WO2025201513A1 - Anticorps anti-il1rap et son utilisation - Google Patents

Anticorps anti-il1rap et son utilisation

Info

Publication number
WO2025201513A1
WO2025201513A1 PCT/CN2025/085730 CN2025085730W WO2025201513A1 WO 2025201513 A1 WO2025201513 A1 WO 2025201513A1 CN 2025085730 W CN2025085730 W CN 2025085730W WO 2025201513 A1 WO2025201513 A1 WO 2025201513A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
antibody
set forth
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/085730
Other languages
English (en)
Chinese (zh)
Inventor
刘庆浩
施前
汝亚齐
蒋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Singlomics Zhuhai Danxu Biopharmaceuticals Co Ltd
Original Assignee
Singlomics Zhuhai Danxu Biopharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Singlomics Zhuhai Danxu Biopharmaceuticals Co Ltd filed Critical Singlomics Zhuhai Danxu Biopharmaceuticals Co Ltd
Publication of WO2025201513A1 publication Critical patent/WO2025201513A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to anti-IL1RAP antibodies and uses of such antibodies, in particular their use in the treatment of cancer, inflammatory diseases and autoimmune diseases.
  • Interleukin-1 receptor accessory protein is a component of the interleukin-1 receptor complex.
  • the interleukin-1 (IL-1) family includes cytokine members including IL-1 ⁇ , IL-1 ⁇ , IL-33, IL-36 ⁇ , IL-36 ⁇ , and IL-36 ⁇ , each of which binds to its specific IL-1 family cell membrane receptor.
  • IL1RAP is recruited to form a ternary receptor complex, triggering intracellular signal transduction and activation of a series of transcription factors (such as NF-kB, AP-1), thereby initiating a cascade of inflammatory and immune responses.
  • IL1RAP is required for downstream signal transduction of IL-1 family cytokines and is highly involved in the inflammatory process through this signaling pathway.
  • the inflammatory process can be impaired at different stages by a variety of stimuli, including genetic mutations in senescent cells, bacterial or viral infections, inflammatory diseases, and environmental stimuli, ultimately progressing to chronic inflammation, which is believed to be associated with the development of cancer.
  • Cancer-associated inflammation can occur through two pathways: (i) genetic events that trigger inflammation and neoplastic transformation; and (ii) infections or environmental exposures that trigger inflammation and promote carcinogenesis. Both pathways lead to a terminal state of chronic inflammation, which plays a significant role in the development, promotion, and proliferation of cancer cells.
  • IL-1 family signaling pathway in which IL-1RAP participates has shown tumor-promoting activity.
  • IL-1RAP has been found to be upregulated in multiple cancers, suggesting that IL-1RAP may play a role in the development and progression of cancer.
  • IL1RAP is a promising therapeutic target for inflammatory diseases, autoimmune diseases, and cancer.
  • the present invention aims to develop antibodies targeting IL-1RAP, which block the signaling pathway mediated by interleukin-1 family cytokines, thereby being used for the treatment of various inflammatory diseases, autoimmune diseases and cancers.
  • the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to IL1RAP, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 127, 128, and 129, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 122, 123, and 124, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 162, 163, and 164, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 157, 158, and 159, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 9, 10, and 11, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 4, 5, and 6, respectively;
  • the VH comprises a HCDR1 having an amino acid sequence as set forth in SEQ ID NO:41, a HCDR2 having an amino acid sequence as set forth in SEQ ID NO:42 or 181, and a HCDR3 having an amino acid sequence as set forth in SEQ ID NO:43; and the VL comprises a LCDR1, a LCDR2, and a LCDR3 having amino acid sequences as set forth in SEQ ID NO:36, 37, and 38, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 77, 78, and 79, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 72, 73, and 74, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 87, 88, and 89, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 82, 83, and 84, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 107, 108, and 109, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 102, 103, and 104, respectively;
  • the VH comprises HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 117, 118 and 119, respectively; and the VL comprises LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 112, 113 and 114, respectively; or
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 126; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 121;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 133; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 133; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 135;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 133; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 137;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 139; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 139; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 135;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 139; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 137;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 141; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 135;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 141; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 137;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 143; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 143; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 135; or
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 143; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 137.
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 161; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 156;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 168; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 166;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 168; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 170;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 168; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 172;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 174; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 166;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 174; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 170;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 174; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 172;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 176; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 166;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:40; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:35;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 47; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 45;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 47; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 49;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 55; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 51;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 57; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 45;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 57; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 49;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 57; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 51;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 57; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 53;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 49;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 51; or
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:53.
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 66; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 61;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 76; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 71;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 86; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 81;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 96; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 91;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 106; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 101;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 116; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 111; or
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:151; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:146.
  • the antibody is a rabbit antibody, a chimeric antibody, or a humanized antibody.
  • the antibody is an isotype selected from IgG, IgA, IgM, IgE, and IgD.
  • the antibody is a subtype selected from IgG1, IgG2, IgG3, and IgG4.
  • the antigen-binding fragment is selected from Fab, Fab', F(ab') 2 , Fd, Fd', Fv, scFv, ds-scFv, and dAb.
  • the antibody is a monoclonal antibody, a bispecific antibody, or a multispecific antibody.
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 134; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 136;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 140; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 132;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 142; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 136;
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 169; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 171;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 175; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 167;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 175; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 171;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 177; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 171; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 177; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 173.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 7;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:24.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:44; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:39;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:50;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 52;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 54;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 56; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 46;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 56; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 56; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 52;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 56; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 54;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 58; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 46;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 58; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 60; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 46;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 60; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 60; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 52; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:60; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:54.
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:70; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:65;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 80; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 75;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 90; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 85;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 100; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 95;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 110; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 105;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 120; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 115; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 155; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 150.
  • the present invention provides a nucleic acid comprising a nucleotide sequence encoding an antibody or antigen-binding fragment thereof disclosed herein. In one embodiment, it encodes an antibody or antigen-binding fragment thereof disclosed herein.
  • the invention provides a vector comprising a nucleic acid disclosed herein.
  • the invention provides a host cell comprising a nucleic acid or a vector disclosed herein.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) an antibody or antigen-binding fragment thereof disclosed herein; and (ii) a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition further comprises a second therapeutic agent.
  • the second therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, a small molecule drug, an siRNA, and an antisense oligonucleotide.
  • the present invention provides a conjugate comprising an antibody or antigen-binding fragment thereof disclosed herein and a chemical moiety conjugated thereto.
  • the present invention provides a method for treating a disease in a subject, comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof disclosed herein, a nucleic acid disclosed herein, a vector disclosed herein, a host cell disclosed herein, a pharmaceutical composition disclosed herein, or a conjugate disclosed herein, wherein the disease is an IL1RAP-mediated disease and/or a disease associated with IL1RAP expression.
