPGDQVVSVVF IKELDGWVFVELDVGSEGNADGAQIQEMLLRVISSGSVASYVTSPQ GFQFRRLGTVPQFPRACTEAEFACHSYNECVALEYRCDRRPDCRD MSDELNCEEPVLGISPTFSLLVETTSLPPRPETTIMRQPPVTHAPQPL LPGSVRPLPCGPQEAACRNGHCIPRDYLCDGQEDCEDGSDELDCG PPPPCEPNEFPCGNGHCALKLWRCDGDFDCEDRTDEANCPTKRPE EVCGPTQFRCVSTNMCIPASFHCDEESDCPDRSDEFGCMPPQVVTP PRESIQASRGQTVTFTCVAIGVPTPIINWRLNWGHIPSHPRVTVTSE GGRGTLIIRDVKESDQGAYTCEAMNARGMVFGIPDGVLELVPQRG PCPDGHFYLEHSAACLPCFCFGITSVCQSTRRFRDQIRLRFDQPDDF KGVNVTMPAQPGTPPLSSTQLQIDPSLHEFQLVDLSRRFLVHDSFW ALPEQFLGNKVDSYGGSLRYNVRYELARGMLEPVQRPDVVLMGA GYRLLSRGHTPTQPGALNQRQVQFSEEHWVHESGRPVQRAELLQV LQSLEAVLIQTVYNTKMASVGLSDIAMDTTVTHATSHGRAHSVEE CRCPIGYSGLSCESCDAHFTRVPGGPYLGTCSGCNCNGHASSCDPV YGHCLNCQHNTEGPQCNKCKAGFFGDAMKATATSCRPCPCPYID ASRRFSDTCFLDTDGQATCDACAPGYTGRRCESCAPGYEGNPIQPG GKCRPVNQEIVRCDERGSMGTSGEACRCKNNVVGRLCNECADGS FHLSTRNPDGCLKCFCMGVSRHCTSSSWSRAQLHGASEEPGHFSLT NAASTHTTNEGIFSPTPGELGFSSFHRLLSGPYFWSLPSRFLGDKVT SYGGELRFTVTQRSQPGSTPLHGQPLVVLQGNNIILEHHVAQEPSP GQPSTFIVPFREQAWQRPDGQPATREHLLMALAGIDTLLIRASYAQ QPAESRVSGISMDVAVPEETGQDPALEVEQCSCPPGYRGPSCQDCD TGYTRTPSGLYLGTCERCSCHGHSEACEPETGACQGCQHHTEGPR CEQCQPGYYGDAQRGTPQDCQLCPCYGDPAAGQAAHTCFLDTDG HPTCDACSPGHSGRHCERCAPGYYGNPSQGQPCQRDSQVPGPIGC NCDPQGSVSSQCDAAGQCQCKAQVEGLTCSHCRPHHFHLSASNPD 262 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GCLPCFCMGITQQCASSAYTRHLISTHFAPGDFQGFALVNPQRNSR LTGEFTVEPVPEGAQLSFGNFAQLGHESFYWQLPETYQGDKVAAY GGKLRYTLSYTAGPQGSPLSDPDVQITGNNIMLVASQPALQGPERR SYEIMFREEFWRRPDGQPATREHLLMALADLDELLIRATFSSVPLA ASISAVSLEVAQPGPSNRPRALEVEECRCPPGYIGLSCQDCAPGYTR TGSGLYLGHCELCECNGHSDLCHPETGACSQCQHNAAGEFCELCA PGYYGDATAGTPEDCQPCACPLTNPENMFSRTCESLGAGGYRCTA CEPGYTGQYCEQCGPGYVGNPSVQGGQCLPETNQAPLVVEVHPA RSIVPQGGSHSLRCQVSGSPPHYFYWSREDGRPVPSGTQQRHQGSE LHFPSVQPSDAGVYICTCRNLHQSNTSRAELLVTEAPSKPITVTVEE QRSQSVRPGADVTFICTAKSKSPAYTLVWTRLHNGKLPTRAMDFN GILTIRNVQLSDAGTYVCTGSNMFAMDQGTATLHVQASGTLSAPV VSIHPPQLTVQPGQLAEFRCSATGSPTPTLEWTGGPGGQLPAKAQI HGGILRLPAVEPTDQAQYLCRAHSSAGQQVARAVLHVHGGGGPR VQVSPERTQVHAGRTVRLYCRAAGVPSATITWRKEGGSLPPQARS ERTDIATLLIPAITTADAGFYLCVATSPAGTAQARIQVVVLSASDAS PPPVKIESSSPSVTEGQTLDLNCVVAGSAHAQVTWYRRGGSLPPHT QVHGSRLRLPQVSPADSGEYVCRVENGSGPKEASITVSVLHGTHSG PSYTPVPGSTRPIRIEPSSSHVAEGQTLDLNCVVPGQAHAQVTWHK RGGSLPARHQTHGSLLRLHQVTPADSGEYVCHVVGTSGPLEASVL VTIEASVIPGPIPPVRIESSSSTVAEGQTLDLSCVVAGQAHAQVTWY KRGGSLPARHQVRGSRLYIFQASPADAGQYVCRASNGMEASITVT VTGTQGANLAYPAGSTQPIRIEPSSSQVAEGQTLDLNCVVPGQSHA QVTWHKRGGSLPVRHQTHGSLLRLYQASPADSGEYVCRVLGSSVP LEASVLVTIEPAGSVPALGVTPTVRIESSSSQVAEGQTLDLNCLVAG QAHAQVTWHKRGGSLPARHQVHGSRLRLLQVTPADSGEYVCRVV GSSGTQEASVLVTIQQRLSGSHSQGVAYPVRIESSSASLANGHTLD LNCLVASQAPHTITWYKRGGSLPSRHQIVGSRLRIPQVTPADSGEY VCHVSNGAGSRETSLIVTIQGSGSSHVPSVSPPIRIESSSPTVVEGQT LDLNCVVARQPQAIITWYKRGGSLPSRHQTHGSHLRLHQMSVADS GEYVCRANNNIDALEASIVISVSPSAGSPSAPGSSMPIRIESSSSHVA EGETLDLNCVVPGQAHAQVTWHKRGGSLPSHHQTRGSRLRLHHV SPADSGEYVCRVMGSSGPLEASVLVTIEASGSSAVHVPAPGGAPPI RIEPSSSRVAEGQTLDLKCVVPGQAHAQVTWHKRGGNLPARHQV HGPLLRLNQVSPADSGEYSCQVTGSSGTLEASVLVTIEPSSPGPIPAP GLAQPIYIEASSSHVTEGQTLDLNCVVPGQAHAQVTWYKRGGSLP ARHQTHGSQLRLHLVSPADSGEYVCRAASGPGPEQEASFTVTVPPS EGSSYRLRSPVISIDPPSSTVQQGQDASFKCLIHDGAAPISLEWKTR NQELEDNVHISPNGSIITIVGTRPSNHGTYRCVASNAYGVAQSVVN LSVHGPPTVSVLPEGPVWVKVGKAVTLECVSAGEPRSSARWTRISS TPAKLEQRTYGLMDSHAVLQISSAKPSDAGTYVCLAQNALGTAQK QVEVIVDTGAMAPGAPQVQAEEAELTVEAGHTATLRCSATGSPAP TIHWSKLRSPLPWQHRLEGDTLIIPRVAQQDSGQYICNATSPAGHA EATIILHVESPPYATTVPEHASVQAGETVQLQCLAHGTPPLTFQWS RVGSSLPGRATARNELLHFERAAPEDSGRYRCRVTNKVGSAEAFA QLLVQGPPGSLPATSIPAGSTPTVQVTPQLETKSIGASVEFHCAVPS DRGTQLRWFKEGGQLPPGHSVQDGVLRIQNLDQSCQGTYICQAHG 263 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: PWGKAQASAQLVIQALPSVLINIRTSVQTVVVGHAVEFECLALGDP KPQVTWSKVGGHLRPGIVQSGGVVRIAHVELADAGQYRCTATNA AGTTQSHVLLLVQALPQISMPQEVRVPAGSAAVFPCIASGYPTPDIS WSKLDGSLPPDSRLENNMLMLPSVRPQDAGTYVCTATNRQGKVK AFAHLQVPERVVPYFTQTPYSFLPLPTIKDAYRKFEIKITFRPDSAD GMLLYNGQKRVPGSPTNLANRQPDFISFGLVGGRPEFRFDAGSGM ATIRHPTPLALGHFHTVTLLRSLTQGSLIVGDLAPVNGTSQGKFQG LDLNEELYLGGYPDYGAIPKAGLSSGFIGCVRELRIQGEEIVFHDLN LTAHGISHCPTCRDRPCQNGGQCHDSESSSYVCVCPAGFTGSRCEH SQALHCHPEACGPDATCVNRPDGRGYTCRCHLGRSGLRCEEGVTV TTPSLSGAGSYLALPALTNTHHELRLDVEFKPLAPDGVLLFSGGKS GPVEDFVSLAMVGGHLEFRYELGSGLAVLRSAEPLALGRWHRVS AERLNKDGSLRVNGGRPVLRSSPGKSQGLNLHTLLYLGGVEPSVP LSPATNMSAHFRGCVGEVSVNGKRLDLTYSFLGSQGIGQCYDSSP CERQPCQHGATCMPAGEYEFQCLCRDGFKGDLCEHEENPCQLREP CLHGGTCQGTRCLCLPGFSGPRCQQGSGHGIAESDWHLEGSGGND APGQYGAYFHDDGFLAFPGHVFSRSLPEVPETIELEVRTSTASGLLL WQGVEVGEAGQGKDFISLGLQDGHLVFRYQLGSGEARLVSEDPIN DGEWHRVTALREGRRGSIQVDGEELVSGRSPGPNVAVNAKGSVYI GGAPDVATLTGGRFSSGITGCVKNLVLHSARPGAPPPQPLDLQHRA QAGANTRPCPS (SEQ ID NO: 179) 180 LAMA2 MPGAAGVLLLLLLSGGLGGVQAQRPQQQRQSQAHQQRGLFPAVL NLASNALITTNATCGEKGPEMYCKLVEHVPGQPVRNPQCRICNQN SSNPNQRHPITNAIDGKNTWWQSPSIKNGIEYHYVTITLDLQQVFQI AYVIVKAANSPRPGNWILERSLDDVEYKPWQYHAVTDTECLTLYN IYPRTGPPSYAKDDEVICTSFYSKIHPLENGEIHISLINGRPSADDPSP ELLEFTSARYIRLRFQRIRTLNADLMMFAHKDPREIDPIVTRRYYYS VKDISVGGMCICYGHARACPLDPATNKSRCECEHNTCGDSCDQCC PGFHQKPWRAGTFLTKTECEACNCHGKAEECYYDENVARRNLSL NIRGKYIGGGVCINCTQNTAGINCETCTDGFFRPKGVSPNYPRPCQP CHCDPIGSLNEVCVKDEKHARRGLAPGSCHCKTGFGGVSCDRCAR GYTGYPDCKACNCSGLGSKNEDPCFGPCICKENVEGGDCSRCKSG FFNLQEDNWKGCDECFCSGVSNRCQSSYWTYGKIQDMSGWYLTD LPGRIRVAPQQDDLDSPQQISISNAEARQALPHSYYWSAPAPYLGN KLPAVGGQLTFTISYDLEEEEEDTERVLQLMIILEGNDLSISTAQDE VYLHPSEEHTNVLLLKEESFTIHGTHFPVRRKEFMTVLANLKRVLL QITYSFGMDAIFRLSSVNLESAVSYPTDGSIAAAVEVCQCPPGYTGS SCESCWPRHRRVNGTIFGGICEPCQCFGHAESCDDVTGECLNCKD HTGGPYCDKCLPGFYGEPTKGTSEDCQPCACPLNIPSNNFSPTCHL DRSLGLICDGCPVGYTGPRCERCAEGYFGQPSVPGGSCQPCQCND NLDFSIPGSCDSLSGSCLICKPGTTGRYCELCADGYFGDAVDAKNC QPCRCNAGGSFSEVCHSQTGQCECRANVQGQRCDKCKAGTFGLQ SARGCVPCNCNSFGSKSFDCEESGQCWCQPGVTGKKCDRCAHGY FNFQEGGCTACECSHLGNNCDPKTGRCICPPNTIGEKCSKCAPNTW GHSITTGCKACNCSTVGSLDFQCNVNTGQCNCHPKFSGAKCTECS RGHWNYPRCNLCDCFLPGTDATTCDSETKKCSCSDQTGQCTCKV NVEGIHCDRCRPGKFGLDAKNPLGCSSCYCFGTTTQCSEAKGLIRT 264 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: WVTLKAEQTILPLVDEALQHTTTKGIVFQHPEIVAHMDLMREDLH LEPFYWKLPEQFEGKKLMAYGGKLKYAIYFEAREETGFSTYNPQV IIRGGTPTHARIIVRHMAAPLIGQLTRHEIEMTEKEWKYYGDDPRV HRTVTREDFLDILYDIHYILIKATYGNFMRQSRISEISMEVAEQGRG TTMTPPADLIEKCDCPLGYSGLSCEACLPGFYRLRSQPGGRTPGPTL GTCVPCQCNGHSSLCDPETSICQNCQHHTAGDFCERCALGYYGIV KGLPNDCQQCACPLISSSNNFSPSCVAEGLDDYRCTACPRGYEGQY CERCAPGYTGSPGNPGGSCQECECDPYGSLPVPCDPVTGFCTCRPG ATGRKCDGCKHWHAREGWECVFCGDECTGLLLGDLARLEQMVM SINLTGPLPAPYKMLYGLENMTQELKHLLSPQRAPERLIQLAEGNL NTLVTEMNELLTRATKVTADGEQTGQDAERTNTRAKSLGEFIKEL ARDAEAVNEKAIKLNETLGTRDEAFERNLEGLQKEIDQMIKELRRK NLETQKEIAEDELVAAEALLKKVKKLFGESRGENEEMEKDLREKL ADYKNKVDDAWDLLREATDKIREANRLFAVNQKNMTALEKKKE AVESGKRQIENTLKEGNDILDEANRLADEINSIIDYVEDIQTKLPPM SEELNDKIDDLSQEIKDRKLAEKVSQAESHAAQLNDSSAVLDGILD EAKNISFNATAAFKAYSNIKDYIDEAEKVAKEAKDLAHEATKLAT GPRGLLKEDAKGCLQKSFRILNEAKKLANDVKENEDHLNGLKTRI ENADARNGDLLRTLNDTLGKLSAIPNDTAAKLQAVKDKARQAND TAKDVLAQITELHQNLDGLKKNYNKLADSVAKTNAVVKDPSKNK IIADADATVKNLEQEADRLIDKLKPIKELEDNLKKNISEIKELINQAR KQANSIKVSVSSGGDCIRTYKPEIKKGSYNNIVVNVKTAVADNLLF YLGSAKFIDFLAIEMRKGKVSFLWDVGSGVGRVEYPDLTIDDSYW YRIVASRTGRNGTISVRALDGPKASIVPSTHHSTSPPGYTILDVDAN AMLFVGGLTGKLKKADAVRVITFTGCMGETYFDNKPIGLWNFRE KEGDCKGCTVSPQVEDSEGTIQFDGEGYALVSRPIRWYPNISTVMF KFRTFSSSALLMYLATRDLRDFMSVELTDGHIKVSYDLGSGMASV VSNQNHNDGKWKSFTLSRIQKQANISIVDIDTNQEENIATSSSGNNF GLDLKADDKIYFGGLPTLRNLSMKARPEVNLKKYSGCLKDIEISRT PYNILSSPDYVGVTKGCSLENVYTVSFPKPGFVELSPVPIDVGTEIN LSFSTKNESGIILLGSGGTPAPPRRKRRQTGQAYYAILLNRGRLEVH LSTGARTMRKIVIRPEPNLFHDGREHSVHVERTRGIFTVQVDENRR YMQNLTVEQPIEVKKLFVGGAPPEFQPSPLRNIPPFEGCIWNLVINS VPMDFARPVSFKNADIGRCAHQKLREDEDGAAPAEIVIQPEPVPTP AFPTPTPVLTHGPCAAESEPALLIGSKQFGLSRNSHIAIAFDDTKVK NRLTIELEVRTEAESGLLFYMARINHADFATVQLRNGLPYFSYDLG SGDTHTMIPTKINDGQWHKIKIMRSKQEGILYVDGASNRTISPKKA DILDVVGMLYVGGLPINYTTRRIGPVTYSIDGCVRNLHMAEAPAD LEQPTSSFHVGTCFANAQRGTYFDGTGFAKAVGGFKVGLDLLVEF EFRTTTTTGVLLGISSQKMDGMGIEMIDEKLMFHVDNGAGRFTAV YDAGVPGHLCDGQWHKVTANKIKHRIELTVDGNQVEAQSPNPAS TSADTNDPVFVGGFPDDLKQFGLTTSIPFRGCIRSLKLTKGTGKPLE VNFAKALELRGVQPVSCPAN (SEQ ID NO: 180) 181 LAMB2 MELTSRERGRGQPLPWELRLGLLLSVLAATLAQAPAPDVPGCSRG SCYPATGDLLVGRADRLTASSTCGLNGPQPYCIVSHLQDEKKCFLC DSRRPFSARDNPHSHRIQNVVTSFAPQRRAAWWQSENGIPAVTIQL DLEAEFHFTHLIMTFKTFRPAAMLVERSADFGRTWHVYRYFSYDC 265 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GADFPGVPLAPPRHWDDVVCESRYSEIEPSTEGEVIYRVLDPAIPIP DPYSSRIQNLLKITNLRVNLTRLHTLGDNLLDPRREIREKYYYALY ELVVRGNCFCYGHASECAPAPGAPAHAEGMVHGACICKHNTRGL NCEQCQDFYRDLPWRPAEDGHSHACRKCECHGHTHSCHFDMAV YLASGNVSGGVCDGCQHNTAGRHCELCRPFFYRDPTKDLRDPAV CRSCDCDPMGSQDGGRCDSHDDPALGLVSGQCRCKEHVVGTRCQ QCRDGFFGLSISDRLGCRRCQCNARGTVPGSTPCDPNSGSCYCKRL VTGRGCDRCLPGHWGLSHDLLGCRPCDCDVGGALDPQCDEGTGQ CHCRQHMVGRRCEQVQPGYFRPFLDHLIWEAEDTRGQVLDVVER LVTPGETPSWTGSGFVRLQEGQTLEFLVASVPKAMDYDLLLRLEP QVPEQWAELELIVQRPGPVPAHSLCGHLVPKDDRIQGTLQPHARY LIFPNPVCLEPGISYKLHLKLVRTGGSAQPETPYSGPGLLIDSLVLLP RVLVLEMFSGGDAAALERQATFERYQCHEEGLVPSKTSPSEACAP LLISLSTLIYNGALPCQCNPQGSLSSECNPHGGQCLCKPGVVGRRC DLCAPGYYGFGPTGCQACQCSHEGALSSLCEKTSGQCLCRTGAFG LRCDRCQRGQWGFPSCRPCVCNGHADECNTHTGACLGCRDHTGG EHCERCIAGFHGDPRLPYGGQCRPCPCPEGPGSQRHFATSCHQDEY SQQIVCHCRAGYTGLRCEACAPGHFGDPSRPGGRCQLCECSGNIDP MDPDACDPHTGQCLRCLHHTEGPHCAHCKPGFHGQAARQSCHRC TCNLLGTNPQQCPSPDQCHCDPSSGQCPCLPNVQGPSCDRCAPNF WNLTSGHGCQPCACHPSRARGPTCNEFTGQCHCRAGFGGRTCSEC QELHWGDPGLQCHACDCDSRGIDTPQCHRFTGHCSCRPGVSGVRC DQCARGFSGIFPACHPCHACFGDWDRVVQDLAARTQRLEQRAQE LQQTGVLGAFESSFWHMQEKLGIVQGIVGARNTSAASTAQLVEAT EELRREIGEATEHLTQLEADLTDVQDENFNANHALSGLERDRLAL NLTLRQLDQHLDLLKHSNFLGAYDSIRHAHSQSAEAERRANTSAL AVPSPVSNSASARHRTEALMDAQKEDFNSKHMANQRALGKLSAH THTLSLTDINELVCGAPGDAPCATSPCGGAGCRDEDGQPRCGGLS CNGAAATADLALGRARHTQAELQRALAEGGSILSRVAETRRQASE AQQRAQAALDKANASRGQVEQANQELQELIQSVKDFLNQEGADP DSIEMVATRVLELSIPASAEQIQHLAGAIAERVRSLADVDAILARTV GDVRRAEQLLQDARRARSWAEDEKQKAETVQAALEEAQRAQGIA QGAIRGAVADTRDTEQTLYQVQERMAGAERALSSAGERARQLDA LLEALKLKRAGNSLAASTAEETAGSAQGRAQEAEQLLRGPLGDQY QTVKALAERKAQGVLAAQARAEQLRDEARDLLQAAQDKLQRLQ ELEGTYEENERALESKAAQLDGLEARMRSVLQAINLQVQIYNTCQ (SEQ ID NO: 181) 182 MIF MPMFIVNTNVPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPD QLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLAERLRISP DRVYINYYDMNAANVGWNNSTFA (SEQ ID NO: 182) 183 NAMPT MNPAAEAEFNILLATDSYKVTHYKQYPPNTSKVYSYFECREKKTE NSKLRKVKYEETVFYGLQYILNKYLKGKVVTKEKIQEAKDVYKEH FQDDVFNEKGWNYILEKYDGHLPIEIKAVPEGFVIPRGNVLFTVEN TDPECYWLTNWIETILVQSWYPITVATNSREQKKILAKYLLETSGN LDGLEYKLHDFGYRGVSSQETAGIGASAHLVNFKGTDTVAGLALI KKYYGTKDPVPGYSVPAAEHSTITAWGKDHEKDAFEHIVTQFSSV PVSVVSDSYDIYNACEKIWGEDLRHLIVSRSTQAPLIIRPDSGNPLD 266 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: TVLKVLEILGKKFPVTENSKGYKLLPPYLRVIQGDGVDINTLQEIVE GMKQKMWSIENIAFGSGGGLLQKLTRDLLNCSFKCSYVVTNGLGI NVFKDPVADPNKRSKKGRLSLHRTPAGNFVTLEEGKGDLEEYGQD LLHTVFKNGKVTKSYSFDEIRKNAQLNIELEAAHH (SEQ ID NO: 183) 184 NRG1 MSERKEGRGKGKGKKKERGSGKKPESAAGSQSPALPPRLKEMKS QESAAGSKLVLRCETSSEYSSLRFKWFKNGNELNRKNKPQNIKIQK KPGKSELRINKASLADSGEYMCKVISKLGNDSASANITIVESNEIITG MPASTEGAYVSSESPIRISVSTEGANTSSSTSTSTTGTSHLVKCAEKE KTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARCTENVPMKVQ NQEKAEELYQKRVLTITGICIALLVVGIMCVVAYCKTKKQRKKLH DRLRQSLRSERNNMMNIANGPHHPNPPPENVQLVNQYVSKNVISS EHIVEREAETSFSTSHYTSTAHHSTTVTQTPSHSWSNGHTESILSES HSVIVMSSVENSRHSSPTGGPRGRLNGTGGPRECNSFLRHARETPD SYRDSPHSERYVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSM TVSMPSMAVSPFMEEERPLLLVTPPRLREKKFDHHPQQFSSFHHNP AHDSNSLPASPLRIVEDEEYETTQEYEPAQEPVKKLANSRRAKRTK PNGHIANRLEVDSNTSSQSSNSESETEDERVGEDTPFLGIQNPLAAS LEATPAFRLADSRTNPAGRFSTQEEIQARLSSVIANQDPIAV (SEQ ID NO: 184) 185 TNC MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEE NQPVVFNHVYNIKLPVGSQCSVDLESASGEKDLAPPSEPSESFQEH TVDGENQIVFTHRINIPRRACGCAAAPDVKELLSRLEELENLVSSLR EQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVCEPGWKG PNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQ GKCVNGVCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDG FAGDDCNKPLCLNNCYNRGRCVENECVCDEGFTGEDCSELICPND CFDRGRCINGTCYCEEGFTGEDCGKPTCPHACHTQGRCEEGQCVC DEGFAGVDCSEKRCPADCHNRGRCVDGRCECDDGFTGADCGELK CPNGCSGHGRCVNGQCVCDEGYTGEDCSQLRCPNDCHSRGRCVE GKCVCEQGFKGYDCSDMSCPNDCHQHGRCVNGMCVCDDGYTGE DCRDRQCPRDCSNRGLCVDGQCVCEDGFTGPDCAELSCPNDCHG QGRCVNGQCVCHEGFMGKDCKEQRCPSDCHGQGRCVDGQCICHE GFTGLDCGQHSCPSDCNNLGQCVSGRCICNEGYSGEDCSEVSPPKD LVVTEVTEETVNLAWDNEMRVTEYLVVYTPTHEGGLEMQFRVPG DQTSTIIQELEPGVEYFIRVFAILENKKSIPVSARVATYLPAPEGLKF KSIKETSVEVEWDPLDIAFETWEIIFRNMNKEDEGEITKSLRRPETS YRQTGLAPGQEYEISLHIVKNNTRGPGLKRVTTTRLDAPSQIEVKD VTDTTALITWFKPLAEIDGIELTYGIKDVPGDRTTIDLTEDENQYSIG NLKPDTEYEVSLISRRGDMSSNPAKETFTTGLDAPRNLRRVSQTDN SITLEWRNGKAAIDSYRIKYAPISGGDHAEVDVPKSQQATTKTTLT GLRPGTEYGIGVSAVKEDKESNPATINAATELDTPKDLQVSETAET SLTLLWKTPLAKFDRYRLNYSLPTGQWVGVQLPRNTTSYVLRGLE PGQEYNVLLTAEKGRHKSKPARVKASTEQAPELENLTVTEVGWD GLRLNWTAADQAYEHFIIQVQEANKVEAARNLTVPGSLRAVDIPG LKAATPYTVSIYGVIQGYRTPVLSAEASTGETPNLGEVVVAEVGW DALKLNWTAPEGAYEYFFIQVQEADTVEAAQNLTVPGGLRSTDLP 267 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GLKAATHYTITIRGVTQDFSTTPLSVEVLTEEVPDMGNLTVTEVSW DALRLNWTTPDGTYDQFTIQVQEADQVEEAHNLTVPGSLRSMEIP GLRAGTPYTVTLHGEVRGHSTRPLAVEVVTEDLPQLGDLAVSEVG WDGLRLNWTAADNAYEHFVIQVQEVNKVEAAQNLTLPGSLRAVD IPGLEAATPYRVSIYGVIRGYRTPVLSAEASTAKEPEIGNLNVSDITP ESFNLSWMATDGIFETFTIEIIDSNRLLETVEYNISGAERTAHISGLPP STDFIVYLSGLAPSIRTKTISATATTEALPLLENLTISDINPYGFTVSW MASENAFDSFLVTVVDSGKLLDPQEFTLSGTQRKLELRGLITGIGY EVMVSGFTQGHQTKPLRAEIVTEAEPEVDNLLVSDATPDGFRLSW TADEGVFDNFVLKIRDTKKQSEPLEITLLAPERTRDITGLREATEYEI ELYGISKGRRSQTVSAIATTAMGSPKEVIFSDITENSATVSWRAPTA QVESFRITYVPITGGTPSMVTVDGTKTQTRLVKLIPGVEYLVSIIAM KGFEESEPVSGSFTTALDGPSGLVTANITDSEALARWQPAIATVDS YVISYTGEKVPEITRTVSGNTVEYALTDLEPATEYTLRIFAEKGPQK SSTITAKFTTDLDSPRDLTATEVQSETALLTWRPPRASVTGYLLVY ESVDGTVKEVIVGPDTTSYSLADLSPSTHYTAKIQALNGPLRSNMI QTIFTTIGLLYPFPKDCSQAMLNGDTTSGLYTIYLNGDKAEALEVF CDMTSDGGGWIVFLRRKNGRENFYQNWKAYAAGFGDRREEFWL GLDNLNKITAQGQYELRVDLRDHGETAFAVYDKFSVGDAKTRYK LKVEGYSGTAGDSMAYHNGRSFSTFDKDTDSAITNCALSYKGAF WYRNCHRVNLMGRYGDNNHSQGVNWFHWKGHEHSIQFAEMKL RPSNFRNLEGRRKRA (SEQ ID NO: 185) 186 TSLP MFPFALLYVLSVSFRKIFILQLVGLVLTYDFTNCDFEKIKAAYLSTIS KDLITYMSGTKSTEFNNTVSCSNRPHCLTEIQSLTFNPTAGCASLAK EMFAMKTKAALAIWCPGYSETQINATQAMKKRRKRKVTTNKCLE QVSQLQGLWRRFNRPLLKQQ (SEQ ID NO: 186) 187 VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGV GARGVALKLFVQLLGCSRFGGAVVRAGEAEPSGAARSASSGREEP QPEEGEEEEEKEEERGPQWRLGARKPGSWTGEAAVCADSAPAAR APQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASE TMNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVK FMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCND EGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKD RARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFV QDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR (SEQ ID NO: 187) 188 WNT5A MKKSIGILSPGVALGMAGSAMSSKFFLVALAIFFSFAQVVIEANSW WSLGMNNPVQMSEVYIIGAQPLCSQLAGLSQGQKKLCHLYQDHM QYIGEGAKTGIKECQYQFRHRRWNCSTVDNTSVFGRVMQIGSRET AFTYAVSAAGVVNAMSRACREGELSTCGCSRAARPKDLPRDWLW GGCGDNIDYGYRFAKEFVDARERERIHAKGSYESARILMNLHNNE AGRRTVYNLADVACKCHGVSGSCSLKTCWLQLADFRKVGDALKE KYDSAAAMRLNSRGKLVQVNSRFNSPTTQDLVYIDPSPDYCVRNE STGSLGTQGRLCNKTSEGMDGCELMCCGRGYDQFKTVQTERCHC KFHWCCYVKCKKCTEIVDQFVCK (SEQ ID NO: 188) 189 BTLA MKTLPAMLGTGKLFWVFFLIPYLDIWNIHGKESCDVQLYIKRQSEH SILAGDPFELECPVKYCANRPHVTWCKLNGTTCVKLEDRQTSWKE 268 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: EKNISFFILHFEPVLPNDNGSYRCSANFQSNLIESHSTTLYVTDVKS ASERPSKDEMASRPWLLYRLLPLGGLPLLITTCFCLFCCLRRHQGK QNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDNDP DLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVK EAPTEYASICVRS (SEQ ID NO: 189) 190 SEMA4D MRMCTPIRGLLMALAVMFGTAMAFAPIPRITWEHREVHLVQFHEP DIYNYSALLLSEDKDTLYIGAREAVFAVNALNISEKQHEVYWKVS EDKKAKCAEKGKSKQTECLNYIRVLQPLSATSLYVCGTNAFQPAC DHLNLTSFKFLGKNEDGKGRCPFDPAHSYTSVMVDGELYSGTSYN FLGSEPIISRNSSHSPLRTEYAIPWLNEPSFVFADVIRKSPDSPDGED DRVYFFFTEVSVEYEFVFRVLIPRIARVCKGDQGGLRTLQKKWTSF LKARLICSRPDSGLVFNVLRDVFVLRSPGLKVPVFYALFTPQLNNV GLSAVCAYNLSTAEEVFSHGKYMQSTTVEQSHTKWVRYNGPVPK PRPGACIDSEARAANYTSSLNLPDKTLQFVKDHPLMDDSVTPIDNR PRLIKKDVNYTQIVVDRTQALDGTVYDVMFVSTDRGALHKAISLE HAVHIIEETQLFQDFEPVQTLLLSSKKGNRFVYAGSNSGVVQAPLA FCGKHGTCEDCVLARDPYCAWSPPTATCVALHQTESPSRGLIQEM SGDASVCPDKSKGSYRQHFFKHGGTAELKCSQKSNLARVFWKFQ NGVLKAESPKYGLMGRKNLLIFNLSEGDSGVYQCLSEERVKNKTV FQVVAKHVLEVKVVPKPVVAPTLSVVQTEGSRIATKVLVASTQGS SPPTPAVQATSSGAITLPPKPAPTGTSCEPKIVINTVPQLHSEKTMYL KSSDNRLLMSLFLFFFVLFLCLFFYNCYKGYLPRQCLKFRSALLIGK KKPKSDFCDREQSLKETLVEPGSFSQQNGEHPKPALDTGYETEQDT ITSKVPTDREDSQRIDDLSARDKPFDVKCELKFADSDADGD (SEQ ID NO: 190) 191 LRP6 MGAVLRSLLACSFCVLLRAAPLLLYANRRDLRLVDATNGKENATI VVGGLEDAAAVDFVFSHGLIYWSDVSEEAIKRTEFNKTESVQNVV VSGLLSPDGLACDWLGEKLYWTDSETNRIEVSNLDGSLRKVLFWQ ELDQPRAIALDPSSGFMYWTDWGEVPKIERAGMDGSSRFIIINSEIY WPNGLTLDYEEQKLYWADAKLNFIHKSNLDGTNRQAVVKGSLPH PFALTLFEDILYWTDWSTHSILACNKYTGEGLREIHSDIFSPMDIHA FSQQRQPNATNPCGIDNGGCSHLCLMSPVKPFYQCACPTGVKLLE NGKTCKDGATELLLLARRTDLRRISLDTPDFTDIVLQLEDIRHAIAI DYDPVEGYIYWTDDEVRAIRRSFIDGSGSQFVVTAQIAHPDGIAVD WVARNLYWTDTGTDRIEVTRLNGTMRKILISEDLEEPRAIVLDPMV GYMYWTDWGEIPKIERAALDGSDRVVLVNTSLGWPNGLALDYDE GKIYWGDAKTDKIEVMNTDGTGRRVLVEDKIPHIFGFTLLGDYVY WTDWQRRSIERVHKRSAEREVIIDQLPDLMGLKATNVHRVIGSNP CAEENGGCSHLCLYRPQGLRCACPIGFELISDMKTCIVPEAFLLFSR RADIRRISLETNNNNVAIPLTGVKEASALDFDVTDNRIYWTDISLKT ISRAFMNGSALEHVVEFGLDYPEGMAVDWLGKNLYWADTGTNRI EVSKLDGQHRQVLVWKDLDSPRALALDPAEGFMYWTEWGGKPK IDRAAMDGSERTTLVPNVGRANGLTIDYAKRRLYWTDLDTNLIES SNMLGLNREVIADDLPHPFGLTQYQDYIYWTDWSRRSIERANKTS GQNRTIIQGHLDYVMDILVFHSSRQSGWNECASSNGHCSHLCLAV PVGGFVCGCPAHYSLNADNRTCSAPTTFLLFSQKSAINRMVIDEQQ SPDIILPIHSLRNVRAIDYDPLDKQLYWIDSRQNMIRKAQEDGSQGF 269 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: TVVVSSVPSQNLEIQPYDLSIDIYSRYIYWTCEATNVINVTRLDGRS VGVVLKGEQDRPRAVVVNPEKGYMYFTNLQERSPKIERAALDGT EREVLFFSGLSKPIALALDSRLGKLFWADSDLRRIESSDLSGANRIV LEDSNILQPVGLTVFENWLYWIDKQQQMIEKIDMTGREGRTKVQA RIAQLSDIHAVKELNLQEYRQHPCAQDNGGCSHICLVKGDGTTRC