  • FIG4 shows the blocking activity of the humanized antibody of the present invention on the IL36 ⁇ pathway detected by A431 cells.
  • FIG5 shows the blocking activity of the humanized antibody of the present invention on the IL36 ⁇ pathway detected by A431 cells.
  • FIG6 shows the blocking activity of the humanized antibody of the present invention on the IL33 pathway detected by HUVEC cells.
  • FIG7 shows the PASI score and body weight changes of psoriasis mouse models treated with the humanized antibody of the present invention.
  • FIG8 shows the ADCC killing activity of the humanized antibodies of the present invention against cells overexpressing hIL1RAP.
  • FIG9 shows the changes in tumor volume in the NCI-H358CDX mouse model treated with the defucosylation antibody of the present invention.
  • an antibody includes a plurality of antibodies and in some embodiments, reference to “an antibody” includes a plurality of antibodies, and so forth.
  • the term "antibody” refers to an immunoglobulin molecule that has the ability to specifically bind to a specific antigen. Such molecules typically comprise two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (or domain) (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2, and CH3. Each light chain consists of a light chain variable region (or domain) (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain, CL.
  • the variable regions of the heavy and light chains of an antibody contain a binding domain that interacts with an antigen.
  • the constant region of an antibody can mediate the binding of an immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system, such as C1q (the first component in the classical pathway of complement activation).
  • the heavy chain of an immunoglobulin can be divided into three functional regions: the Fd region, the hinge region, and the Fc region (crystallizable fragment).
  • the Fd region comprises the VH and CH1 domains and combines with the light chain to form the Fab (antigen binding fragment).
  • the Fc fragment is responsible for immunoglobulin effector functions, including, for example, complement fixation and binding to the cognate Fc receptors of effector cells.
  • the hinge region found in IgG, IgA, and IgD immunoglobulin classes acts as a flexible spacer, allowing the Fab portion to move freely in space relative to the Fc region.
  • the hinge domain is structurally diverse, with different sequences and lengths between immunoglobulin classes and subclasses.
  • the immunoglobulin hinge region can be further subdivided into three regions in terms of structure and function: the upper hinge, the core hinge, and the lower hinge.
  • the upper hinge encompasses the amino acids from the carboxyl terminus of CH1 to the first residue in the hinge that restricts movement, typically the first cysteine residue that forms an interchain disulfide bond between the two heavy chains.
  • the length of the upper hinge region is associated with the fragment flexibility of the antibody.
  • the core hinge region contains inter-heavy chain disulfide bonds.
  • the lower hinge region connects to the amino terminus of the CH2 domain and includes residues within the CH2 domain. The conformational changes permitted by the structure and flexibility of the immunoglobulin hinge region polypeptide sequence can influence the effector functions of the antibody Fc portion.
  • a “light chain variable region” (VL) or “heavy chain variable region” (VH) consists of a "framework” region separated by three “complementarity determining regions” or “CDRs.”
  • the framework regions serve to align the CDRs that specifically bind to an antigenic epitope.
  • the CDRs include the amino acid residues in the antibody that are primarily responsible for antigen binding.
  • Both the VL and VH domains comprise the following framework (FR) and CDR regions from amino-terminus to carboxyl-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the CDR1, CDR2, and CDR3 of the VL domain are also referred to herein as LCDR1, LCDR2, and LCDR3, respectively; the CDR1, CDR2, and CDR3 of the VH domain are also referred to herein as HCDR1, HCDR2, and HCDR3, respectively.
  • each VL and VH domain is consistent with any conventional definition of a CDR, including the Kabat definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991)), the Chothia definition (Chothia and Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature 342:878-883, 1989); a composite of the Chothia Kabat CDRs, in which CDR-H1 is a composite of the Chothia and Kabat CDRs; the AbM definition used by Oxford Molecular's antibody modeling software; and the CONTACT definition of Martin et al.
  • Kabat definition Kabat definition
  • Chothia definition Chothia and Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature 342:878-883, 1989
  • CDR-H1 is a composite of the Chothia and Kabat CDRs
  • Kabat provides a widely used numbering convention (Kabat numbering system), in which corresponding residues between different heavy chains or between different light chains are given the same number.
  • the present disclosure can use CDRs defined according to any of these numbering systems, but preferred embodiments use CDRs defined by Kabat.
  • immunoglobulin molecules can be divided into five classes (isotypes): IgA, IgD, IgE, IgG, and IgM, and can be further divided into different subtypes, such as IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, etc.
  • the light chain of the antibody can be divided into lambda ( ⁇ ) chain and kappa ( ⁇ ) chain.
  • antibody should be understood in its broadest sense and includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, antibody fragments, and multispecific antibodies (e.g., bispecific antibodies) containing at least two antigen-binding regions. Antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations in glycosylation sites. Antibodies also include post-translationally modified antibodies, fusion proteins containing antigenic determinants of antibodies, and immunoglobulin molecules containing any other modifications to antigen recognition sites, as long as these antibodies exhibit the desired biological activity.
  • the term "monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies. That is, except for a small number of naturally occurring mutations, each antibody comprising the population is identical. Monoclonal antibodies are highly specific and are directed against a single antigen.
  • the term “monoclonal antibody” herein is not limited to antibodies produced by hybridoma technology, nor should it be construed as requiring antibodies produced by any particular method.
  • bispecific antibody should be understood in the context of the present invention as an antibody having two different antigen-binding regions defined by different antibody sequences. This can be understood as binding to different targets, but also includes binding to different epitopes of a target.
  • the term "bispecific antibody” as used herein should be understood in its broadest sense, including full-length bispecific antibodies and antigen-binding fragments thereof. Bispecific antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations in glycosylation sites. Bispecific antibodies also include post-translationally modified antibodies, fusion proteins containing the antigenic determinants of antibodies, and immunoglobulin molecules containing any other modifications to the antigen recognition site, as long as these antibodies exhibit the desired biological activity.
  • antigen-binding fragment of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • antigen-binding fragments encompassed by the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bond at the hinge region; (iii) a Fab' fragment, which is essentially a Fab with a partial hinge region; (iv) a Fd fragment, which consists of the VH and CH1 domains; (v) a Fd' fragment, which has the VH and CH1 domains and one or more cysteine residues at the C-terminus of the CH1 domain; (vi) an Fv fragment, which consists of the VL and VH domains of a single arm of an antibody; (vii) a dAb fragment, which consists of the VH domain; (viii) isolated complementarity determining regions (CDRs);
  • the two domains VL and VH of the Fv fragment are encoded by different genes, they can be connected by synthetic linkers using recombinant methods so that they can be made into a single protein chain, in which the VL and VH regions are paired to form a monovalent molecule (called single-chain Fv (scFv)).
  • single-chain Fv single-chain Fv
  • Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody.