SCPMHLVLLQDELSCGEPPTCSPQQFTCFTGEIDCIPVAWRCDGFTE CEDHSDELNCPVCSESQFQCASGQCIDGALRCNGDANCQDKSDEK NCEVLCLIDQFRCANGQCIGKHKKCDHNVDCSDKSDELDCYPTEE PAPQATNTVGSVIGVIVTIFVSGTVYFICQRMLCPRMKGDGETMTN DYVVHGPASVPLGYVPHPSSLSGSLPGMSRGKSMISSLSIMGGSSG PPYDRAHVTGASSSSSSSTKGTYFPAILNPPPSPATERSHYTMEFGY SSNSPSTHRSYSYRPYSYRHFAPPTTPCSTDVCDSDYAPSRRMTSV ATAKGYTSDLNYDSEPVPPPPTPRSQYLSAEENYESCPPSPYTERSY SHHLYPPPPSPCTDSS (SEQ ID NO: 191) 192 ADGRE5 MGGRVFLAFCVWLTLPGAETQDSRGCARWCPQNSSCVNATACRC NPGFSSFSEIITTPTETCDDINECATPSKVSCGKFSDCWNTEGSYDC VCSPGYEPVSGAKTFKNESENTCQDVDECQQNPRLCKSYGTCVNT LGSYTCQCLPGFKFIPEDPKVCTDVNECTSGQNPCHSSTHCLNNVG SYQCRCRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCF NTVGSYSCRCRPGWKPRHGIPNNQKDTVCEDMTFSTWTPPPGVHS QTLSRFFDKVQDLGRDSKTSSAEVTIQNVIKLVDELMEAPGDVEAL APPVRHLIATQLLSNLEDIMRILAKSLPKGPFTYISPSNTELTLMIQE RGDKNVTMGQSSARMKLNWAVAAGAEDPGPAVAGILSIQNMTTL LANASLNLHSKKQAELEEIYESSIRGVQLRRLSAVNSIFLSHNNTKE LNSPILFAFSHLESSDGEAGRDPPAKDVMPGPRQELLCAFWKSDSD RGGHWATEGCQVLGSKNGSTTCQCSHLSSFAILMAHYDVEDWKL TLITRVGLALSLFCLLLCILTFLLVRPIQGSRTTIHLHLCICLFVGSTIF LAGIENEGGQVGLRCRLVAGLLHYCFLAAFCWMSLEGLELYFLVV RVFQGQGLSTRWLCLIGYGVPLLIVGVSAAIYSKGYGRPRYCWLD FEQGFLWSFLGPVTFIILCNAVIFVTTVWKLTQKFSEINPDMKKLKK ARALTITAIAQLFLLGCTWVFGLFIFDDRSLVLTYVFTILNCLQGAF LYLLHCLLNKKVREEYRKWACLVAGGSKYSEFTSTTSGTGHNQTR ALRASESGI (SEQ ID NO: 192) 193 APOE MKVLWAALLVTFLAGCQAKVEQAVETEPEPELRQQTEWQSGQR WELALGRFWDYLRWVQTLSEQVQEELLSSQVTQELRALMDETMK ELKAYKSELEEQLTPVAEETRARLSKELQAAQARLGADMEDVCG RLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQK RLAVYQAGAREGAERGLSAIRERLGPLVEQGRVRAATVGSLAGQP LQERAQAWGERLRARMEEMGSRTRDRLDEVKEQVAEVRAKLEE QAQQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEKVQAAVG TSAAPVPSDNH (SEQ ID NO: 193) 194 COL1A2 MLSFVDTRTLLLLAVTLCLATCQSLQEETVRKGPAGDRGPRGERG PPGPPGRDGEDGPTGPPGPPGPPGPPGLGGNFAAQYDGKGVGLGP GPMGLMGPRGPPGAAGAPGPQGFQGPAGEPGEPGQTGPAGARGP AGPPGKAGEDGHPGKPGRPGERGVVGPQGARGFPGTPGLPGFKGI RGHNGLDGLKGQPGAPGVKGEPGAPGENGTPGQTGARGLPGERG RVGAPGPAGARGSDGSVGPVGPAGPIGSAGPPGFPGAPGPKGEIGA 270 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: VGNAGPAGPAGPRGEVGLPGLSGPVGPPGNPGANGLTGAKGAAG LPGVAGAPGLPGPRGIPGPVGAAGATGARGLVGEPGPAGSKGESG NKGEPGSAGPQGPPGPSGEEGKRGPNGEAGSAGPPGPPGLRGSPGS RGLPGADGRAGVMGPPGSRGASGPAGVRGPNGDAGRPGEPGLMG PRGLPGSPGNIGPAGKEGPVGLPGIDGRPGPIGPAGARGEPGNIGFP GPKGPTGDPGKNGDKGHAGLAGARGAPGPDGNNGAQGPPGPQG VQGGKGEQGPPGPPGFQGLPGPSGPAGEVGKPGERGLHGEFGLPG PAGPRGERGPPGESGAAGPTGPIGSRGPSGPPGPDGNKGEPGVVGA VGTAGPSGPSGLPGERGAAGIPGGKGEKGEPGLRGEIGNPGRDGA RGAPGAVGAPGPAGATGDRGEAGAAGPAGPAGPRGSPGERGEVG PAGPNGFAGPAGAAGQPGAKGERGAKGPKGENGVVGPTGPVGAA GPAGPNGPPGPAGSRGDGGPPGMTGFPGAAGRTGPPGPSGISGPPG PPGPAGKEGLRGPRGDQGPVGRTGEVGAVGPPGFAGEKGPSGEAG TAGPPGTPGPQGLLGAPGILGLPGSRGERGLPGVAGAVGEPGPLGI AGPPGARGPPGAVGSPGVNGAPGEAGRDGNPGNDGPPGRDGQPG HKGERGYPGNIGPVGAAGAPGPHGPVGPAGKHGNRGETGPSGPV GPAGAVGPRGPSGPQGIRGDKGEPGEKGPRGLPGLKGHNGLQGLP GIAGHHGDQGAPGSVGPAGPRGPAGPSGPAGKDGRTGHPGTVGP AGIRGPQGHQGPAGPPGPPGPPGPPGVSGGGYDFGYDGDFYRADQ PRSAPSLRPKDYEVDATLKSLNNQIETLLTPEGSRKNPARTCRDLR LSHPEWSSGYYWIDPNQGCTMDAIKVYCDFSTGETCIRAQPENIPA KNWYRSSKDKKHVWLGETINAGSQFEYNVEGVTSKEMATQLAF MRLLANYASQNITYHCKNSIAYMDEETGNLKKAVILQGSNDVELV AEGNSRFTYTVLVDGCSKKTNEWGKTIIEYKTNKPSRLPFLDIAPL DIGGADQEFFVDIGPVCFK (SEQ ID NO: 194) 195 COL4A2 MGRDQRAVAGPALRRWLLLGTVTVGFLAQSVLAGVKKFDVPCG GRDCSGGCQCYPEKGGRGQPGPVGPQGYNGPPGLQGFPGLQGRK GDKGERGAPGVTGPKGDVGARGVSGFPGADGIPGHPGQGGPRGR PGYDGCNGTQGDSGPQGPPGSEGFTGPPGPQGPKGQKGEPYALPK EERDRYRGEPGEPGLVGFQGPPGRPGHVGQMGPVGAPGRPGPPGP PGPKGQQGNRGLGFYGVKGEKGDVGQPGPNGIPSDTLHPIIAPTGV TFHPDQYKGEKGSEGEPGIRGISLKGEEGIMGFPGLRGYPGLSGEK GSPGQKGSRGLDGYQGPDGPRGPKGEAGDPGPPGLPAYSPHPSLA KGARGDPGFPGAQGEPGSQGEPGDPGLPGPPGLSIGDGDQRRGLP GEMGPKGFIGDPGIPALYGGPPGPDGKRGPPGPPGLPGPPGPDGFLF GLKGAKGRAGFPGLPGSPGARGPKGWKGDAGECRCTEGDEAIKG LPGLPGPKGFAGINGEPGRKGDRGDPGQHGLPGFPGLKGVPGNIG APGPKGAKGDSRTITTKGERGQPGVPGVPGMKGDDGSPGRDGLD GFPGLPGPPGDGIKGPPGDPGYPGIPGTKGTPGEMGPPGLGLPGLK GQRGFPGDAGLPGPPGFLGPPGPAGTPGQIDCDTDVKRAVGGDRQ EAIQPGCIGGPKGLPGLPGPPGPTGAKGLRGIPGFAGADGGPGPRG LPGDAGREGFPGPPGFIGPRGSKGAVGLPGPDGSPGPIGLPGPDGPP GERGLPGEVLGAQPGPRGDAGVPGQPGLKGLPGDRGPPGFRGSQG MPGMPGLKGQPGLPGPSGQPGLYGPPGLHGFPGAPGQEGPLGLPGI PGREGLPGDRGDPGDTGAPGPVGMKGLSGDRGDAGFTGEQGHPG SPGFKGIDGMPGTPGLKGDRGSPGMDGFQGMPGLKGRPGFPGSKG EAGFFGIPGLKGLAGEPGFKGSRGDPGPPGPPPVILPGMKDIKGEKG 271 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: DEGPMGLKGYLGAKGIQGMPGIPGLSGIPGLPGRPGHIKGVKGDIG VPGIPGLPGFPGVAGPPGITGFPGFIGSRGDKGAPGRAGLYGEIGAT GDFGDIGDTINLPGRPGLKGERGTTGIPGLKGFFGEKGTEGDIGFPG ITGVTGVQGPPGLKGQTGFPGLTGPPGSQGELGRIGLPGGKGDDG WPGAPGLPGFPGLRGIRGLHGLPGTKGFPGSPGSDIHGDPGFPGPPG ERGDPGEANTLPGPVGVPGQKGDQGAPGERGPPGSPGLQGFPGITP PSNISGAPGDKGAPGIFGLKGYRGPPGPPGSAALPGSKGDTGNPGA PGTPGTKGWAGDSGPQGRPGVFGLPGEKGPRGEQGFMGNTGPTG AVGDRGPKGPKGDPGFPGAPGTVGAPGIAGIPQKIAVQPGTVGPQ GRRGPPGAPGEMGPQGPPGEPGFRGAPGKAGPQGRGGVSAVPGFR GDEGPIGHQGPIGQEGAPGRPGSPGLPGMPGRSVSIGYLLVKHSQT DQEPMCPVGMNKLWSGYSLLYFEGQEKAHNQDLGLAGSCLARFS TMPFLYCNPGDVCYYASRNDKSYWLSTTAPLPMMPVAEDEIKPYI SRCSVCEAPAIAIAVHSQDVSIPHCPAGWRSLWIGYSFLMHTAAGD EGGGQSLVSPGSCLEDFRATPFIECNGGRGTCHYYANKYSFWLTTI PEQSFQGSPSADTLKAGLIRTHISRCQVCMKNL (SEQ ID NO: 195) 196 COL6A1 MRAARALLPLLLQACWTAAQDEPETPRAVAFQDCPVDLFFVLDTS ESVALRLKPYGALVDKVKSFTKRFIDNLRDRYYRCDRNLVWNAG ALHYSDEVEIIQGLTRMPGGRDALKSSVDAVKYFGKGTYTDCAIK KGLEQLLVGGSHLKENKYLIVVTDGHPLEGYKEPCGGLEDAVNEA KHLGVKVFSVAITPDHLEPRLSIIATDHTYRRNFTAADWGQSRDAE EAISQTIDTIVDMIKNNVEQVCCSFECQPARGPPGLRGDPGFEGERG KPGLPGEKGEAGDPGRPGDLGPVGYQGMKGEKGSRGEKGSRGPK GYKGEKGKRGIDGVDGVKGEMGYPGLPGCKGSPGFDGIQGPPGP KGDPGAFGLKGEKGEPGADGEAGRPGSSGPSGDEGQPGEPGPPGE KGEAGDEGNPGPDGAPGERGGPGERGPRGTPGTRGPRGDPGEAGP QGDQGREGPVGVPGDPGEAGPIGPKGYRGDEGPPGSEGARGAPGP AGPPGDPGLMGERGEDGPAGNGTEGFPGFPGYPGNRGAPGINGTK GYPGLKGDEGEAGDPGDDNNDIAPRGVKGAKGYRGPEGPQGPPG HQGPPGPDECEILDIIMKMCSCCECKCGPIDLLFVLDSSESIGLQNFE IAKDFVVKVIDRLSRDELVKFEPGQSYAGVVQYSHSQMQEHVSLR SPSIRNVQELKEAIKSLQWMAGGTFTGEALQYTRDQLLPPSPNNRI ALVITDGRSDTQRDTTPLNVLCSPGIQVVSVGIKDVFDFIPGSDQLN VISCQGLAPSQGRPGLSLVKENYAELLEDAFLKNVTAQICIDKKCP DYTCPITFSSPADITILLDGSASVGSHNFDTTKRFAKRLAERFLTAG RTDPAHDVRVAVVQYSGTGQQRPERASLQFLQNYTALASAVDAM DFINDATDVNDALGYVTRFYREASSGAAKKRLLLFSDGNSQGATP AAIEKAVQEAQRAGIEIFVVVVGRQVNEPHIRVLVTGKTAEYDVA YGESHLFRVPSYQALLRGVFHQTVSRKVALG (SEQ ID NO: 196) 197 COL6A2 MLQGTCSVLLLWGILGAIQAQQQEVISPDTTERNNNCPEKTDCPIH VYFVLDTSESVTMQSPTDILLFHMKQFVPQFISQLQNEFYLDQVAL SWRYGGLHFSDQVEVFSPPGSDRASFIKNLQGISSFRRGTFTDCAL ANMTEQIRQDRSKGTVHFAVVITDGHVTGSPCGGIKLQAERAREE GIRLFAVAPNQNLKEQGLRDIASTPHELYRNDYATMLPDSTEIDQD TINRIIKVMKHEAYGECYKVSCLEIPGPSGPKGYRGQKGAKGNMG EPGEPGQKGRQGDPGIEGPIGFPGPKGVPGFKGEKGEFGADGRKG APGLAGKNGTDGQKGKLGRIGPPGCKGDPGNRGPDGYPGEAGSP 272 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GERGDQGGKGDPGRPGRRGPPGEIGAKGSKGYQGNSGAPGSPGV KGAKGGPGPRGPKGEPGRRGDPGTKGSPGSDGPKGEKGDPGPEGP RGLAGEVGNKGAKGDRGLPGPRGPQGALGEPGKQGSRGDPGDAG PRGDSGQPGPKGDPGRPGFSYPGPRGAPGEKGEPGPRGPEGGRGD FGLKGEPGRKGEKGEPADPGPPGEPGPRGPRGVPGPEGEPGPPGDP GLTECDVMTYVRETCGCCDCEKRCGALDVVFVIDSSESIGYTNFTL EKNFVINVVNRLGAIAKDPKSETGTRVGVVQYSHEGTFEAIQLDDE RIDSLSSFKEAVKNLEWIAGGTWTPSALKFAYDRLIKESRRQKTRV FAVVITDGRHDPRDDDLNLRALCDRDVTVTAIGIGDMFHEKHESE NLYSIACDKPQQVRNMTLFSDLVAEKFIDDMEDVLCPDPQIVCPDL PCQTELSVAQCTQRPVDIVFLLDGSERLGEQNFHKARRFVEQVAR RLTLARRDDDPLNARVALLQFGGPGEQQVAFPLSHNLTAIHEALET TQYLNSFSHVGAGVVHAINAIVRSPRGGARRHAELSFVFLTDGVT GNDSLHESAHSMRKQNVVPTVLALGSDVDMDVLTTLSLGDRAAV FHEKDYDSLAQPGFFDRFIRWIC (SEQ ID NO: 197) 198 COL6A3 MRKHRHLPLVAVFCLFLSGFPTTHAQQQQADVKNGAAADIIFLVD SSWTIGEEHFQLVREFLYDVVKSLAVGENDFHFALVQFNGNPHTE FLLNTYRTKQEVLSHISNMSYIGGTNQTGKGLEYIMQSHLTKAAGS RAGDGVPQVIVVLTDGHSKDGLALPSAELKSADVNVFAIGVEDAD EGALKEIASEPLNMHMFNLENFTSLHDIVGNLVSCVHSSVSPERAG DTETLKDITAQDSADIIFLIDGSNNTGSVNFAVILDFLVNLLEKLPIG TQQIRVGVVQFSDEPRTMFSLDTYSTKAQVLGAVKALGFAGGELA NIGLALDFVVENHFTRAGGSRVEEGVPQVLVLISAGPSSDEIRYGV VALKQASVFSFGLGAQAASRAELQHIATDDNLVFTVPEFRSFGDLQ EKLLPYIVGVAQRHIVLKPPTIVTQVIEVNKRDIVFLVDGSSALGLA NFNAIRDFIAKVIQRLEIGQDLIQVAVAQYADTVRPEFYFNTHPTKR EVITAVRKMKPLDGSALYTGSALDFVRNNLFTSSAGYRAAEGIPKL LVLITGGKSLDEISQPAQELKRSSIMAFAIGNKGADQAELEEIAFDS SLVFIPAEFRAAPLQGMLPGLLAPLRTLSGTPEVHSNKRDIIFLLDGS ANVGKTNFPYVRDFVMNLVNSLDIGNDNIRVGLVQFSDTPVTEFS LNTYQTKSDILGHLRQLQLQGGSGLNTGSALSYVYANHFTEAGGS RIREHVPQLLLLLTAGQSEDSYLQAANALTRAGILTFCVGASQANK AELEQIAFNPSLVYLMDDFSSLPALPQQLIQPLTTYVSGGVEEVPLA QPESKRDILFLFDGSANLVGQFPVVRDFLYKIIDELNVKPEGTRIAV AQYSDDVKVESRFDEHQSKPEILNLVKRMKIKTGKALNLGYALDY AQRYIFVKSAGSRIEDGVLQFLVLLVAGRSSDRVDGPASNLKQSGV VPFIFQAKNADPAELEQIVLSPAFILAAESLPKIGDLHPQIVNLLKSV HNGAPAPVSGEKDVVFLLDGSEGVRSGFPLLKEFVQRVVESLDVG QDRVRVAVVQYSDRTRPEFYLNSYMNKQDVVNAVRQLTLLGGPT PNTGAALEFVLRNILVSSAGSRITEGVPQLLIVLTADRSGDDVRNPS VVVKRGGAVPIGIGIGNADITEMQTISFIPDFAVAIPTFRQLGTVQQ VISERVTQLTREELSRLQPVLQPLPSPGVGGKRDVVFLIDGSQSAGP EFQYVRTLIERLVDYLDVGFDTTRVAVIQFSDDPKVEFLLNAHSSK DEVQNAVQRLRPKGGRQINVGNALEYVSRNIFKRPLGSRIEEGVPQ FLVLISSGKSDDEVDDPAVELKQFGVAPFTIARNADQEELVKISLSP EYVFSVSTFRELPSLEQKLLTPITTLTSEQIQKLLASTRYPPPAVESD AADIVFLIDSSEGVRPDGFAHIRDFVSRIVRRLNIGPSKVRVGVVQF 273 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: SNDVFPEFYLKTYRSQAPVLDAIRRLRLRGGSPLNTGKALEFVARN LFVKSAGSRIEDGVPQHLVLVLGGKSQDDVSRFAQVIRSSGIVSLG VGDRNIDRTELQTITNDPRLVFTVREFRELPNIEERIMNSFGPSAATP APPGVDTPPPSRPEKKKADIVFLLDGSINFRRDSFQEVLRFVSEIVDT VYEDGDSIQVGLVQYNSDPTDEFFLKDFSTKRQIIDAINKVVYKGG RHANTKVGLEHLRVNHFVPEAGSRLDQRVPQIAFVITGGKSVEDA QDVSLALTQRGVKVFAVGVRNIDSEEVGKIASNSATAFRVGNVQE LSELSEQVLETLHDAMHETLCPGVTDAAKACNLDVILGFDGSRDQ NVFVAQKGFESKVDAILNRISQMHRVSCSGGRSPTVRVSVVANTPS GPVEAFDFDEYQPEMLEKFRNMRSQHPYVLTEDTLKVYLNKFRQS SPDSVKVVIHFTDGADGDLADLHRASENLRQEGVRALILVGLERV VNLERLMHLEFGRGFMYDRPLRLNLLDLDYELAEQLDNIAEKACC GVPCKCSGQRGDRGPIGSIGPKGIPGEDGYRGYPGDEGGPGERGPP GVNGTQGFQGCPGQRGVKGSRGFPGEKGEVGEIGLDGLDGEDGD KGLPGSSGEKGNPGRRGDKGPRGEKGERGDVGIRGDPGNPGQDSQ ERGPKGETGDLGPMGVPGRDGVPGGPGETGKNGGFGRRGPPGAK GNKGGPGQPGFEGEQGTRGAQGPAGPAGPPGLIGEQGISGPRGSG GAAGAPGERGRTGPLGRKGEPGEPGPKGGIGNRGPRGETGDDGRD GVGSEGRRGKKGERGFPGYPGPKGNPGEPGLNGTTGPKGIRGRRG NSGPPGIVGQKGDPGYPGPAGPKGNRGDSIDQCALIQSIKDKCPCC YGPLECPVFPTELAFALDTSEGVNQDTFGRMRDVVLSIVNDLTIAE SNCPRGARVAVVTYNNEVTTEIRFADSKRKSVLLDKIKNLQVALTS KQQSLETAMSFVARNTFKRVRNGFLMRKVAVFFSNTPTRASPQLR EAVLKLSDAGITPLFLTRQEDRQLINALQINNTAVGHALVLPAGRD LTDFLENVLTCHVCLDICNIDPSCGFGSWRPSFRDRRAAGSDVDID MAFILDSAETTTLFQFNEMKKYIAYLVRQLDMSPDPKASQHFARV AVVQHAPSESVDNASMPPVKVEFSLTDYGSKEKLVDFLSRGMTQL QGTRALGSAIEYTIENVFESAPNPRDLKIVVLMLTGEVPEQQLEEA QRVILQAKCKGYFFVVLGIGRKVNIKEVYTFASEPNDVFFKLVDKS TELNEEPLMRFGRLLPSFVSSENAFYLSPDIRKQCDWFQGDQPTKN LVKFGHKQVNVPNNVTSSPTSNPVTTTKPVTTTKPVTTTTKPVTTT TKPVTIINQPSVKPAAAKPAPAKPVAAKPVATKMATVRPPVAVKP ATAAKPVAAKPAAVRPPAAAAAKPVATKPEVPRPQAAKPAATKP ATTKPMVKMSREVQVFEITENSAKLHWERAEPPGPYFYDLTVTSA HDQSLVLKQNLTVTDRVIGGLLAGQTYHVAVVCYLRSQVRATYH GSFSTKKSQPPPPQPARSASSSTINLMVSTEPLALTETDICKLPKDEG TCRDFILKWYYDPNTKSCARFWYGGCGGNENKFGSQKECEKVCA PVLAKPGVISVMGT (SEQ ID NO: 198) 199 FGF7 MHKWILTWILPTLLYRSCFHIICLVGTISLACNDMTPEQMATNVNC SSPERHTRSYDYMEGGDIRVRRLFCRTQWYLRIDKRGKVKGTQEM KNNYNIMEIRTVAVGIVAIKGVESEFYLAMNKEGKLYAKKECNED CNFKELILENHYNTYASAKWTHNGGEMFVALNQKGIPVRGKKTK KEQKTAHFLPMAIT (SEQ ID NO: 199) 200 HLA-E MVDGTLLLLLSEALALTQTWAGSHSLKYFHTSVSRPGRGEPRFISV GYVDDTQFVRFDNDAASPRMVPRAPWMEQEGSEYWDRETRSAR DTAQIFRVNLRTLRGYYNQSEAGSHTLQWMHGCELGPDGRFLRG YEQFAYDGKDYLTLNEDLRSWTAVDTAAQISEQKSNDASEAEHQ 274 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: RAYLEDTCVEWLHKYLEKGKETLLHLEPPKTHVTHHPISDHEATL RCWALGFYPAEITLTWQQDGEGHTQDTELVETRPAGDGTFQKWA AVVVPSGEEQRYTCHVQHEGLPEPVTLRWKPASQPTIPIVGIIAGLV LLGSVVSGAVVAAVIWRKKSSGGKGGSYSKAEWSDSAQGSESHS L (SEQ ID NO: 200) 201 IL6 MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQP LTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLP KMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQ ARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQ WLQDMTTHLILRSFKEFLQSSLRALRQM (SEQ ID NO: 201) 202 LAMB1 MGLLQLLAFSFLALCRARVRAQEPEFSYGCAEGSCYPATGDLLIGR AQKLSVTSTCGLHKPEPYCIVSHLQEDKKCFICNSQDPYHETLNPD SHLIENVVTTFAPNRLKIWWQSENGVENVTIQLDLEAEFHFTHLIM TFKTFRPAAMLIERSSDFGKTWGVYRYFAYDCEASFPGISTGPMKK VDDIICDSRYSDIEPSTEGEVIFRALDPAFKIEDPYSPRIQNLLKITNL RIKFVKLHTLGDNLLDSRMEIREKYYYAVYDMVVRGNCFCYGHA SECAPVDGFNEEVEGMVHGHCMCRHNTKGLNCELCMDFYHDLP WRPAEGRNSNACKKCNCNEHSISCHFDMAVYLATGNVSGGVCDD CQHNTMGRNCEQCKPFYYQHPERDIRDPNFCERCTCDPAGSQNEG ICDSYTDFSTGLIAGQCRCKLNVEGEHCDVCKEGFYDLSSEDPFGC KSCACNPLGTIPGGNPCDSETGHCYCKRLVTGQHCDQCLPEHWGL SNDLDGCRPCDCDLGGALNNSCFAESGQCSCRPHMIGRQCNEVEP GYYFATLDHYLYEAEEANLGPGVSIVERQYIQDRIPSWTGAGFVR VPEGAYLEFFIDNIPYSMEYDILIRYEPQLPDHWEKAVITVQRPGRIP TSSRCGNTIPDDDNQVVSLSPGSRYVVLPRPVCFEKGTNYTVRLEL PQYTSSDSDVESPYTLIDSLVLMPYCKSLDIFTVGGSGDGVVTNSA WETFQRYRCLENSRSVVKTPMTDVCRNIIFSISALLHQTGLACECD PQGSLSSVCDPNGGQCQCRPNVVGRTCNRCAPGTFGFGPSGCKPC ECHLQGSVNAFCNPVTGQCHCFQGVYARQCDRCLPGHWGFPSCQ PCQCNGHADDCDPVTGECLNCQDYTMGHNCERCLAGYYGDPIIG SGDHCRPCPCPDGPDSGRQFARSCYQDPVTLQLACVCDPGYIGSRC DDCASGYFGNPSEVGGSCQPCQCHNNIDTTDPEACDKETGRCLKC LYHTEGEHCQFCRFGYYGDALQQDCRKCVCNYLGTVQEHCNGSD CQCDKATGQCLCLPNVIGQNCDRCAPNTWQLASGTGCDPCNCNA AHSFGPSCNEFTGQCQCMPGFGGRTCSECQELFWGDPDVECRACD CDPRGIETPQCDQSTGQCVCVEGVEGPRCDKCTRGYSGVFPDCTP CHQCFALWDVIIAELTNRTHRFLEKAKALKISGVIGPYRETVDSVE RKVSEIKDILAQSPAAEPLKNIGNLFEEAEKLIKDVTEMMAQVEVK LSDTTSQSNSTAKELDSLQTEAESLDNTVKELAEQLEFIKNSDIRGA LDSITKYFQMSLEAEERVNASTTEPNSTVEQSALMRDRVEDVMME RESQFKEKQEEQARLLDELAGKLQSLDLSAAAEMTCGTPPGASCS ETECGGPNCRTDEGERKCGGPGCGGLVTVAHNAWQKAMDLDQD VLSALAEVEQLSKMVSEAKLRADEAKQSAEDILLKTNATKEKMD KSNEELRNLIKQIRNFLTQDSADLDSIEAVANEVLKMEMPSTPQQL QNLTEDIRERVESLSQVEVILQHSAADIARAEMLLEEAKRASKSAT DVKVTADMVKEALEEAEKAQVAAEKAIKQADEDIQGTQNLLTSIE SETAASEETLFNASQRISELERNVEELKRKAAQNSGEAEYIEKVVY 275 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: TVKQSAEDVKKTLDGELDEKYKKVENLIAKKTEESADARRKAEM LQNEAKTLLAQANSKLQLLKDLERKYEDNQRYLEDKAQELARLE GEVRSLLKDISQKVAVYSTCL (SEQ ID NO: 202) 203 LAMC1 MRGSHRAAPALRPRGRLWPVLAVLAAAAAAGCAQAAMDECTDE GGRPQRCMPEFVNAAFNVTVVATNTCGTPPEEYCVQTGVTGVTK SCHLCDAGQPHLQHGAAFLTDYNNQADTTWWQSQTMLAGVQYP SSINLTLHLGKAFDITYVRLKFHTSRPESFAIYKRTREDGPWIPYQY YSGSCENTYSKANRGFIRTGGDEQQALCTDEFSDISPLTGGNVAFS TLEGRPSAYNFDNSPVLQEWVTATDIRVTLNRLNTFGDEVFNDPK VLKSYYYAISDFAVGGRCKCNGHASECMKNEFDKLVCNCKHNTY GVDCEKCLPFFNDRPWRRATAESASECLPCDCNGRSQECYFDPEL YRSTGHGGHCTNCQDNTDGAHCERCRENFFRLGNNEACSSCHCSP VGSLSTQCDSYGRCSCKPGVMGDKCDRCQPGFHSLTEAGCRPCSC DPSGSIDECNIETGRCVCKDNVEGFNCERCKPGFFNLESSNPRGCTP CFCFGHSSVCTNAVGYSVYSISSTFQIDEDGWRAEQRDGSEASLEW SSERQDIAVISDSYFPRYFIAPAKFLGKQVLSYGQNLSFSFRVDRRD TRLSAEDLVLEGAGLRVSVPLIAQGNSYPSETTVKYVFRLHEATDY PWRPALTPFEFQKLLNNLTSIKIRGTYSERSAGYLDDVTLASARPGP GVPATWVESCTCPVGYGGQFCEMCLSGYRRETPNLGPYSPCVLCA CNGHSETCDPETGVCNCRDNTAGPHCEKCSDGYYGDSTAGTSSDC QPCPCPGGSSCAVVPKTKEVVCTNCPTGTTGKRCELCDDGYFGDP LGRNGPVRLCRLCQCSDNIDPNAVGNCNRLTGECLKCIYNTAGFY CDRCKDGFFGNPLAPNPADKCKACNCNLYGTMKQQSSCNPVTGQ CECLPHVTGQDCGACDPGFYNLQSGQGCERCDCHALGSTNGQCDI RTGQCECQPGITGQHCERCEVNHFGFGPEGCKPCDCHPEGSLSLQC KDDGRCECREGFVGNRCDQCEENYFYNRSWPGCQECPACYRLVK DKVADHRVKLQELESLIANLGTGDEMVTDQAFEDRLKEAEREVM DLLREAQDVKDVDQNLMDRLQRVNNTLSSQISRLQNIRNTIEETG NLAEQARAHVENTERLIEIASRELEKAKVAAANVSVTQPESTGDPN NMTLLAEEARKLAERHKQEADDIVRVAKTANDTSTEAYNLLLRTL AGENQTAFEIEELNRKYEQAKNISQDLEKQAARVHEEAKRAGDKA VEIYASVAQLSPLDSETLENEANNIKMEAENLEQLIDQKLKDYEDL REDMRGKELEVKNLLEKGKTEQQTADQLLARADAAKALAEEAAK KGRDTLQEANDILNNLKDFDRRVNDNKTAAEEALRKIPAINQTITE ANEKTREAQQALGSAAADATEAKNKAHEAERIASAVQKNATSTK AEAERTFAEVTDLDNEVNNMLKQLQEAEKELKRKQDDADQDMM MAGMASQAAQEAEINARKAKNSVTSLLSIINDLLEQLGQLDTVDL NKLNEIEGTLNKAKDEMKVSDLDRKVSDLENEAKKQEAAIMDYN RDIEEIMKDIRNLEDIRKTLPSGCFNTPSIEKP (SEQ ID NO: 203) 204 THBS2 MVWRLVLLALWVWPSTQAGHQDKDTTFDLFSISNINRKTIGAKQF RGPDPGVPAYRFVRFDYIPPVNADDLSKITKIMRQKEGFFLTAQLK QDGKSRGTLLALEGPGLSQRQFEIVSNGPADTLDLTYWIDGTRHV VSLEDVGLADSQWKNVTVQVAGETYSLHVGCDLIDSFALDEPFYE HLQAEKSRMYVAKGSARESHFRGLLQNVHLVFENSVEDILSKKGC QQGQGAEINAISENTETLRLGPHVTTEYVGPSSERRPEVCERSCEEL GNMVQELSGLHVLVNQLSENLKRVSNDNQFLWELIGGPPKTRNM SACWQDGRFFAENETWVVDSCTTCTCKKFKTICHQITCPPATCASP 276 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: SFVEGECCPSCLHSVDGEEGWSPWAEWTQCSVTCGSGTQQRGRSC DVTSNTCLGPSIQTRACSLSKCDTRIRQDGGWSHWSPWSSCSVTCG VGNITRIRLCNSPVPQMGGKNCKGSGRETKACQGAPCPIDGRWSP WSPWSACTVTCAGGIRERTRVCNSPEPQYGGKACVGDVQERQMC NKRSCPVDGCLSNPCFPGAQCSSFPDGSWSCGSCPVGFLGNGTHCE DLDECALVPDICFSTSKVPRCVNTQPGFHCLPCPPRYRGNQPVGVG LEAAKTEKQVCEPENPCKDKTHNCHKHAECIYLGHFSDPMYKCEC QTGYAGDGLICGEDSDLDGWPNLNLVCATNATYHCIKDNCPHLPN SGQEDFDKDGIGDACDDDDDNDGVTDEKDNCQLLFNPRQADYDK DEVGDRCDNCPYVHNPAQIDTDNNGEGDACSVDIDGDDVFNERD NCPYVYNTDQRDTDGDGVGDHCDNCPLVHNPDQTDVDNDLVGD QCDNNEDIDDDGHQNNQDNCPYISNANQADHDRDGQGDACDPD DDNDGVPDDRDNCRLVFNPDQEDLDGDGRGDICKDDFDNDNIPDI DDVCPENNAISETDFRNFQMVPLDPKGTTQIDPNWVIRHQGKELV QTANSDPGIAVGFDEFGSVDFSGTFYVNTDRDDDYAGFVFGYQSS SRFYVVMWKQVTQTYWEDQPTRAYGYSGVSLKVVNSTTGTGEH LRNALWHTGNTPGQVRTLWHDPRNIGWKDYTAYRWHLTHRPKT GYIRVLVHEGKQVMADSGPIYDQTYAGGRLGLFVFSQEMVYFSDL KYECRDI (SEQ ID NO: 204) 205 ALOXA5AP MDQETVGNVVLLAIVTLISVVQNGFFAHKVEHESRTQNGRSFQRT GTLAFERVYTANQNCVDAYPTFLAVLWSAGLLCSQVPAAFAGLM YLFVRQKYFVGYLGERTQSTPGYIFGKRIILFLFLMSVAGIFNYYLIF FFGSDFENYIKTISTTISPLLLIP (SEQ ID NO: 205) 206 CALM2 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTE AELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFR VFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQ VNYEEFVQMMTAK (SEQ ID NO:206) 207 LGALS9 MAFSGSQAPYLSPAVPFSGTIQGGLQDGLQITVNGTVLSSSGTRFA VNFQTGFSGNDIAFHFNPRFEDGGYVVCNTRQNGSWGPEERKTH MPFQKGMPFDLCFLVQSSDFKVMVNGILFVQYFHRVPFHRVDTIS VNGSVQLSYISFQNPRTVPVQPAFSTVPFSQPVCFPPRPRGRRQKPP GVWPANPAPITQTVIHTVQSAPGQMFSTPAIPPMMYPHPAYPMPFI TTILGGLYPSKSILLSGTVLPSAQRFHINLCSGNHIAFHLNPRFDENA VVRNTQIDNSWGSEERSLPRKMPFVRGQSFSVWILCEAHCLKVAV DGQHLFEYYHRLRNLPTINRLEVGGDIQLTHVQT (SEQ ID NO: 207) 208 CDH1 MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHL ERGRVLGRVNFEDCTGRQRTAYFSLDTRFKVGTDGVITVKRPLRF