  • the term also includes a "straight-chain antibody” comprising a pair of tandem Fd fragments (VH-CH1-VH-CH1), which together with a complementary light chain polypeptide form an antigen-binding region, as well as modified forms of any of the aforementioned fragments that retain antigen-binding activity.
  • antigen-binding fragments can be obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
  • chimeric antibody generally refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species.
  • the variable region is derived from an antibody of an experimental animal such as a rodent ("parent antibody”), and the constant region is derived from a human antibody, so that the resulting chimeric antibody is less likely to induce an adverse immune response in a human individual than the parent (e.g., rabbit-derived) antibody.
  • humanized antibody generally refers to an antibody in which some or all of the amino acids outside the CDR region of a non-human antibody (e.g., rabbit antibody) are replaced by corresponding amino acids derived from human immunoglobulin. In the CDR region, small additions, deletions, insertions, replacements, or modifications of amino acids may also be permitted, as long as they still retain the ability of the antibody to bind to a specific antigen.
  • Humanized antibodies may optionally comprise at least a portion of a human immunoglobulin constant region. "Humanized antibodies” retain antigenic specificity similar to that of the original antibody.
  • the "humanized" form of a non-human (e.g., rabbit) antibody may minimally comprise a chimeric antibody derived from a sequence of a non-human immunoglobulin.
  • the CDR region residues in the human immunoglobulin may be replaced with CDR region residues of a non-human species (donor antibody) (such as mouse, rat, rabbit, or non-human primate) with desired properties, affinity, and/or ability.
  • donor antibody such as mouse, rat, rabbit, or non-human primate
  • the FR region residues of the human immunoglobulin may be replaced with corresponding non-human residues.
  • humanized antibodies may contain amino acid modifications that are not present in the recipient antibody or in the donor antibody. These modifications may be made to further improve antibody performance, such as binding affinity.
  • Avidity is a measure of the strength of binding between an antibody and an associated antigen. Avidity relates to the affinity between an antigenic determinant and the antigen binding site of an antibody and the number of associated binding sites present on the antibody.
  • an antibody binds to an antigen with a dissociation constant (KD) of 10-5 M to 10-12 M or less, and preferably 10-7 M to 10-12 M or less, and more preferably 10-8 M to 10-12 M, and/or with a binding affinity of at least 10-7 M -1 , preferably at least 10-8 M -1 , more preferably at least 10-9 M -1 , such as at least 10-12 M -1 . It is generally believed that any KD value greater than 10-4 M represents nonspecific binding.
  • KD dissociation constant
  • the specific binding of an antibody to an antigen or antigenic determinant can be determined in any known suitable manner, including, for example, Scatchard analysis and/or competitive binding assays, such as radioimmunoassay (RIA), enzyme immunoassay (EIA) and sandwich competition assays, and different variants thereof known in the art.
  • Scatchard analysis and/or competitive binding assays such as radioimmunoassay (RIA), enzyme immunoassay (EIA) and sandwich competition assays, and different variants thereof known in the art.
  • epitope refers to the site on an antigen to which an antibody binds.
  • An epitope can be formed by continuous amino acids or by non-continuous amino acids juxtaposed by the tertiary folding of one or more proteins. Epitopes formed by continuous amino acids (also referred to as linear epitopes) are typically retained in exposure to denaturing solvents, while epitopes formed by tertiary folding (also referred to as conformational epitopes) are typically lost in the treatment of denaturing solvents.
  • An epitope typically includes at least 3, more typically at least 5 or 8-10 amino acids in a unique spatial conformation. An epitope defines the minimum binding site of an antibody and is therefore the specific target of an antibody or its antigen-binding fragment.
  • sequence identity refers to the extent to which two sequences (amino acids) have the same residue at the same position when aligned.
  • amino acid sequence is X% identical to SEQ ID NO: Y
  • amino acid sequence is X% identical to SEQ ID NO: Y and is stated as X% of the residues in the amino acid sequence being identical to the residues in the sequence disclosed in SEQ ID NO: Y.
  • such calculations are performed using computer programs.
  • Exemplary programs for comparing and aligning sequence pairs include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).
  • conservative amino acid substitutions when determining the degree of sequence identity between two amino acid sequences, one of skill in the art may consider so-called "conservative" amino acid substitutions, which can generally be described as amino acid substitutions in which an amino acid residue is replaced with another amino acid residue of a similar chemical structure, which has little or essentially no effect on the function, activity, or other biological properties of the polypeptide. Such conservative amino acid substitutions are well known in the art.
  • Particularly preferred conservative substitutions are as follows: Ala to Gly or to Ser; Arg to Lys; Asn to Gln or to His; Asp to Glu; Cys to Ser; Gln to Asn; Glu to Asp; Gly to Ala or to Pro; His to Asn or to Gln; Ile to Leu or to Val; Leu to Ile or to Val; Lys to Arg, to Gln or to Glu; Met to Leu, to Tyr or to Ile; Phe to Met, to Leu or to Tyr; Ser to Thr; Thr to Ser; Trp to Tyr; Tyr to Trp; and/or Phe to Val, to Ile or to Leu.
  • tumor-associated antigen refers to an antigen that is differentially expressed in cancer cells compared to normal cells and, therefore, can be used to target cancer cells.
  • vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • the term "host cell” refers to a cell into which an expression vector has been introduced.
  • conjugate generally refers to a substance formed by linking an antibody to another chemical moiety.
  • the chemical moiety can be a cytotoxic drug, an immunostimulatory molecule, and a detectable label.
  • the drug can be, for example, a microtubule inhibitor, an antibiotic, a DNA synthesis inhibitor, a topoisomerase inhibitor, an RNA polymerase II inhibitor, and an RNA spliceosome inhibitor.
  • the term "pharmaceutical composition” generally refers to a preparation that is in a form that permits the biological activity of the active ingredient to be effective, and that contains no additional ingredients that are unacceptably toxic to a subject to which the composition would be administered.
  • pharmaceutically acceptable means that the carrier or excipient is compatible with the other ingredients of the composition and not substantially deleterious to the recipient thereof, and/or such carrier or excipient is approved or available for inclusion in pharmaceutical compositions for parenteral administration to humans.
  • a physiologically acceptable carrier generally includes pharmaceutically acceptable carriers, excipients or stabilizers that are non-toxic to cells or mammals exposed thereto at the dosages and concentrations employed.
  • a physiologically acceptable carrier is a pH buffered aqueous solution.
  • physiologically acceptable carriers can include buffers, antioxidants, low molecular weight (less than about 10 residues) polypeptides, proteins, hydrophilic polymers, amino acids, monosaccharides, disaccharides and other carbohydrates, chelating agents, sugar alcohols, salt-forming counterions such as sodium; and/or nonionic surfactants.
  • the terms “treat,” “therapy,” “treatment,” and the like refer to the administration of an agent or the performance of a procedure for the purpose of obtaining an effect. These effects may be preventive in terms of completely or partially preventing a disease or its symptoms, and/or therapeutic in terms of achieving a partial or complete cure of a disease and/or disease symptoms.
  • treatment may include treating a disease or condition (e.g., cancer) in a mammal, particularly a human, and includes: (a) preventing the occurrence of a disease or disease symptom in a subject who may be susceptible to the disease (e.g., including a disease that may be associated with or caused by the primary disease) but has not yet been diagnosed with the disease; (b) inhibiting the disease, i.e., arresting its development; and (c) alleviating the disease, i.e., causing regression of the disease.
  • a disease or condition e.g., cancer
  • Treatment may refer to any indicator of success in the treatment, improvement, or prevention of cancer, including any objective or subjective parameter, such as a reduction in symptoms; relief; elimination of disease symptoms or making the disease condition more tolerable for the patient; slowing the rate of deterioration or decline; or reducing the final stage of deterioration.
  • Treatment or improvement of symptoms is based on one or more objective or subjective parameters; including the results of a doctor's examination.
  • treatment includes the administration of an antibody, composition, or conjugate disclosed herein to prevent or delay, alleviate, or arrest or inhibit the development of symptoms or conditions associated with a disease (e.g., cancer).
  • therapeutic effect refers to the reduction, elimination, or prevention of a disease, disease symptom, or disease side effect in a subject.
  • inflammatory diseases should be understood in its broadest sense to include inflammatory diseases and diseases caused by chronic inflammation.
  • inflammatory diseases can be those diseases or conditions characterized by one or more signs of pain (pain caused by the production of noxious substances and nerve irritation), fever (burning caused by vasodilation), redness (redness caused by vasodilation and increased blood flow), swelling (swelling caused by excessive influx or restricted outflow of fluid), and loss of function (which can be partial or complete, temporary or permanent).
  • Inflammation takes many forms and includes, but is not limited to, one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, sclerotic, diffusive, diffuse, exudative, fibrinous, fibrous, localized, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, occlusive, parenchymal, plastic, productive, proliferative, pseudomembranous, suppurative, sclerosing, serofibrinous, serotoninous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative.
  • Inflammatory diseases further include, but are not limited to, those affecting blood vessels (polyarteritis, etc.); diseases affecting joints (temporary arthritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, Reiter's arthritis, etc.); diseases affecting the gastrointestinal tract (inflammatory bowel disease, Crohn's disease, ulcerative colitis, etc.); diseases affecting the skin (dermatitis, psoriasis, etc.); allergic airway diseases (asthma, etc.); or diseases affecting multiple organs and tissues (systemic lupus erythematosus).
  • blood vessels polyarteritis, etc.
  • diseases affecting joints temporary arthritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, Reiter's arthritis, etc.
  • diseases affecting the gastrointestinal tract inflammatory bowel disease, Crohn's disease, ulcerative colitis, etc.
  • chronic inflammation contributes to a variety of diseases, such as cardiovascular disease, cancer, diabetes, chronic kidney disease, fibrosis (pulmonary fibrosis, etc.), chronic obstructive pulmonary disease, COVID-19, acne scars, atherosclerosis, non-alcoholic fatty liver disease, as well as autoimmune diseases and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.), and these diseases contributed to by chronic inflammation are also included in the definition of inflammatory diseases.
  • diseases such as cardiovascular disease, cancer, diabetes, chronic kidney disease, fibrosis (pulmonary fibrosis, etc.), chronic obstructive pulmonary disease, COVID-19, acne scars, atherosclerosis, non-alcoholic fatty liver disease, as well as autoimmune diseases and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.), and these diseases contributed to by chronic inflammation are also included in the definition of inflammatory diseases.
  • the term "effective amount” refers to the amount administered to a subject for treating a disease that is sufficient to effect treatment for the disease.
  • the term "subject” refers to any mammalian subject for whom diagnosis, treatment, or therapy is desired.
  • "mammal” refers to any animal classified as a mammal, including humans, livestock, and laboratory, zoo, sport, or pet animals such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, and the like.
  • the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to IL1RAP, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 127, 128, and 129, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 122, 123, and 124, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 162, 163, and 164, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 157, 158, and 159, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 9, 10, and 11, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 4, 5, and 6, respectively;
  • the VH comprises a HCDR1 having an amino acid sequence as set forth in SEQ ID NO:41, a HCDR2 having an amino acid sequence as set forth in SEQ ID NO:42 or 181, and a HCDR3 having an amino acid sequence as set forth in SEQ ID NO:43; and the VL comprises a LCDR1, a LCDR2, and a LCDR3 having amino acid sequences as set forth in SEQ ID NO:36, 37, and 38, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 67, 68, and 69, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 62, 63, and 64, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 77, 78, and 79, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 72, 73, and 74, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 87, 88, and 89, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 82, 83, and 84, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 97, 98, and 99, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 92, 93, and 94, respectively;
  • the VH comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 107, 108, and 109, respectively; and the VL comprises LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 102, 103, and 104, respectively;
  • the VH comprises HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 117, 118 and 119, respectively; and the VL comprises LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 112, 113 and 114, respectively; or
  • the VH comprises HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NO: 152, 153 and 154, respectively; and the VL comprises LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NO: 147, 148 and 149, respectively.
  • CDR sequences are defined according to the Kabat numbering system.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 126; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 121;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 133; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 133; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 135;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 133; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 137;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 139; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 141; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 143; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 131;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 161; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 156;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 168; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 170;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 174; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 166;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 176; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 172.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 13;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 13;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21; or
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:33; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:40; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:35;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 47; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 45;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 57; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 53;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 45;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 49;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 51; or
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:59; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:53.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 66; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 61;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 76; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 71;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 86; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 81;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 96; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 91;
  • the VH comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:151; and the VL comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:146.
  • Functional variants comprise or consist of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% sequence identity to the amino acid sequence of the parent polypeptide.
  • the number of inserted, deleted and/or substituted amino acids preferably does not exceed 40% of the total number of amino acids in the parent amino acid sequence, more preferably does not exceed 35%, more preferably 1% to 33%, and more preferably 5% to 30%, more preferably 10% to 25%, and more preferably 15% to 20%.
  • the number of inserted, deleted and/or substituted amino acids can be 1 to 20, preferably 1 to 10, more preferably 1 to 7, still more preferably 1 to 5, and most preferably 1 to 2.
  • the number of inserted, deleted and/or substituted amino acids is 1, 2, 3, 4, 5, 6 or 7.
  • insertions, deletions and/or substitutions may be made in the framework (FR) regions, eg, in FR1, FR2, FR3 and/or FR4.