HNPQIHFLVYAWDSTYRKFSTKVTLNTVGHHHRPPPHQASVSGIQ AELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQIKSNKD KEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTL FSHAVSSNGNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGA LPGTSVMEVTATDADDDVNTYNAAIAYTILSQDPELPDKNMFTIN RNTGVISVVTTGLDRESFPTYTLVVQAADLQGEGLSTTATAVITVT DTNDNPPIFNPTTYKGQVPENEANVVITTLKVTDADAPNTPAWEA VYTILNDDGGQFVVTTNPVNNDGILKTAKGLDFEAKQQYILHVAV TNVVPFEVSLTTSTATVTVDVLDVNEAPIFVPPEKRVEVSEDFGVG QEITSYTAQEPDTFMEQKITYRIWRDTANWLEINPDTGAISTRAELD 277 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: REDFEHVKNSTYTALIIATDNGSPVATGTGTLLLILSDVNDNAPIPE PRTIFFCERNPKPQVINIIDADLPPNTSPFTAELTHGASANWTIQYND PTQESIILKPKMALEVGDYKINLKLMDNQNKDQVTTLEVSVCDCE GAAGVCRKAQPVEAGLQIPAILGILGGILALLILILLLLLFLRRRAVV KEPLLPPEDDTRDNVYYYDEEGGGEEDQDFDLSQLHRGLDARPEV TRNDVAPTLMSVPRYLPRPANPDEIGNFIDENLKAADTDPTAPPYD SLLVFDYEGSGSEAASLSSLNSSESDKDQDYDYLNEWGNRFKKLA DMYGGGEDD (SEQ ID NO: 208) 209 IL22 MAALQKSVSSFLMGTLATSCLLLLALLVQGGAAAPISSHCRLDKS NFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCY LMKQVLNFTLEEVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEG DDLHIQRNVQKLKDTVKKLGESGEIKAIGELDLLFMSLRNACI (SEQ ID NO: 209) 210 HLA-F MAPRSLLLLLSGALALTDTWAGSHSLRYFSTAVSRPGRGEPRYIAV EYVDDTQFLRFDSDAAIPRMEPREPWVEQEGPQYWEWTTGYAKA NAQTDRVALRNLLRRYNQSEAGSHTLQGMNGCDMGPDGRLLRG YHQHAYDGKDYISLNEDLRSWTAADTVAQITQRFYEAEEYAEEFR TYLEGECLELLRRYLENGKETLQRADPPKAHVAHHPISDHEATLRC WALGFYPAEITLTWQRDGEEQTQDTELVETRPAGDGTFQKWAAV VVPPGEEQRYTCHVQHEGLPQPLILRWEQSPQPTIPIVGIVAGLVVL GAVVTGAVVAAVMWRKKSSDRNRGSYSQAAV (SEQ ID NO: 210) 211 ANGPTL2 MRPLCVTCWWLGLLAAMGAVAGQEDGFEGTEEGSPREFIYLNRY KRAGESQDKCTYTFIVPQQRVTGAICVNSKEPEVLLENRVHKQELE LLNNELLKQKRQIETLQQLVEVDGGIVSEVKLLRKESRNMNSRVT QLYMQLLHEIIRKRDNALELSQLENRILNQTADMLQLASKYKDLE HKYQHLATLAHNQSEIIAQLEEHCQRVPSARPVPQPPPAAPPRVYQ PPTYNRIINQISTNEIQSDQNLKVLPPPLPTMPTLTSLPSSTDKPSGP WRDCLQALEDGHDTSSIYLVKPENTNRLMQVWCDQRHDPGGWT VIQRRLDGSVNFFRNWETYKQGFGNIDGEYWLGLENIYWLTNQG NYKLLVTMEDWSGRKVFAEYASFRLEPESEYYKLRLGRYHGNAG DSFTWHNGKQFTTLDRDHDVYTGNCAHYQKGGWWYNACAHSN LNGVWYRGGHYRSRYQDGVYWAEFRGGSYSLKKVVMMIRPNPN TFH (SEQ ID NO: 211) 212 DLL1 MGSRCALALAVLSALLCQVWSSGVFELKLQEFVNKKGLLGNRNC CRGGAGPPPCACRTFFRVCLKHYQASVSPEPPCTYGSAVTPVLGV DSFSLPDGGGADSAFSNPIRFPFGFTWPGTFSLIIEALHTDSPDDLAT ENPERLISRLATQRHLTVGEEWSQDLHSSGRTDLKYSYRFVCDEH YYGEGCSVFCRPRDDAFGHFTCGERGEKVCNPGWKGPYCTEPICL PGCDEQHGFCDKPGECKCRVGWQGRYCDECIRYPGCLHGTCQQP WQCNCQEGWGGLFCNQDLNYCTHHKPCKNGATCTNTGQGSYTC SCRPGYTGATCELGIDECDPSPCKNGGSCTDLENSYSCTCPPGFYG KICELSAMTCADGPCFNGGRCSDSPDGGYSCRCPVGYSGFNCEKKI DYCSSSPCSNGAKCVDLGDAYLCRCQAGFSGRHCDDNVDDCASS PCANGGTCRDGVNDFSCTCPPGYTGRNCSAPVSRCEHAPCHNGAT CHERGHRYVCECARGYGGPNCQFLLPELPPGPAVVDLTEKLEGQG GPFPWVAVCAGVILVLMLLLGCAAVVVCVRLRLQKHRPPADPCR GETETMNNLANCQREKDISVSIIGATQIKNTNKKADFHGDHSADK 278 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: NGFKARYPAVDYNLVQDLKGDDTAVRDAHSKRDTKCQPQGSSGE EKGTPTTLRGGEASERKRPDSGCSTSKDTKYQSVYVISEEKDECVI ATEV (SEQ ID NO: 212) 213 JAG1 MRSPRTRGRSGRPLSLLLALLCALRAKVCGASGQFELEILSMQNVN GELQNGNCCGGARNPGDRKCTRDECDTYFKVCLKEYQSRVTAGG PCSFGSGSTPVIGGNTFNLKASRGNDRNRIVLPFSFAWPRSYTLLVE AWDSSNDTVQPDSIIEKASHSGMINPSRQWQTLKQNTGVAHFEYQI RVTCDDYYYGFGCNKFCRPRDDFFGHYACDQNGNKTCMEGWMG PECNRAICRQGCSPKHGSCKLPGDCRCQYGWQGLYCDKCIPHPGC VHGICNEPWQCLCETNWGGQLCDKDLNYCGTHQPCLNGGTCSNT GPDKYQCSCPEGYSGPNCEIAEHACLSDPCHNRGSCKETSLGFECE CSPGWTGPTCSTNIDDCSPNNCSHGGTCQDLVNGFKCVCPPQWTG KTCQLDANECEAKPCVNAKSCKNLIASYYCDCLPGWMGQNCDINI NDCLGQCQNDASCRDLVNGYRCICPPGYAGDHCERDIDECASNPC LNGGHCQNEINRFQCLCPTGFSGNLCQLDIDYCEPNPCQNGAQCY NRASDYFCKCPEDYEGKNCSHLKDHCRTTPCEVIDSCTVAMASND TPEGVRYISSNVCGPHGKCKSQSGGKFTCDCNKGFTGTYCHENIN DCESNPCRNGGTCIDGVNSYKCICSDGWEGAYCETNINDCSQNPC HNGGTCRDLVNDFYCDCKNGWKGKTCHSRDSQCDEATCNNGGT CYDEGDAFKCMCPGGWEGTTCNIARNSSCLPNPCHNGGTCVVNG ESFTCVCKEGWEGPICAQNTNDCSPHPCYNSGTCVDGDNWYRCE CAPGFAGPDCRININECQSSPCAFGATCVDEINGYRCVCPPGHSGA KCQEVSGRPCITMGSVIPDGAKWDDDCNTCQCLNGRIACSKVWC GPRPCLLHKGHSECPSGQSCIPILDDQCFVHPCTGVGECRSSSLQPV KTKCTSDSYYQDNCANITFTFNKEMMSPGLTTEHICSELRNLNILK NVSAEYSIYIACEPSPSANNEIHVAISAEDIRDDGNPIKEITDKIIDLV SKRDGNSSLIAAVAEVRVQRRPLKNRTDFLVPLLSSVLTVAWICCL VTAFYWCLRKRRKPGSHTHSASEDNTTNNVREQLNQIKNPIEKHG ANTVPIKDYENKNSKMSKIRTHNSEVEEDDMDKHQQKARFAKQP AYTLVDREEKPPNGTPTKHPNWTNKQDNRDLESAQSLNRMEYIV (SEQ ID NO: 213) 214 JAG2 MRAQGRGRLPRRLLLLLALWVQAARPMGYFELQLSALRNVNGEL LSGACCDGDGRTTRAGGCGHDECDTYVRVCLKEYQAKVTPTGPC SYGHGATPVLGGNSFYLPPAGAAGDRARARARAGGDQDPGLVVI PFQFAWPRSFTLIVEAWDWDNDTTPNEELLIERVSHAGMINPEDR WKSLHFSGHVAHLELQIRVRCDENYYSATCNKFCRPRNDFFGHYT CDQYGNKACMDGWMGKECKEAVCKQGCNLLHGGCTVPGECRC SYGWQGRFCDECVPYPGCVHGSCVEPWQCNCETNWGGLLCDKD LNYCGSHHPCTNGGTCINAEPDQYRCTCPDGYSGRNCEKAEHACT SNPCANGGSCHEVPSGFECHCPSGWSGPTCALDIDECASNPCAAG GTCVDQVDGFECICPEQWVGATCQLDANECEGKPCLNAFSCKNLI GGYYCDCIPGWKGINCHINVNDCRGQCQHGGTCKDLVNGYQCVC PRGFGGRHCELERDECASSPCHSGGLCEDLADGFHCHCPQGFSGPL CEVDVDLCEPSPCRNGARCYNLEGDYYCACPDDFGGKNCSVPREP CPGGACRVIDGCGSDAGPGMPGTAASGVCGPHGRCVSQPGGNFSC ICDSGFTGTYCHENIDDCLGQPCRNGGTCIDEVDAFRCFCPSGWEG ELCDTNPNDCLPDPCHSRGRCYDLVNDFYCACDDGWKGKTCHSR 279 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: EFQCDAYTCSNGGTCYDSGDTFRCACPPGWKGSTCAVAKNSSCLP NPCVNGGTCVGSGASFSCICRDGWEGRTCTHNTNDCNPLPCYNGG ICVDGVNWFRCECAPGFAGPDCRINIDECQSSPCAYGATCVDEING YRCSCPPGRAGPRCQEVIGFGRSCWSRGTPFPHGSSWVEDCNSCRC LDGRRDCSKVWCGWKPCLLAGQPEALSAQCPLGQRCLEKAPGQC LRPPCEAWGECGAEEPPSTPCLPRSGHLDNNCARLTLHFNRDHVP QGTTVGAICSGIRSLPATRAVARDRLLVLLCDRASSGASAVEVAVS FSPARDLPDSSLIQGAAHAIVAAITQRGNSSLLLAVTEVKVETVVT GGSSTGLLVPVLCGAFSVLWLACVVLCVWWTRKRRKERERSRLP REESANNQWAPLNPIRNPIERPGGHKDVLYQCKNFTPPPRRADEAL PGPAGHAAVREDEEDEDLGRGEEDSLEAEKFLSHKFTKDPGRSPG RPAHWASGPKVDNRAVRSINEARYAGKE (SEQ ID NO: 214) 215 TGFB1 MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRI EAIRGQILSKLRLASPPSQGEVPPGPLPEAVLALYNSTRDRVAGESA EPEPEPEADYYAKEVTRVLMVETHNEIYDKFKQSTHSIYMFFNTSE LREAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNNSWRYLSN RLLAPSDSPEWLSFDVTGVVRQWLSRGGEIEGFRLSAHCSCDSRDN TLQVDINGFTTGRRGDLATIHGMNRPFLLLMATPLERAQHLQSSRH RRALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANF CLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIV YYVGRKPKVEQLSNMIVRSCKCS (SEQ ID NO: 215) 216 TGFB3 MKMHLQRALVVLALLNFATVSLSLSTCTTLDFGHIKKKRVEAIRG QILSKLRLTSPPEPTVMTHVPYQVLALYNSTRELLEEMHGEREEGC TQENTESEYYAKEIHKFDMIQGLAEHNELAVCPKGITSKVFRFNVS SVEKNRTNLFRAEFRVLRVPNPSSKRNEQRIELFQILRPDEHIAKQR YIGGKNLPTRGTAEWLSFDVTDTVREWLLRRESNLGLEISIHCPCH TFQPNGDILENIHEVMEIKFKGVDNEDDHGRGDLGRLKKQKDHHN PHLILMMIPPHRLDNPGQGGQRKKRALDTNYCFRNLEENCCVRPL YIDFRQDLGWKWVHEPKGYYANFCSGPCPYLRSADTTHSTVLGL YNTLNPEASASPCCVPQDLEPLTILYYVGRTPKVEQLSNMVVKSCK CS (SEQ ID NO: 216) 217 VEGFC MHLLGFFSVACSLLAAALLPGPREAPAAAAAFESGLDLSDAEPDA GEATAYASKDLEEQLRSVSSVDELMTVLYPEYWKMYKCQLRKGG WQHNREQANLNSRTEETIKFAAAHYNTEILKSIDNEWRKTQCMPR EVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGLQCMNTSTS YLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIR RSLPATLPQCQAANKTCPTNYMWNNHICRCLAQEDFMFSSDAGD DSTDGFHDICGPNKELDEETCQCVCRAGLRPASCGPHKELDRNSC QCVCKNKLFPSQCGANREFDENTCQCVCKRTCPRNQPLNPGKCAC ECTESPQKCLLKGKKFHHQTCSCYRRPCTNRQKACEPGFSYSEEVC RCVPSYWKRPQMS (SEQ ID NO: 217) 218 PGF MPVMRLFPCFLQLLAGLALPAVPPQQWALSAGNGSSEVEVVPFQE VWGRSYCRALERLVDVVSEYPSEVEHMFSPSCVSLLRCTGCCGDE NLHCVPVETANVTMQLLKIRSGDRPSYVELTFSQHVRCECRHSPG RQSPDMPGDFRADAPSFLPPRRSLPMLFRMEWGCALTGSQSAVWP SSPVPEEIPRMHPGRNGKKQQRKPLREKMKPERCGDAVPRR (SEQ ID NO: 218) 280 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: 219 IL18 MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLS VIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQP RGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRS VPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMF TVQNED (SEQ ID NO: 219) 220 APP MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMH MNVQNGKWDSDPSGTKTCIDTKEGILQYCQEVYPELQITNVVEAN QPVTIQNWCKRGRKQCKTHPHFVIPYRCLVGEFVSDALLVPDKCK FLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDK FRGVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSE DKVVEVAEEEEVAEVEEEEADDDEDDEDGDEVEEEAEEPYEEATE RTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTE GKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPL ARDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKH RERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEA ANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHV FNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTH LRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLA NMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHSF GADSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVK MDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIAT VIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYEN PTYKFFEQMQN (SEQ ID NO: 220) 221 TNFSF15 MAEDLGLSFGETASVEMLPEHGSCRPKARSSSARWALTCCLVLLP FLAGLTTYLLVSQLRAQGEACVQFQALKGQEFAPSHQQVYAPLRA DGDKPRAHLTVVRQTPTQHFKNQFPALHWEHELGLAFTKNRMNY