  • the substitution of one or more amino acids can be a conservative substitution of one or more amino acids.
  • conservative substitutions are preferably substitutions in which one amino acid in the following groups (a) to (e) is substituted with another amino acid residue in the same group: (a) small aliphatic, nonpolar or weakly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (c) polar, positively charged residues: His, Arg and Lys; (d) large aliphatic, nonpolar residues: Met, Leu, Ile, Val and Cys; and (e) aromatic residues: Phe, Tyr and Trp.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 133; and VL comprises the amino acid sequence set forth in SEQ ID NO: 131;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 133; and VL comprises the amino acid sequence set forth in SEQ ID NO: 135;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 133; and VL comprises the amino acid sequence set forth in SEQ ID NO: 137;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 139; and VL comprises the amino acid sequence set forth in SEQ ID NO: 135;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 141; and VL comprises the amino acid sequence set forth in SEQ ID NO: 131;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 141; and VL comprises the amino acid sequence set forth in SEQ ID NO: 135;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 141; and VL comprises the amino acid sequence set forth in SEQ ID NO: 137;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 143; and VL comprises the amino acid sequence set forth in SEQ ID NO: 131;
  • VH comprises the amino acid sequence shown in SEQ ID NO: 143; and VL comprises the amino acid sequence shown in SEQ ID NO: 135; or
  • VH comprises the amino acid sequence shown in SEQ ID NO:143; and VL comprises the amino acid sequence shown in SEQ ID NO:137.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 161; and VL comprises the amino acid sequence set forth in SEQ ID NO: 156;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 168; and VL comprises the amino acid sequence set forth in SEQ ID NO: 166;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 168; and VL comprises the amino acid sequence set forth in SEQ ID NO: 172;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 174; and VL comprises the amino acid sequence set forth in SEQ ID NO: 166;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 174; and VL comprises the amino acid sequence set forth in SEQ ID NO: 170;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 176; and VL comprises the amino acid sequence set forth in SEQ ID NO: 166;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 176; and VL comprises the amino acid sequence set forth in SEQ ID NO: 170; or
  • VH comprises the amino acid sequence shown in SEQ ID NO:176; and VL comprises the amino acid sequence shown in SEQ ID NO:172.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • VH comprises the amino acid sequence set forth in SEQ ID NO:8; and VL comprises the amino acid sequence set forth in SEQ ID NO:3;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 15; and VL comprises the amino acid sequence set forth in SEQ ID NO: 13;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 15; and VL comprises the amino acid sequence set forth in SEQ ID NO: 17;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 15; and VL comprises the amino acid sequence set forth in SEQ ID NO: 19;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 25; and VL comprises the amino acid sequence set forth in SEQ ID NO: 13;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 25; and VL comprises the amino acid sequence set forth in SEQ ID NO: 17;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 25; and VL comprises the amino acid sequence set forth in SEQ ID NO: 19;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 25; and VL comprises the amino acid sequence set forth in SEQ ID NO: 21;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 25; and VL comprises the amino acid sequence set forth in SEQ ID NO: 23;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 27; and VL comprises the amino acid sequence set forth in SEQ ID NO: 13;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 27; and VL comprises the amino acid sequence set forth in SEQ ID NO: 17;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 27; and VL comprises the amino acid sequence set forth in SEQ ID NO: 19;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 27; and VL comprises the amino acid sequence set forth in SEQ ID NO: 21;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 27; and VL comprises the amino acid sequence set forth in SEQ ID NO: 23;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and VL comprises the amino acid sequence set forth in SEQ ID NO: 13;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and VL comprises the amino acid sequence set forth in SEQ ID NO: 17;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and VL comprises the amino acid sequence set forth in SEQ ID NO: 19;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and VL comprises the amino acid sequence set forth in SEQ ID NO: 21;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and VL comprises the amino acid sequence set forth in SEQ ID NO: 23;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:31; and VL comprises the amino acid sequence set forth in SEQ ID NO:13;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:31; and VL comprises the amino acid sequence set forth in SEQ ID NO:17;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:31; and VL comprises the amino acid sequence set forth in SEQ ID NO:19;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:31; and VL comprises the amino acid sequence set forth in SEQ ID NO:21;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:31; and VL comprises the amino acid sequence set forth in SEQ ID NO:23;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 33; and VL comprises the amino acid sequence set forth in SEQ ID NO: 13;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 33; and VL comprises the amino acid sequence set forth in SEQ ID NO: 17;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 33; and VL comprises the amino acid sequence set forth in SEQ ID NO: 19;
  • VH comprises the amino acid sequence shown in SEQ ID NO: 33; and VL comprises the amino acid sequence shown in SEQ ID NO: 21; or
  • VH comprises the amino acid sequence shown in SEQ ID NO:33; and VL comprises the amino acid sequence shown in SEQ ID NO:23.
  • the antibody or antigenic fragment thereof comprises a VH and a VL, wherein:
  • VH comprises the amino acid sequence set forth in SEQ ID NO:40; and VL comprises the amino acid sequence set forth in SEQ ID NO:35;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:47; and VL comprises the amino acid sequence set forth in SEQ ID NO:45;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:47; and VL comprises the amino acid sequence set forth in SEQ ID NO:49;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:47; and VL comprises the amino acid sequence set forth in SEQ ID NO:53;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 55; and VL comprises the amino acid sequence set forth in SEQ ID NO: 45;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 55; and VL comprises the amino acid sequence set forth in SEQ ID NO: 51;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 55; and VL comprises the amino acid sequence set forth in SEQ ID NO: 53;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 57; and VL comprises the amino acid sequence set forth in SEQ ID NO: 45;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 57; and VL comprises the amino acid sequence set forth in SEQ ID NO: 49;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 57; and VL comprises the amino acid sequence set forth in SEQ ID NO: 51;
  • VH comprises the amino acid sequence shown in SEQ ID NO: 66; and the VL comprises the amino acid sequence shown in SEQ ID NO: 61;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:76; and VL comprises the amino acid sequence set forth in SEQ ID NO:71;
  • VH comprises the amino acid sequence set forth in SEQ ID NO:86; and VL comprises the amino acid sequence set forth in SEQ ID NO:81;
  • VH comprises the amino acid sequence set forth in SEQ ID NO: 116; and VL comprises the amino acid sequence set forth in SEQ ID NO: 111; or
  • the antibody is a monoclonal antibody, a bispecific antibody, or a multispecific antibody.
  • the antibody is a bispecific antibody.
  • the bispecific antibody comprises an antibody or antigen-binding fragment thereof as described herein that binds to TL1RAP and a second antigen-binding domain that binds to a second antigen.
  • the second antigen can be selected from a tumor-associated antigen, a proinflammatory cytokine, an immune cell antigen, and an immune checkpoint molecule.
  • the antibodies of the present invention bind to human or cynomolgus monkey IL1RAP with a KD value of 10-10 to 10-8 M.
  • the antibodies of the present invention are capable of blocking proinflammatory signaling pathways mediated by activation of IL-1 family cytokines, i.e., IL-1 ⁇ , IL-1 ⁇ , IL-33, IL-36 ⁇ , IL-36 ⁇ , and IL-36 ⁇ .
  • the antibodies of the present invention are capable of blocking proinflammatory signaling pathways mediated by activation of IL-1 ⁇ , IL-1 ⁇ , IL-33, IL-36 ⁇ , IL-36 ⁇ , and IL-36 ⁇ in a dose-dependent manner.
  • the Fc region is murine IgG2a Fc. In one embodiment, the Fc region is murine IgG2b Fc. In one embodiment, the Fc region is murine IgG2c Fc. In one embodiment, the Fc region is murine IgG3 Fc. In a preferred embodiment, the Fc region is human IgG1 Fc.
  • the Fc region has reduced effector function, such as reduced ADCC, ADCP, CDC and/or C1q, Fc ⁇ RI, Fc ⁇ RII or Fc ⁇ RIIIA binding.
  • the Fc region can be an IgG1 isotype, or a non-IgG1 type, such as IgG2, IgG3 or IgG4, which has been mutated so that the ability to mediate effector function is reduced or even eliminated.
  • Such mutations have been described, for example, in Dall'Acqua WF et al., J Immunol. 177(2):1129-1138 (2006) and Hezareh M, J Virol.; 75(24):12161-12168 (2001).
  • the Fc region may comprise an amino acid sequence having one or more of the following amino acid substitutions: E233P, L234A, L234F, L235A, L235E, G237A, N297A, N297D, P331S, and P329G.
  • the Fc region comprises L234A and L235A (LA mutation).
  • the Fc region comprises a mutation that removes an acceptor site for Asn-linked glycosylation or is otherwise manipulated to alter glycosylation properties.
  • an N297Q mutation can be used to remove an Asn-linked glycosylation site.
  • the Fc region comprises an IgG1 sequence having an N297Q mutation.
  • the Fc region is glycoengineered to reduce fucose and thereby enhance ADCC, for example by adding compounds to the culture medium during antibody production, as described in US2009317869 or as described in van Berkel et al. (2010) Biotechnol. Bioeng. 105:350, or by using FUT8 knockout cells, for example as described in Yamane-Ohnuki et al. (2004) Biotechnol. Bioeng 87:614. Alternatively, one can use et al. (1999) Nature Biotech 17:176 to optimize ADCC.
  • the Fc region is engineered to enhance complement activation, for example as described in Natsume et al. (2009) Cancer Sci. 100:2411.
  • the Fc region comprises an antibody that is afucosylated using an engineered cell line expression method using fucose knockout at amino acid position N297 according to Kabat numbering.
  • the Fc region has an extended serum half-life.
  • changing e.g., reducing or increasing
  • the in vivo half-life of an antibody see, for example, International Publications WO 02/060919, WO 98/23289, and WO 97/34631; and U.S. Patents Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745, all of which are incorporated herein by reference in their entirety.
  • one, two, or more amino acid mutations are introduced into an IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge region-Fc domain fragment) to reduce the in vivo half-life of the antibody.
  • one, two or more amino acid mutations are introduced into IgG constant domains or their FcRn binding fragments (preferably Fc or hinge region-Fc domain fragments) to increase the in vivo half-life of the antibody.
  • the antibody may have one or more amino acid mutations (e.g., substitutions) (numbered according to the EU numbering system) in the second constant (CH2) domain (residues 231-340 of human IgG1) and/or the third constant (CH3) domain (residues 341-447 of human IgG1).
  • the constant region of the antibody IgG1 described herein is included in a substitution in which methionine (M) at position 252 is changed to tyrosine (Y), serine (S) at position 254 is changed to threonine (T); and threonine (T) at position 256 is changed to glutamic acid (E) (numbered according to the EU numbering system).
  • mutant IgGs See U.S. Patent No. 7,658,921, which is incorporated herein by reference in its entirety.
  • Such mutant IgGs have been shown to exhibit a four-fold increase in half-life compared to the wild-type form of the same antibody (see Dall Acqua WF et al. (2006) J Biol Chem 281:23514-24, which is incorporated herein by reference in its entirety).
  • the Fc region comprises M252Y, S254T, and T256E (YTE mutations).
  • the Fc region of the invention comprises a conservative substitution, eg, K214R.
  • the antibodies of the present invention can be used for different types of diseases by including different Fc regions.
  • the antibodies of the present invention can have ADCC activity or enhance ADCC by introducing mutations or defucosylation in the Fc region, making them more suitable for treating cancer.
  • the antibodies of the present invention can be used to reduce ADCC by introducing mutations in the Fc region, making them more suitable for treating inflammatory or autoimmune diseases. Examples of Fc region mutations or modifications are described above.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 130; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 125;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 134; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 132;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 134; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 136;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 134; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 138;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 140; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 132;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 140; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 136;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 140; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 138;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 142; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 132;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 142; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 136;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 142; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 138;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 144; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 132;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 145; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 132;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 144; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 136; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 144; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 138; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 182; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 183.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 165; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 160;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 169; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 167;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 169; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 171;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 169; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 173;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 175; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 167;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 175; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 171;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 175; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 173;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 177; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 167;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 177; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 171; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 177; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 173.