TNKFLLIPESGDYFIYSQVTFRGMTSECSEIRQAGRPNKPDSITVVIT KVTDSYPEPTQLLMGTKSVCEVGSNWFQPIYLGAMFSLQEGDKLM VNVSDISLVDYTKEDKTFFGAFLL (SEQ ID NO: 221) 222 VCAM1 MPGKMVVILGASNILWIMFAASQAFKIETTPESRYLAQIGDSVSLT CSTTGCESPFFSWRTQIDSPLNGKVTNEGTTSTLTMNPVSFGNEHS YLCTATCESRKLEKGIQVEIYSFPKDPEIHLSGPLEAGKPITVKCSVA DVYPFDRLEIDLLKGDHLMKSQEFLEDADRKSLETKSLEVTFTPVI EDIGKVLVCRAKLHIDEMDSVPTVRQAVKELQVYISPKNTVISVNP STKLQEGGSVTMTCSSEGLPAPEIFWSKKLDNGNLQHLSGNATLTL IAMRMEDSGIYVCEGVNLIGKNRKEVELIVQEKPFTVEISPGPRIAA QIGDSVMLTCSVMGCESPSFSWRTQIDSPLSGKVRSEGTNSTLTLSP VSFENEHSYLCTVTCGHKKLEKGIQVELYSFPRDPEIEMSGGLVNG SSVTVSCKVPSVYPLDRLEIELLKGETILENIEFLEDTDMKSLENKSL EMTFIPTIEDTGKALVCQAKLHIDDMEFEPKQRQSTQTLYVNVAPR DTTVLVSPSSILEEGSSVNMTCLSQGFPAPKILWSRQLPNGELQPLS ENATLTLISTKMEDSGVYLCEGINQAGRSRKEVELIIQVTPKDIKLT AFPSESVKEGDTVIISCTCGNVPETWIILKKKAETGDTVLKSIDGAY TIRKAQLKDAGVYECESKNKVGSQLRSLTLDVQGRENNKDYFSPE LLVLYFASSLIIPAIGMIIYFARKANMKGSYSLVEAQKSKV (SEQ ID NO: 222) 223 ITGAM MALRVLLLTALTLCHGFNLDTENAMTFQENARGFGQSVVQLQGS 281 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: RVVVGAPQEIVAANQRGSLYQCDYSTGSCEPIRLQVPVEAVNMSL GLSLAATTSPPQLLACGPTVHQTCSENTYVKGLCFLFGSNLRQQPQ KFPEALRGCPQEDSDIAFLIDGSGSIIPHDFRRMKEFVSTVMEQLKK SKTLFSLMQYSEEFRIHFTFKEFQNNPNPRSLVKPITQLLGRTHTAT GIRKVVRELFNITNGARKNAFKILVVITDGEKFGDPLGYEDVIPEAD REGVIRYVIGVGDAFRSEKSRQELNTIASKPPRDHVFQVNNFEALK TIQNQLREKIFAIEGTQTGSSSSFEHEMSQEGFSAAITSNGPLLSTVG SYDWAGGVFLYTSKEKSTFINMTRVDSDMNDAYLGYAAAIILRNR VQSLVLGAPRYQHIGLVAMFRQNTGMWESNANVKGTQIGAYFGA SLCSVDVDSNGSTDLVLIGAPHYYEQTRGGQVSVCPLPRGRARWQ CDAVLYGEQGQPWGRFGAALTVLGDVNGDKLTDVAIGAPGEEDN RGAVYLFHGTSGSGISPSHSQRIAGSKLSPRLQYFGQSLSGGQDLT MDGLVDLTVGAQGHVLLLRSQPVLRVKAIMEFNPREVARNVFEC NDQVVKGKEAGEVRVCLHVQKSTRDRLREGQIQSVVTYDLALDS GRPHSRAVFNETKNSTRRQTQVLGLTQTCETLKLQLPNCIEDPVSPI VLRLNFSLVGTPLSAFGNLRPVLAEDAQRLFTALFPFEKNCGNDNI CQDDLSITFSFMSLDCLVVGGPREFNVTVTVRNDGEDSYRTQVTFF FPLDLSYRKVSTLQNQRSQRSWRLACESASSTEVSGALKSTSCSIN HPIFPENSEVTFNITFDVDSKASLGNKLLLKANVTSENNMPRTNKT EFQLELPVKYAVYMVVTSHGVSTKYLNFTASENTSRVMQHQYQV SNLGQRSLPISLVFLVPVRLNQTVIWDRPQVTFSENLSSTCHTKERL PSHSDFLAELRKAPVVNCSIAVCQRIQCDIPFFGIQEEFNATLKGNL SFDWYIKTSHNHLLIVSTAEILFNDSVFTLLPGQGAFVRSQTETKVE PFEVPNPLPLIVGSSVGGLLLLALITAALYKLGFFKRQYKDMMSEG GPPGAEPQ (SEQ ID NO: 223) 224 FGF2 MVGVGGGDVEDVTPRPGGCQISGRGARGCNGIPGAAAWEAALPR RRPRRHPSVNPRSRAAGSPRTRGRRTEERPSGSRLGDRGRGRALPG GRLGGRGRGRAPERVGGRGRGRGTAAPRAAPAARGSRPGPAGTM AAGSITTLPALPEDGGSGAFPPGHFKDPKRLYCKNGGFFLRIHPDG RVDGVREKSDPHIKLQLQAEERGVVSIKGVCANRYLAMKEDGRLL ASKCVTDECFFFERLESNNYNTYRSRKYTSWYVALKRTGQYKLGS KTGPGQKAILFLPMSAKS (SEQ ID NO: 224) 225 POSTN MIPFLPMFSLLLLLIVNPINANNHYDKILAHSRIRGRDQGPNVCALQ QILGTKKKYFSTCKNWYKKSICGQKTTVLYECCPGYMRMEGMKG CPAVLPIDHVYGTLGIVGATTTQRYSDASKLREEIEGKGSFTYFAPS NEAWDNLDSDIRRGLESNVNVELLNALHSHMINKRMLTKDLKNG MIIPSMYNNLGLFINHYPNGVVTVNCARIIHGNQIATNGVVHVIDR VLTQIGTSIQDFIEAEDDLSSFRAAAITSDILEALGRDGHFTLFAPTN EAFEKLPRGVLERIMGDKVASEALMKYHILNTLQCSESIMGGAVFE TLEGNTIEIGCDGDSITVNGIKMVNKKDIVTNNGVIHLIDQVLIPDS AKQVIELAGKQQTTFTDLVAQLGLASALRPDGEYTLLAPVNNAFS DDTLSMDQRLLKLILQNHILKVKVGLNELYNGQILETIGGKQLRVF VYRTAVCIENSCMEKGSKQGRNGAIHIFREIIKPAEKSLHEKLKQD KRFSTFLSLLEAADLKELLTQPGDWTLFVPTNDAFKGMTSEEKEILI RDKNALQNIILYHLTPGVFIGKGFEPGVTNILKTTQGSKIFLKEVND TLLVNELKSKESDIMTTNGVIHVVDKLLYPADTPVGNDQLLEILNK LIKYIQIKFVRGSTFKEIPVTVYTTKIITKVVEPKIKVIEGSLQPIIKTE 282 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: GPTLTKVKIEGEPEFRLIKEGETITEVIHGEPIIKKYTKIIDGVPVEITE KETREERIITGPEIKYTRISTGGGETEETLKKLLQEEVTKVTKFIEGG DGHLFEDEEIKRLLQGDTPVRKLQANKKVQGSRRRLREGRSQ (SEQ ID NO: 225) 226 LAMA5 MAKRLCAGSALCVRGPRGPAPLLLVGLALLGAARAREEAGGGFSL HPPYFNLAEGARIAASATCGEEAPARGSPRPTEDLYCKLVGGPVAG GDPNQTIRGQYCDICTAANSNKAHPASNAIDGTERWWQSPPLSRG LEYNEVNVTLDLGQVFHVAYVLIKFANSPRPDLWVLERSMDFGRT YQPWQFFASSKRDCLERFGPQTLERITRDDAAICTTEYSRIVPLENG EIVVSLVNGRPGAMNFSYSPLLREFTKATNVRLRFLRTNTLLGHLM GKALRDPTVTRRYYYSIKDISIGGRCVCHGHADACDAKDPTDPFRL QCTCQHNTCGGTCDRCCPGFNQQPWKPATANSANECQSCNCYGH ATDCYYDPEVDRRRASQSLDGTYQGGGVCIDCQHHTTGVNCERC LPGFYRSPNHPLDSPHVCRRCNCESDFTDGTCEDLTGRCYCRPNFS GERCDVCAEGFTGFPSCYPTPSSSNDTREQVLPAGQIVNCDCSAAG TQGNACRKDPRVGRCLCKPNFQGTHCELCAPGFYGPGCQPCQCSS PGVADDRCDPDTGQCRCRVGFEGATCDRCAPGYFHFPLCQLCGCS PAGTLPEGCDEAGRCLCQPEFAGPHCDRCRPGYHGFPNCQACTCD PRGALDQLCGAGGLCRCRPGYTGTACQECSPGFHGFPSCVPCHCS AEGSLHAACDPRSGQCSCRPRVTGLRCDTCVPGAYNFPYCEAGSC HPAGLAPVDPALPEAQVPCMCRAHVEGPSCDRCKPGFWGLSPSNP EGCTRCSCDLRGTLGGVAECQPGTGQCFCKPHVCGQACASCKDG FFGLDQADYFGCRSCRCDIGGALGQSCEPRTGVCRCRPNTQGPTCS EPARDHYLPDLHHLRLELEEAATPEGHAVRFGFNPLEFENFSWRG YAQMAPVQPRIVARLNLTSPDLFWLVFRYVNRGAMSVSGRVSVR EEGRSATCANCTAQSQPVAFPPSTEPAFITVPQRGFGEPFVLNPGT WALRVEAEGVLLDYVVLLPSAYYEAALLQLRVTEACTYRPSAQQ SGDNCLLYTHLPLDGFPSAAGLEALCRQDNSLPRPCPTEQLSPSHPP LITCTGSDVDVQLQVAVPQPGRYALVVEYANEDARQEVGVAVHT PQRAPQQGLLSLHPCLYSTLCRGTARDTQDHLAVFHLDSEASVRL TAEQARFFLHGVTLVPIEEFSPEFVEPRVSCISSHGAFGPNSAACLPS RFPKPPQPIILRDCQVIPLPPGLPLTHAQDLTPAMSPAGPRPRPPTAV DPDAEPTLLREPQATVVFTTHVPTLGRYAFLLHGYQPAHPTFPVEV LINAGRVWQGHANASFCPHGYGCRTLVVCEGQALLDVTHSELTV TVRVPKGRWLWLDYVLVVPENVYSFGYLREEPLDKSYDFISHCAA QGYHISPSSSSLFCRNAAASLSLFYNNGARPCGCHEVGATGPTCEP FGGQCPCHAHVIGRDCSRCATGYWGFPNCRPCDCGARLCDELTG QCICPPRTIPPDCLLCQPQTFGCHPLVGCEECNCSGPGIQELTDPTCD TDSGQCKCRPNVTGRRCDTCSPGFHGYPRCRPCDCHEAGTAPGVC DPLTGQCYCKENVQGPKCDQCSLGTFSLDAANPKGCTRCFCFGAT ERCRSSSYTRQEFVDMEGWVLLSTDRQVVPHERQPGTEMLRADL RHVPEAVPEAFPELYWQAPPSYLGDRVSSYGGTLRYELHSETQRG DVFVPMESRPDVVLQGNQMSITFLEPAYPTPGHVHRGQLQLVEGN FRHTETRNTVSREELMMVLASLEQLQIRALFSQISSAVFLRRVALE VASPAGQGALASNVELCLCPASYRGDSCQECAPGFYRDVKGLFLG RCVPCQCHGHSDRCLPGSGVCVDCQHNTEGAHCERCQAGFVSSR DDPSAPCVSCPCPLSVPSNNFAEGCVLRGGRTQCLCKPGYAGASCE 283 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: RCAPGFFGNPLVLGSSCQPCDCSGNGDPNLLFSDCDPLTGACRGCL RHTTGPRCEICAPGFYGNALLPGNCTRCDCTPCGTEACDPHSGHCL CKAGVTGRRCDRCQEGHFGFDGCGGCRPCACGPAAEGSECHPQS GQCHCRPGTMGPQCRECAPGYWGLPEQGCRRCQCPGGRCDPHTG RCNCPPGLSGERCDTCSQQHQVPVPGGPVGHSIHCEVCDHCVVLL LDDLERAGALLPAIHEQLRGINASSMAWARLHRLNASIADLQSQL RSPLGPRHETAQQLEVLEQQSTSLGQDARRLGGQAVGTRDQASQL LAGTEATLGHAKTLLAAIRAVDRTLSELMSQTGHLGLANASAPSG EQLLRTLAEVERLLWEMRARDLGAPQAAAEAELAAAQRLLARVQ EQLSSLWEENQALATQTRDRLAQHEAGLMDLREALNRAVDATRE AQELNSRNQERLEEALQRKQELSRDNATLQATLHAARDTLASVFR LLHSLDQAKEELERLAASLDGARTPLLQRMQTFSPAGSKLRLVEA AEAHAQQLGQLALNLSSIILDVNQDRLTQRAIEASNAYSRILQAVQ AAEDAAGQALQQADHTWATVVRQGLVDRAQQLLANSTALEEAM LQEQQRLGLVWAALQGARTQLRDVRAKKDQLEAHIQAAQAMLA MDTDETSKKIAHAKAVAAEAQDTATRVQSQLQAMQENVERWQG QYEGLRGQDLGQAVLDAGHSVSTLEKTLPQLLAKLSILENRGVHN ASLALSASIGRVRELIAQARGAASKVKVPMKFNGRSGVQLRTPRD LADLAAYTALKFYLQGPEPEPGQGTEDRFVMYMGSRQATGDYMG VSLRDKKVHWVYQLGEAGPAVLSIDEDIGEQFAAVSLDRTLQFGH MSVTVERQMIQETKGDTVAPGAEGLLNLRPDDFVFYVGGYPSTFT PPPLLRFPGYRGCIEMDTLNEEVVSLYNFERTFQLDTAVDRPCARS KSTGDPWLTDGSYLDGTGFARISFDSQISTTKRFEQELRLVSYSGVL FFLKQQSQFLCLAVQEGSLVLLYDFGAGLKKAVPLQPPPPLTSASK AIQVFLLGGSRKRVLVRVERATVYSVEQDNDLELADAYYLGGVPP DQLPPSLRRLFPTGGSVRGCVKGIKALGKYVDLKRLNTTGVSAGC TADLLVGRAMTFHGHGFLRLALSNVAPLTGNVYSGFGFHSAQDSA LLYYRASPDGLCQVSLQQGRVSLQLLRTEVKTQAGFADGAPHYV AFYSNATGVWLYVDDQLQQMKPHRGPPPELQPQPEGPPRLLLGGL PESGTIYNFSGCISNVFVQRLLGPQRVFDLQQNLGSVNVSTGCAPA LQAQTPGLGPRGLQATARKASRRSRQPARHPACMLPPHLRTTRDS YQFGGSLSSHLEFVGILARHRNWPSLSMHVLPRSSRGLLLFTARLR PGSPSLALFLSNGHFVAQMEGLGTRLRAQSRQRSRPGRWHKVSVR WEKNRILLVTDGARAWSQEGPHRQHQGAEHPQPHTLFVGGLPASS HSSKLPVTVGFSGCVKRLRLHGRPLGAPTRMAGVTPCILGPLEAGL FFPGSGGVITLDLPGATLPDVGLELEVRPLAVTGLIFHLGQARTPPY LQLQVTEKQVLLRADDGAGEFSTSVTRPSVLCDGQWHRLAVMKS GNVLRLEVDAQSNHTVGPLLAAAAGAPAPLYLGGLPEPMAVQPW PPAYCGCMRRLAVNRSPVAMTRSVEVHGAVGASGCPAA (SEQ ID NO: 226) 227 LAMB3 MRPFFLLCFALPGLLHAQQACSRGACYPPVGDLLVGRTRFLRASST CGLTKPETYCTQYGEWQMKCCKCDSRQPHNYYSHRVENVASSSG PMRWWQSQNDVNPVSLQLDLDRRFQLQEVMMEFQGPMPAGMLI ERSSDFGKTWRVYQYLAADCTSTFPRVRQGRPQSWQDVRCQSLP QRPNARLNGGKVQLNLMDLVSGIPATQSQKIQEVGEITNLRVNFTR LAPVPQRGYHPPSAYYAVSQLRLQGSCFCHGHADRCAPKPGASAG PSTAVQVHDVCVCQHNTAGPNCERCAPFYNNRPWRPAEGQDAHE 284 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: CQRCDCNGHSETCHFDPAVFAASQGAYGGVCDNCRDHTEGKNCE RCQLHYFRNRRPGASIQETCISCECDPDGAVPGAPCDPVTGQCVCK EHVQGERCDLCKPGFTGLTYANPQGCHRCDCNILGSRRDMPCDEE SGRCLCLPNVVGPKCDQCAPYHWKLASGQGCEPCACDPHNSLSPQ CNQFTGQCPCREGFGGLMCSAAAIRQCPDRTYGDVATGCRACDC DFRGTEGPGCDKASGRCLCRPGLTGPRCDQCQRGYCNRYPVCVA CHPCFQTYDADLREQALRFGRLRNATASLWSGPGLEDRGLASRIL DAKSKIEQIRAVLSSPAVTEQEVAQVASAILSLRRTLQGLQLDLPLE EETLSLPRDLESLDRSFNGLLTMYQRKREQFEKISSADPSGAFRMLS TAYEQSAQAAQQVSDSSRLLDQLRDSRREAERLVRQAGGGGGTG SPKLVALRLEMSSLPDLTPTFNKLCGNSRQMACTPISCPGELCPQD NGTACGSRCRGVLPRAGGAFLMAGQVAEQLRGFNAQLQRTRQMI RAAEESASQIQSSAQRLETQVSASRSQMEEDVRRTRLLIQQVRDFL TDPDTDAATIQEVSEAVLALWLPTDSATVLQKMNEIQAIAARLPNV DLVLSQTKQDIARARRLQAEAEEARSRAHAVEGQVEDVVGNLRQ GTVALQEAQDTMQGTSRSLRLIQDRVAEVQQVLRPAEKLVTSMT KQLGDFWTRMEELRHQARQQGAEAVQAQQLAEGASEQALSAQE GFERIKQKYAELKDRLGQSSMLGEQGARIQSVKTEAEELFGETME MMDRMKDMELELLRGSQAIMLRSADLTGLEKRVEQIRDHINGRV LYYATCK (SEQ ID NO: 227) 228 GZMA MRNSYRFLASSLSVVVSLLLIPEDVCEKIIGGNEVTPHSRPYMVLLS