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 7;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22; or
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:34; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:24.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:44; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:39;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 46;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:50;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 52;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 54;
  • the HC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 155; and the LC comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 150.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 142
  • LC comprises the amino acid sequence set forth in SEQ ID NO: 138;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 144; and LC comprises the amino acid sequence set forth in SEQ ID NO: 132;
  • HC comprises the amino acid sequence shown in SEQ ID NO: 144; and LC comprises the amino acid sequence shown in SEQ ID NO: 136; or
  • HC comprises the amino acid sequence shown in SEQ ID NO: 144; and LC comprises the amino acid sequence shown in SEQ ID NO: 138; or
  • HC comprises the amino acid sequence shown in SEQ ID NO:182; and LC comprises the amino acid sequence shown in SEQ ID NO:183.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 165; and LC comprises the amino acid sequence set forth in SEQ ID NO: 160;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 169; and LC comprises the amino acid sequence set forth in SEQ ID NO: 173;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 175; and LC comprises the amino acid sequence set forth in SEQ ID NO: 167;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 175; and LC comprises the amino acid sequence set forth in SEQ ID NO: 171;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 175; and LC comprises the amino acid sequence set forth in SEQ ID NO: 173;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 177; and LC comprises the amino acid sequence set forth in SEQ ID NO: 167;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 177; and LC comprises the amino acid sequence set forth in SEQ ID NO: 171; or
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • HC comprises the amino acid sequence set forth in SEQ ID NO:12; and LC comprises the amino acid sequence set forth in SEQ ID NO:7;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 26; and LC comprises the amino acid sequence set forth in SEQ ID NO: 18;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 26; and LC comprises the amino acid sequence set forth in SEQ ID NO: 22;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 28; and LC comprises the amino acid sequence set forth in SEQ ID NO: 14;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 28; and LC comprises the amino acid sequence set forth in SEQ ID NO: 20;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 28; and LC comprises the amino acid sequence set forth in SEQ ID NO: 22;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 28; and LC comprises the amino acid sequence set forth in SEQ ID NO: 24;
  • HC comprises the amino acid sequence shown in SEQ ID NO: 30; and LC comprises the amino acid sequence shown in SEQ ID NO: 24;
  • HC comprises the amino acid sequence set forth in SEQ ID NO:32; and LC comprises the amino acid sequence set forth in SEQ ID NO:14;
  • HC comprises the amino acid sequence set forth in SEQ ID NO:32; and LC comprises the amino acid sequence set forth in SEQ ID NO:18;
  • HC comprises the amino acid sequence shown in SEQ ID NO: 34; and LC comprises the amino acid sequence shown in SEQ ID NO: 22; or
  • HC comprises the amino acid sequence shown in SEQ ID NO:34; and LC comprises the amino acid sequence shown in SEQ ID NO:24.
  • the antibody comprises a heavy chain (HC) and a light chain (LC), wherein:
  • HC comprises the amino acid sequence set forth in SEQ ID NO:48; and LC comprises the amino acid sequence set forth in SEQ ID NO:52;
  • HC comprises the amino acid sequence set forth in SEQ ID NO:48; and LC comprises the amino acid sequence set forth in SEQ ID NO:54;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 56; and LC comprises the amino acid sequence set forth in SEQ ID NO: 50;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 56; and LC comprises the amino acid sequence set forth in SEQ ID NO: 52;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 58; and LC comprises the amino acid sequence set forth in SEQ ID NO: 46;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 58; and LC comprises the amino acid sequence set forth in SEQ ID NO: 50;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 58; and LC comprises the amino acid sequence set forth in SEQ ID NO: 52;
  • HC comprises the amino acid sequence set forth in SEQ ID NO: 58; and LC comprises the amino acid sequence set forth in SEQ ID NO: 54;
  • HC comprises the amino acid sequence shown in SEQ ID NO: 60; and LC comprises the amino acid sequence shown in SEQ ID NO: 50;
  • HC comprises the amino acid sequence shown in SEQ ID NO: 60; and LC comprises the amino acid sequence shown in SEQ ID NO: 52; or
  • HC comprises the amino acid sequence set forth in SEQ ID NO:70; and LC comprises the amino acid sequence set forth in SEQ ID NO:65;
  • HC comprises the amino acid sequence set forth in SEQ ID NO:80; and LC comprises the amino acid sequence set forth in SEQ ID NO:75;
  • HC comprises the amino acid sequence shown in SEQ ID NO: 120; and LC comprises the amino acid sequence shown in SEQ ID NO: 115; or
  • nucleic acids comprising a nucleotide sequence encoding an anti-IL1 RAP antibody or antigen-binding fragment thereof disclosed herein.
  • nucleic acid includes single-stranded and double-stranded nucleotide polymers. Nucleic acids can be ribonucleotides or deoxyribonucleotides or modified forms of either type of nucleotide. The modifications include base modifications such as bromouridine and inosine derivatives, ribose modifications such as 2', 3'-dideoxyribose, internucleotide linkage modifications such as phosphorothioates, phosphorodithioates, selenophosphates, diselenphosphates, phenylthiophosphates, aniline phosphates, and phosphoramidates.
  • the present invention provides nucleic acid molecules encoding any of the heavy chain variable region sequences disclosed herein.
  • the present invention also provides nucleic acid molecules that are at least 90%, at least 95%, at least 98%, or at least 99% identical to the nucleic acid encoding any of the heavy chain variable region sequences disclosed herein.
  • the present invention provides nucleic acid molecules encoding any one of the light chain variable region sequences disclosed herein.
  • the present invention also provides nucleic acid molecules that are at least 90%, at least 95%, at least 98%, or at least 99% identical to the nucleic acid encoding any one of the light chain variable region sequences disclosed herein.
  • the present invention provides a nucleic acid molecule encoding a heavy chain variable region sequence comprising a CDR sequence of any one of the heavy chain variable region sequences disclosed herein.
  • the present invention also provides a nucleic acid molecule encoding a heavy chain variable region sequence comprising a CDR sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to a CDR sequence of any one of the heavy chain variable region sequences disclosed herein.
  • the present invention provides a nucleic acid molecule encoding a light chain variable region sequence, the light chain variable region sequence comprising the CDR sequence of any one of the light chain variable region sequences disclosed herein.
  • the present invention also provides a nucleic acid molecule encoding a light chain variable region sequence, the light chain variable region sequence comprising a CDR sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the CDR sequence of any one of the light chain variable region sequences disclosed herein.
  • the nucleic acid is ribonucleic acid (RNA) or deoxyribonucleic acid (DNA).
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • the deoxyribonucleic acid (DNA) can be introduced into human cells in vivo.
  • the deoxyribonucleic acid (DNA) of the present invention is contained in a carrier or delivery agent.
  • the deoxyribonucleic acid (DNA) of the present invention is integrated into the genome of the cell.
  • the ribonucleic acid (RNA) can be introduced into human cells in vivo.
  • the ribonucleic acid (RNA) of the present invention is contained in a vector or delivery agent.
  • the present disclosure provides a vector comprising a nucleic acid disclosed herein, which comprises a nucleotide sequence encoding an anti-IL1 RAP antibody or an antigen-binding fragment thereof disclosed herein.
  • the vector is an expression vector capable of expressing a polypeptide comprising the heavy chain or light chain variable region of an antibody.
  • the present invention provides an expression vector comprising any of the above-mentioned nucleic acid molecules.
  • the vector is a viral vector.
  • the vector is a retroviral vector, a DNA vector, a murine leukemia virus vector, a SFG vector, a plasmid, an RNA vector, an adenoviral vector, a baculoviral vector, an Epstein Barr virus vector, a papovavirus vector, a vaccinia virus vector, a herpes simplex virus vector, an adenovirus-associated vector (AAV), a lentiviral vector, or any combination thereof.
  • AAV adenovirus-associated vector
  • Suitable exemplary vectors include, for example, pGAR, pBABE-puro, pBABE-neo largeTcDNA, pBABE-hygro-hTERT, pMKO.1GFP, MSCV-IRES-GFP, pMSCV PIG (Puro IRES GFP empty plasmid), pMSCV-loxp-dsRed-loxp-eGFP-Puro-WPRE, MSCV IRES luciferase, pMIG, MDH1-PGK-GFP_2.0, TtRMPVIR, pMSCV-IRES-mCherry FP, pRetroX GFP T2A Cre, pRXTN, pLncEXP and pLXIN-Luc.