LDRKTICAGALIAKDWVLTAAHCNLNKRSQVILGAHSITREEPTKQ IMLVKKEFPYPCYDPATREGDLKLLQLMEKAKINKYVTILHLPKK GDDVKPGTMCQVAGWGRTHNSASWSDTLREVNITIIDRKVCNDR NHYNFNPVIGMNMVCAGSLRGGRDSCNGDSGSPLLCEGVFRGVTS FGLENKCGDPRGPGVYILLSKKHLNWIIMTIKGAV (SEQ ID NO: 228) 229 PRSS3 MCGPDDRCPARWPGPGRAVKCGKGLAAARPGRVERGGAQRGGA GLELHPLLGGRTWRAARDADGCEALGTVAVPFDDDDKIVGGYTC EENSLPYQVSLNSGSHFCGGSLISEQWVVSAAHCYKTRIQVRLGEH NIKVLEGNEQFINAAKIIRHPKYNRDTLDNDIMLIKLSSPAVINARV STISLPTTPPAAGTECLISGWGNTLSFGADYPDELKCLDAPVLTQAE CKASYPGKITNSMFCVGFLEGGKDSCQRDSGGPVVCNGQLQGVVS WGHGCAWKNRPGVYTKVYNYVDWIKDTIAANS (SEQ ID NO: 229) 230 SERPING1 MASRLTLLTLLLLLLAGDRASSNPNATSSSSQDPESLQDRGEGKVA TTVISKMLFVEPILEVSSLPTTNSTTNSATKITANTTDEPTTQPTTEP TTQPTIQPTQPTTQLPTDSPTQPTTGSFCPGPVTLCSDLESHSTEAVL GDALVDFSLKLYHAFSAMKKVETNMAFSPFSIASLLTQVLLGAGE NTKTNLESILSYPKDFTCVHQALKGFTTKGVTSVSQIFHSPDLAIRD TFVNASRTLYSSSPRVLSNNSDANLELINTWVAKNTNNKISRLLDS LPSDTRLVLLNAIYLSAKWKTTFDPKKTRMEPFHFKNSVIKVPMM NSKKYPVAHFIDQTLKAKVGQLQLSHNLSLVILVPQNLKHRLEDM EQALSPSVFKAIMEKLEMSKFQPTLLTLPRIKVTTSQDMLSIMEKLE FFDFSYDLNLCGLTEDPDLQVSAMQHQTVLELTETGVEAAAASAIS VARTLLVFEVQQPFLFVLWDQQHKFPVFMGRVYDPRA (SEQ ID NO: 230) 285 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: 231 EDN1 MDYLLMIFSLLFVACQGAPETAVLGAELSAVGENGGEKPTPSPPW RLRRSKRCSCSSLMDKECVYFCHLDIIWVNTPEHVVPYGLGSPRSK RALENLLPTKATDRENRCQCASQKDKKCWNFCQAGKELRAEDIM EKDWNNHKKGKDCSKLGKKCIYQQLVRGRKIRRSSEEHLRQTRSE TMRNSVKSSFHDPKLKGKPSRERYVTHNRAHW (SEQ ID NO: 231) 232 EDN3 MEPGLWLLFGLTVTSAAGFVPCSQSGDAGRRGVSQAPTAARSEGD CEETVAGPGEETVAGPGEGTVAPTALQGPSPGSPGQEQAAEGAPE HHRSRRCTCFTYKDKECVYYCHLDIIWINTPEQTVPYGLSNYRGSF RGKRSAGPLPGNLQLSHRPHLRCACVGRYDKACLHFCTQTLDVSS NSRTAEKTDKEEEGKVEVKDQQSKQALDLHHPKLMPGSGLALAP STCPRCLFQEGAP (SEQ ID NO: 232) 233 HLA.DRA MAISGVPVLGFFIIAVLMSAQESWAIKEEHVIIQAEFYLNPDQSGEF MFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVD KANLEIMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTP PVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDV YDCRVEHWGLDEPLLKHWEFDAPSPLPETTENVVCALGLTVGLV GIIIGTIFIIKGLRKSNAAERRGPL (SEQ ID NO: 233) 234 CD1D MGCLLFLLLWALLQAWGSAEVPQRLFPLRCLQISSFANSSWTRTD GLAWLGELQTHSWSNDSDTVRSLKPWSQGTFSDQQWETLQHIFR VYRSSFTRDVKEFAKMLRLSYPLELQVSAGCEVHPGNASNNFFHV AFQGKDILSFQGTSWEPTQEAPLWVNLAIQVLNQDKWTRETVQW LLNGTCPQFVSGLLESGKSELKKQVKPKAWLSRGPSPGPGRLLLVC HVSGFYPKPVWVKWMRGEQEQQGTQPGDILPNADETWYLRATL DVVAGEAAGLSCRVKHSSLEGQDIVLYWGGSYTSMGLIALAVLA CLLFLLIVGFTSRFKRQTSYQGVL (SEQ ID NO: 234) 235 TNFSF10 MAMMEVQGGPSLGQTCVLIVIFTVLLQSLCVAVTYVYFTNELKQ MQDKYSKSGIACFLKEDDSYWDPNDEESMNSPCWQVKWQLRQL VRKMILRTSEETISTVQEKQQNISPLVRERGPQRVAAHITGTRGRSN TLSSPNSKNEKALGRKINSWESSRSGHSFLSNLHLRNGELVIHEKGF YYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMKSAR NSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEAS FFGAFLVG (SEQ ID NO: 235) 236 VWF MIPARFAGVLLALALILPGTLCAEGTRGRSSTARCSLFGSDFVNTFD GSMYSFAGYCSYLLAGGCQKRSFSIIGDFQNGKRVSLSVYLGEFFD IHLFVNGTVTQGDQRVSMPYASKGLYLETEAGYYKLSGEAYGFV ARIDGSGNFQVLLSDRYFNKTCGLCGNFNIFAEDDFMTQEGTLTSD PYDFANSWALSSGEQWCERASPPSSSCNISSGEMQKGLWEQCQLL KSTSVFARCHPLVDPEPFVALCEKTLCECAGGLECACPALLEYART CAQEGMVLYGWTDHSACSPVCPAGMEYRQCVSPCARTCQSLHIN EMCQERCVDGCSCPEGQLLDEGLCVESTECPCVHSGKRYPPGTSLS RDCNTCICRNSQWICSNEECPGECLVTGQSHFKSFDNRYFTFSGICQ YLLARDCQDHSFSIVIETVQCADDRDAVCTRSVTVRLPGLHNSLVK LKHGAGVAMDGQDVQLPLLKGDLRIQHTVTASVRLSYGEDLQMD WDGRGRLLVKLSPVYAGKTCGLCGNYNGNQGDDFLTPSGLAEPR VEDFGNAWKLHGDCQDLQKQHSDPCALNPRMTRFSEEACAVLTS PTFEACHRAVSPLPYLRNCRYDVCSCSDGRECLCGALASYAAACA GRGVRVAWREPGRCELNCPKGQVYLQCGTPCNLTCRSLSYPDEEC 286 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: NEACLEGCFCPPGLYMDERGDCVPKAQCPCYYDGEIFQPEDIFSDH HTMCYCEDGFMHCTMSGVPGSLLPDAVLSSPLSHRSKRSLSCRPP MVKLVCPADNLRAEGLECTKTCQNYDLECMSMGCVSGCLCPPGM VRHENRCVALERCPCFHQGKEYAPGETVKIGCNTCVCQDRKWNC TDHVCDATCSTIGMAHYLTFDGLKYLFPGECQYVLVQDYCGSNPG TFRILVGNKGCSHPSVKCKKRVTILVEGGEIELFDGEVNVKRPMKD ETHFEVVESGRYIILLLGKALSVVWDRHLSISVVLKQTYQEKVCGL CGNFDGIQNNDLTSSNLQVEEDPVDFGNSWKVSSQCADTRKVPLD SSPATCHNNIMKQTMVDSSCRILTSDVFQDCNKLVDPEPYLDVCIY DTCSCESIGDCACFCDTIAAYAHVCAQHGKVVTWRTATLCPQSCE ERNLRENGYECEWRYNSCAPACQVTCQHPEPLACPVQCVEGCHA HCPPGKILDELLQTCVDPEDCPVCEVAGRRFASGKKVTLNPSDPEH CQICHCDVVNLTCEACQEPGGLVVPPTDAPVSPTTLYVEDISEPPLH DFYCSRLLDLVFLLDGSSRLSEAEFEVLKAFVVDMMERLRISQKW VRVAVVEYHDGSHAYIGLKDRKRPSELRRIASQVKYAGSQVASTS EVLKYTLFQIFSKIDRPEASRITLLLMASQEPQRMSRNFVRYVQGL KKKKVIVIPVGIGPHANLKQIRLIEKQAPENKAFVLSSVDELEQQRD EIVSYLCDLAPEAPPPTLPPDMAQVTVGPGLLGVSTLGPKRNSMVL DVAFVLEGSDKIGEADFNRSKEFMEEVIQRMDVGQDSIHVTVLQY SYMVTVEYPFSEAQSKGDILQRVREIRYQGGNRTNTGLALRYLSD HSFLVSQGDREQAPNLVYMVTGNPASDEIKRLPGDIQVVPIGVGPN ANVQELERIGWPNAPILIQDFETLPREAPDLVLQRCCSGEGLQIPTL SPAPDCSQPLDVILLLDGSSSFPASYFDEMKSFAKAFISKANIGPRLT QVSVLQYGSITTIDVPWNVVPEKAHLLSLVDVMQREGGPSQIGDA LGFAVRYLTSEMHGARPGASKAVVILVTDVSVDSVDAAADAARS NRVTVFPIGIGDRYDAAQLRILAGPAGDSNVVKLQRIEDLPTMVTL GNSFLHKLCSGFVRICMDEDGNEKRPGDVWTLPDQCHTVTCQPD GQTLLKSHRVNCDRGLRPSCPNSQSPVKVEETCGCRWTCPCVCTG SSTRHIVTFDGQNFKLTGSCSYVLFQNKEQDLEVILHNGACSPGAR QGCMKSIEVKHSALSVELHSDMEVTVNGRLVSVPYVGGNMEVNV YGAIMHEVRFNHLGHIFTFTPQNNEFQLQLSPKTFASKTYGLCGIC DENGANDFMLRDGTVTTDWKTLVQEWTVQRPGQTCQPILEEQCL VPDSSHCQVLLLPLFAECHKVLAPATFYAICQQDSCHQEQVCEVIA SYAHLCRTNGVCVDWRTPDFCAMSCPPSLVYNHCEHGCPRHCDG NVSSCGDHPSEGCFCPPDKVMLEGSCVPEEACTQCIGEDGVQHQF LEAWVPDHQPCQICTCLSGRKVNCTTQPCPTAKAPTCGLCEVARL RQNADQCCPEYECVCDPVSCDLPPVPHCERGLQPTLTNPGECRPNF TCACRKEECKRVSPPSCPPHRLPTLRKTQCCDEYECACNCVNSTVS CPLGYLASTATNDCGCTTTTCLPDKVCVHRSTIYPVGQFWEEGCD VCTCTDMEDAVMGLRVAQCSQKPCEDSCRSGFTYVLHEGECCGR CLPSACEVVTGSPRGDSQSSWKSVGSQWASPENPCLINECVRVKEE VFIQQRNVSCPQLEVPVCPSGFQLSCKTSACCPSCRCERMEACMLN GTVIGPGKTVMIDVCTTCRCMVQVGVISGFKLECRKTTCNPCPLG YKEENNTGECCGRCLPTACTIQLRGGQIMTLKRDETLQDGCDTHF CKVNERGEYFWEKRVTGCPPFDEHKCLAEGGKIMKIPGTCCDTCE EPECNDITARLQYVKVGSCKSEVEVDIHYCQGKCASKAMYSIDIND VQDQCSCCSPTRTEPMQVALHCTNGSVVYHEVLNAMECKCSPRK 287 WBD (US) 4854-8046-9185v2 SEQ SEQUENCE SEQUENCE ID DESCRIPTION NO: CSK (SEQ ID NO: 236) 237 LIF MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNL MNQIRSQLAQLNGSANALFILYYTAQGEPFPNNLDKLCGPNVTDFP PFHANGTEKAKLVELYRIVVYLGTSLGNITRDQKILNPSALSLHSKL NATADILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKK KLGCQLLGKYKQIIAVLAQAF (SEQ ID NO: 237) 238 ADAM12 MAARPLPVSPARALLLALAGALLAPCEARGVSLWNQGRADEVVS ASVGSGDLWIPVKSFDSKNHPEVLNIRLQRESKELIINLERNEGLIAS SFTETHYLQDGTDVSLARNYTVILGHCYYHGHVRGYSDSAVSLST CSGLRGLIVFENESYVLEPMKSATNRYKLFPAKKLKSVRGSCGSHH NTPNLAAKNVFPPPSQTWARRHKRETLKATKYVELVIVADNREFQ RQGKDLEKVKQRLIEIANHVDKFYRPLNIRIVLVGVEVWNDMDKC SVSQDPFTSLHEFLDWRKMKLLPRKSHDNAQLVSGVYFQGTTIGM APIMSMCTADQSGGIVMDHSDNPLGAAVTLAHELGHNFGMNHDT LDRGCSCQMAVEKGGCIMNASTGYPFPMVFSSCSRKDLETSLEKG MGVCLFNLPEVRESFGGQKCGNRFVEEGEECDCGEPEECMNRCCN ATTCTLKPDAVCAHGLCCEDCQLKPAGTACRDSSNSCDLPEFCTG ASPHCPANVYLHDGHSCQDVDGYCYNGICQTHEQQCVTLWGPGA KPAPGICFERVNSAGDPYGNCGKVSKSSFAKCEMRDAKCGKIQCQ GGASRPVIGTNAVSIETNIPLQQGGRILCRGTHVYLGDDMPDPGLV LAGTKCADGKICLNRQCQNISVFGVHECAMQCHGRGVCNNRKNC HCEAHWAPPFCDKFGFGGSTDSGPIRQADNQGLTIGILVTILCLLAA GFVVYLKRKTLIRLLFTNKKTTIEKLRCVRPSRPPRGFQPCQAHLG HLGKGLMRKPPDSYPPKDNPRRLLQCQNVDISRPLNGLNVPQPQS TQRVLPPLHRAPRAPSVPARPLPAKPALRQAQGTCKPNPPQKPLPA DPLARTTRLTHALARTPGQWETGLRLAPLRPAPQYPHQVPRSTHT AYIK (SEQ ID NO: 238) 239 HLA-DQB1 MSWKKALRIPGGLRAATVTLMLAMLSTPVAEGRDSPEDFVYQFK AMCYFTNGTERVRYVTRYIYNREEYARFDSDVEVYRAVTPLGPPD AEYWNSQKEVLERTRAELDTVCRHNYQLELRTTLQRRVEPTVTIS PSRTEALNHHNLLVCSVTDFYPAQIKVRWFRNDQEETTGVVSTPLI RNGDWTFQILVMLEMTPQHGDVYTCHVEHPSLQNPITVEWRAQS ESAQSKMLSGIGGFVLGLIFLGLGLIIHHRSQKGLLH (SEQ ID NO: 239) 240 GZMB MQPILLLLAFLLLPRADAGEIIGGHEAKPHSRPYMAYLMIWDQKSL KRCGGFLIRDDFVLTAAHCWGSSINVTLGAHNIKEQEPTQQFIPVK RPIPHPAYNPKNFSNDIMLLQLERKAKRTRAVQPLRLPSNKAQVKP GQTCSVAGWGQTAPLGKHSHTLQEVKMTVQEDRKCESDLRHYY DSTIELCVGDPEIKKTSFKGDSGGPLVCNKVAQGIVSYGRNNGMPP RACTKVSSFVHWIKKTMKRY (SEQ ID NO: 240) 241 CCL20 MCCTKSLLLAALMSVLLLHLCGESEAASNFDCCLGYTDRILHPKFI VGFTRQLANEGCDINAIIFHTKKKLSVCANPKQTWVKYIVRLLSKK VKNM (SEQ ID NO: 241) 288 WBD (US) 4854-8046-9185v2

Claims

CLAIMS What is claimed: 1. A method for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin, said method comprising determining an expression level of at least one response marker in a biological sample from the human subject, wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, wherein the human subject will respond to treatment if the level of the at least one response marker correlates with a reference level for a human subject who has responded to treatment with the humanized antibody, or wherein the human subject will not respond to treatment if the level of the at least one response marker correlates with a reference level for a human subject who has not responded to treatment with the humanized antibody, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human α4β7 integrin comprises the CDRs: Light chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6; and Heavy chain: CDR1 SEQ ID NO: 1 CDR2 SEQ ID NO: 2 and CDR3 SEQ ID NO: 3.
2. A method for determining whether a human subject having ulcerative colitis will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin, said method comprising 289 WBD (US) 4854-8046-9185v2 comparing the expression level of at least one response marker in a biological sample from the human subject to a non-response control level of the at least one response marker; wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, and determining whether the level of the at least one response marker from the biological sample is equal to or higher than the level of the at least one response marker of a non- response control, wherein a higher level of the at least one response marker from the biological sample from the human subject relative to the level of the at least one response marker from the non-response control indicates that the human subject will respond to treatment, wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human α4β7 integrin comprises the CDRs: Light chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6; and Heavy chain: CDR1 SEQ ID NO: 1 CDR2 SEQ ID NO: 2 and CDR3 SEQ ID NO: 3.
3. A method of treating ulcerative colitis in a human subject, said method comprising determining an expression level of at least one response marker in a biological sample from the human subject, wherein the human subject will respond to treatment with a humanized antibody having binding specificity for human α4β7 integrin if the level of the at least one response marker correlates with a reference level for a human subject who has responded to treatment, wherein the at least one response marker is expressed in inflammatory monocytes, regulatory T cells (Tregs), or inflammatory fibroblasts, further comprising administering to the human subject the humanized antibody, 290 WBD (US) 4854-8046-9185v2 wherein the human subject having ulcerative colitis has not previously received the humanized antibody for treatment, and wherein the humanized antibody having binding specificity for human α4β7 integrin comprises the CDRs: Light chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6; and Heavy chain: CDR1 SEQ ID NO: 1 CDR2 SEQ ID NO: 2 and CDR3 SEQ ID NO: 3.
4. The method of any one of claims 1-3, wherein the biological sample is a peripheral blood sample or a gut mucosal biopsy sample from the human subject.
5. The method of claim 4, wherein the sample comprises colonic inflammatory monocytes that express galectin-3 and CD68 at immunofluorescence staining.
6. The method of any one of the previous claims, wherein the sample is collected within two weeks prior to treatment.
7. The method of any one of the previous claims, wherein the expression level of the at least one response marker is determined by single-cell RNAseq.
8. The method of any one of the previous claims, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.
9. The method of any one of the previous claims, wherein the human subject had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof. 291 WBD (US) 4854-8046-9185v2
10. The method of any one of the previous claims, wherein the human subject previously received treatment with at least one corticosteroid.
11. The method of any one of the previous claims, wherein response to treatment is assessed by Physician Global Assessment (PGA) score at 14 weeks after the start of treatment.
12. The method of any one of the previous claims, further comprising measuring the level of dendritic cells (DCs), innate lymphoid cells (ILCs), natural killer (NK) cells, and/or inflammatory monocytes in the sample from the human subject, wherein an increased level relative to a response control level of DCs, ILCs, NK cells, and/or inflammatory monocytes indicates that the human subject will not respond to treatment.
13. The method of any one of claims 1-3, wherein the at least one response marker is selected from a gene expressed in colonic inflammatory monocytes and involved in neutrophil mediated immunity, cellular response to lipopolysaccharide, the interferon-gamma-mediated signaling pathway, and/or the cytokine-mediated signaling pathway, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
14. The method of claim 1, wherein the at least one response marker is selected from a gene expressed in colonic inflammatory monocytes and involved in the regulation of T cell apoptotic process, ribosome assembly and biogenesis, and/or cellular metabolic process, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
15. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and selected from CYP27A1, C4orf3, IRAK3, CXCL9, SLCO4A1, CLEC4E, TREM1, IL1B, FLT1, SOD2, HIF1A, GBP2, SLAMF1, IL1A, PTGS2, BCL2L1, SOCS3, DUSP7, PLEK, SPP1, TGM2, EGR2, INHBA, and/or IL1RN, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment. 292 WBD (US) 4854-8046-9185v2
16. The method of claim 15, wherein the at least one response marker is expressed in colonic inflammatory monocytes and selected from HIF1A, SOCS3, and/or IL1RN.
17. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and selected from PLAU, CYP27A1, SMAD3, C4orf3, IRAK3, SLCO4A1, REV3L, CLEC4E, IL1B, FLT1, HCAR3, SOD2, HIF1A, TLR8, BMF, APOL3, ARHGEF10L, GSDMD, GBP2, SLAMF1, IL1A, PTGS2, PDPN, BCL2L1, SOCS3, PLEK, SPP1, EGR2 and/or IL1RN, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
18. The method of claim 1, wherein the at least one response marker is expressed in colonic inflammatory monocytes and selected from TREM1 and/or TGM2, wherein increased expression of TREM1 and/or TGM2 indicates that the human subject will not respond to treatment.
19. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and selected from IL1B, IL1RN, CCL2, ANXA1, ADAM17, CXCL9, and/or TNF, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
20. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and is selected from IL1B, IL1RN, CCL3, CCL4, CXCL2 and/or CXCL3, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
21. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and is selected from S10011A, S100A6, S100A4, LGALS1 and/or LGALS3, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment. 293 WBD (US) 4854-8046-9185v2
22. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and selected from ADAM17 and/or TNF, wherein increased expression of ADAM17 and/or TNF indicates the human subject will respond to treatment.
23. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from TIMP3, ADAMDEC1, CXCL14, AGT, LAMA4 and/or WNT2B, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
24. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and is selected from CCL5, CEBPB, IL23A, and/or DCHS2, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
25. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and is selected from SELE, LTB, OSM, and/or CXCL10, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
26. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and is selected from IL18RAP, ITGB1, IL17RA, IL10RA, IFNGR1, and/or IFNGR2, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
27. The method of claim 26, wherein the at least one response marker is ITGB1 and/or IL10RA.
28. The method of any one of claims 1-3, wherein the at least one response marker is expressed in colonic inflammatory monocytes and is IL1R1 and/or IL1RAP, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment. 294 WBD (US) 4854-8046-9185v2
29. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from TNFRSF1, CCR6, CD80, CD40LG, IL2RG, CD40, IL2RB, IL18R1, IL10RA, IL7R, TNFRSF14, and/or TNF, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
30. The method of claim 29, wherein the at least one response marker is CD40LG, IL18R1, IL10RA, IL7R, and/or TNFRSF14.
31. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and is IL12RB, IL2RG, and/or TNFRSF1B, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
32. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from IL-11, CXCL2, and/or CXCL14, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
33. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from CXCL12, CXCL16, and/or CCL2, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
34. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory monocytes and is selected from IL10RA, TNFRSF1A, TNFRSF1B, ITGA5_ITGB1, HAVCR2, CD36, PILRA, LILRB1, NECTIN2, PLXNB2, CD74_CXCR4, CD74_CD44, TLR4, ITGA4_ITGB1, CD44, CD36, CD47, NOTCH2, IL7R, CD40, TGFBR2, NRP2, and/or FLT1, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment. 295 WBD (US) 4854-8046-9185v2
35. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CD40LG, IL18R1, IL10RA, IL7R, TNFRSF14, TNFRSF1B, CD99, TIGIT, IL6ST, TGFB2, GLG1, NOTCH1, TGFBR2, CD74, and/or TNFRSF25, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
36. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from TNFRSF1A, CD47, CD55, ITGA4_ITGB1, NRP1, NRP2, NRP1_NRP2, ICAM1, NECTIN2, PLXNB2, TNFRSF14, FGFR1, CD74_CD44, ITGAV_ITGB5, ITGAV_ITGB8, CD44, JAM3, JAM2, F11R, PTPRM, ITGA8, ITGAV, IL6ST, ACVR1, BMPR2, F2R, TGFBR1_TGFBR2_ACVRL1, LRP1, BMPR2_ACVR1, EDNRB, and/or CD74, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
37. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory monocytes and is selected from ALOX5, CD4, CEACAM5, ITGAX_ITGB2, TNFRSF10B_TNFRSF10D, CD99, CSF3R, CSF1R/CSF3R, LILRB3, ITGAV, FPR3/FPR2, and/or IL6ST, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
38. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from CXCR4, ITGB1, CD28, CTLA4, CD28_CTLA4, CD4, IGF2R, ITGAL_ITGB2, RPSA, and/or CCR6, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
39. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from MYLK, ITGA1, ITGB8, SDC4_ITGB1, RPSA, and/or IL6ST/LIFR, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment. 296 WBD (US) 4854-8046-9185v2
40. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory monocytes and is selected from ANXA1, AREG, CCL2, CCL3, CCL4, CD46, CXCL10, CXCL3, HBEGF, HLA-DRB1, ICAM1, IL10, IL1A, IL1B, IL1RN, SELL, TNF, TNFSF13B, IL7R, CD47, PLXNB2, ITGA5, CD74, IL6ST, CD4, ITGA4, CSF3R, CSF1R, TNFRSF1B, TNFRSF1A, CD36, IL1RAP, FPR2, IL1R1, and/or ITGB1, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
41. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from ANXA1, BMP7, CD40, CD46, COL18A1, CSF1, CSF3, CTGF, FGF2, HSPG2, ICAM1, IL-11, JAM3, LAMA2, LAMB2, MIF, NAMPT, NECTIN2, NRG1, TNC, TSLP, VEGFA, WNT5A, NRP1, TNFRSF1A, PLXNB2, IL6ST, FGFR1, LRP6, TNFRSF14, BMPR2, and/or ITGAV, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
42. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from BTLA, CD28, CD46, ITGA4, ITGB2, LTB, SEMA4D, TNF, IL7R, TIGIT, CD74, IL6ST, IL10RA, TNFRSF14, TNFRSF1B, CD44, IL1R2, and/or IL1R1, wherein increased expression of the at least one response marker indicates that the human subject will respond to treatment.
43. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory monocytes and is selected from ADGRE5, CD99, HLA-E, ITGB2, and/or ALOX5, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
44. The method of any one of claims 1-3, wherein the at least one response marker is expressed in inflammatory fibroblasts and is selected from APOE, CCL2, CD99, COL1A2, COL4A2, COL6A1, COL6A2, COL6A3, CXCL12, FGF7, HLA-E, IL6, LAMA4, LAMB1, LAMC1, THBS2, ITGA1, and/or MYLK, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment. 297 WBD (US) 4854-8046-9185v2
45. The method of any one of claims 1-3, wherein the at least one response marker is expressed in regulatory T cells (Tregs) and is selected from ALOXA5AP, AREG, CALM2, HLA-E, and/or CXCR4, wherein increased expression of the at least one response marker indicates that the human subject will not respond to treatment.
46. The method of any one of the previous claims, wherein mRNA expression level and/or protein expression level of the at least one response marker is determined.
47. The method of claim 46, wherein the mRNA expression level is determined by in situ hybridization or RNA sequencing.
48. The method of claim 46, wherein the protein expression level is determined by flow cytometry, mass cytometry, or immunohistochemistry.
49. The method of any one of the previous claims, wherein a human subject that is determined to respond to treatment is administered the humanized antibody.
50. The method of any one of the previous claims, wherein a human subject that is determined not to respond to treatment is further treated with a higher dose and/or more frequent administration of the humanized antibody.
51. The method of any one of the previous claims, wherein a human subject that is determined not to respond to treatment is further treated with a combination therapy that includes the humanized antibody and a second agent.
52. The method of claim 51, wherein the second agent is a JAK inhibitor, an anti-TNFα inhibitor, or an IL-23 inhibitor.
53. The method of claim 52, wherein the anti-TNFα inhibitor is infliximab, adalimumab, golimumab, or certolizumab pegol; wherein the IL-23 inhibitor is ustekinumab, risankizumab, 298 WBD (US) 4854-8046-9185v2 guselkumab, or mirikizumab; wherein the JAK inhibitor is tofacitinib.
54. The method of any one of the previous claims, wherein a response with reference to ulcerative colitis subjects refers to at least one response selected from the group consisting of a clinical response of a decrease in SCCAI by at least 3 points post-VDZ with no reported rectal bleeding, endoscopic response, and mucosal healing.
55. The method of any one of the previous claims, wherein a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission.
56. The method of any one of the previous claims, wherein a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission and CSF endoscopic remission.
57. The method of any one of the previous claims, wherein a response with reference to ulcerative colitis subjects refers to corticosteroid-free (CSF) symptomatic remission, CSF endoscopic remission, and CSF histologic remission.
58. The method of any one of claims 1-57, wherein the humanized antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.
59. The method of any one of claims 1-57, wherein the humanized antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain comprising the amino acid sequence of SEQ ID NO: 8.
60. The method of any one of claims 1-57, wherein the humanized antibody is vedolizumab. 299 WBD (US) 4854-8046-9185v2
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