  • Phage vectors such as ⁇ GT10, ⁇ GT11, ⁇ ZapII (Stratagene), ⁇ EMBL4 and ⁇ NM1149 can also be used.
  • plant expression vectors that can be used in the present disclosure include pBI01, pBI101.2, pBI101.3, pBI121 and pBIN19 (Clontech).
  • animal expression vectors that can be used in the present disclosure include pcDNA, pEUK-Cl, pMAM, and pMAMneo (Clontech).
  • Recombinant expression vectors can be prepared using standard recombinant DNA techniques as described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Press, Cold Spring Harbor, N.Y. 2001; and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, NY, 1994.
  • Circular or linear expression vector constructs can be prepared to contain a replication system functional in a prokaryotic or eukaryotic host cell.
  • the replication system can be derived, for example, from COLEL, 2 ⁇ plasmid, lambda, SV40, bovine papilloma virus, and the like.
  • the vector can be an adenovirus vector comprising a nucleotide sequence encoding an antibody disclosed herein.
  • the vector can be administered to a subject, and then enters the subject's cells in vivo, thereby integrating the nucleotide sequence encoding the antibody disclosed herein into the genome of the cells, and then the cells express the antibody disclosed herein.
  • the present disclosure provides host cells comprising a nucleic acid disclosed herein or a vector disclosed herein.
  • the cell can be a prokaryotic cell, a fungal cell, a yeast cell, or a higher eukaryotic cell such as a mammalian cell.
  • Suitable prokaryotic cells include, but are not limited to, eubacteria, such as Gram-negative or Gram-positive organisms, such as Enterobacteriaceae, such as Escherichia, for example Escherichia coli; Enterobacter; Erwinia; Klebsiella; Proteus; Salmonella, for example Salmonella typhimurium.
  • the cell is a human cell.
  • the cell is an immune cell.
  • the host cell includes, for example, a CHO cell, such as a CHOS cell and a CHO-K1 cell, or a HEK293 cell, such as a HEK293A, HEK293T, and HEK293FS.
  • a CHO cell such as a CHOS cell and a CHO-K1 cell
  • a HEK293 cell such as a HEK293A, HEK293T, and HEK293FS.
  • the host cells of the present invention are prepared by introducing the vectors disclosed herein or the nucleic acids disclosed herein in vitro or ex vivo.
  • the host cells of the present invention can be administered to a subject, and the host cells express the antibodies disclosed herein in vivo.
  • the present invention provides a host cell into which any of the above vectors has been introduced.
  • the present invention also provides a method for preparing the antibody of the present invention, the method comprising a) culturing the host cell of the present invention under conditions suitable for producing the antibody; and b) obtaining the antibody from the culture.
  • the pharmaceutical composition that is suitable for injectable purposes comprises sterile aqueous solution (if it is water-soluble) or dispersion and the sterile powder for the temporary preparation of sterile injectable solution or dispersion.
  • suitable carrier comprises physiological saline, antibacterial water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • said composition must be sterile and should be the fluid that exists with the degree of being easy to inject.It must be stable under preparation and storage conditions, and must prevent the contamination effect of microorganisms such as bacteria and fungi.
  • Carrier can be solvent or dispersion medium, and solvent or dispersion medium contain for example water, ethanol, polyol (for example glycerol, propylene glycol and liquid polyethylene glycol etc.), and its suitable mixture.
  • suitable mobility can be for example by using coating such as lecithin, by keeping the particle size needed and by using surfactant to keep in the case
  • IL1RAP-mediated diseases and/or diseases associated with IL1RAP expression include diseases associated with abnormal function of IL-1, IL-33, and/or IL-36 signaling and thus also mediated by the co-receptor activity of IL1RAP.
  • any composition or formulation comprising an anti-IL1RAP antibody of the present disclosure can be used to treat any disease associated with abnormal function of the IL-1, IL-33, and/or IL-36 signaling pathway and thus mediated by the co-receptor activity of IL1RAP.
  • these conditions include, but are not limited to, inflammatory diseases, autoimmune diseases, metabolic diseases, infections, and cancer.
  • the sample can be any sample, including but not limited to a blood sample, tissue from a biopsy, autopsy, and pathology specimens. Samples also include body fluids such as blood, serum, plasma, sputum, spinal fluid, or urine.
  • a control sample is a sample from a subject without an inflammatory disease. In specific embodiments, the sample is a blood or tissue sample.
  • IL1RAP can be measured in a biological sample by a competitive immunoassay that utilizes an IL1RAP protein standard labeled with a detectable substance and an unlabeled anti-IL1RAP antibody.
  • a competitive immunoassay that utilizes an IL1RAP protein standard labeled with a detectable substance and an unlabeled anti-IL1RAP antibody.
  • the biological sample, the labeled IL1RAP protein standard, and the anti-TLR2 antibody are combined, and the amount of the labeled IL1RAP protein standard bound to the unlabeled antibody is determined.
  • the amount of IL1RAP in the biological sample is inversely proportional to the amount of the labeled IL1RAP protein standard bound to the anti-IL1RAP antibody.
  • anti-IL1RAP antibodies can be used to detect the production of IL1RAP in cells in cell culture.
  • the antibodies can be used to detect the amount of IL1RAP in a biological sample (such as a tissue sample or a blood or serum sample).
  • the IL1RAP is cell surface IL1RAP.
  • the kit further comprises (i) a device for administering the aforementioned antibody or antigen-binding fragment thereof, the aforementioned nucleic acid molecule, the aforementioned vector, the aforementioned host cell, the aforementioned conjugate and/or the aforementioned pharmaceutical composition; and/or (ii) instructions for use.
  • the present application provides a kit that may include an antibody or antigen-binding fragment thereof, nucleic acid molecule, vector, host cell, conjugate, and/or pharmaceutical composition disclosed herein. It may include the antibodies, nucleic acid molecules, vector, host cell, antibody drug conjugate described herein in a single common container.
  • the kit may include instructions for use, which include information about the antibodies, pharmaceutical compositions, and dosage forms in the kit. Typically, such information helps patients and physicians use the encapsulated antibodies, pharmaceutical compositions, and dosage forms effectively and safely.
  • the kit may also include additional components to facilitate the application for which the kit is designed.
  • the kit may additionally contain tools for detecting the label (e.g., enzyme substrates for enzymatic labeling, filter sets for detecting fluorescent labels, suitable secondary labels such as secondary antibodies, etc.).
  • the kit may also include buffers and other reagents routinely used to implement a particular method. Such kits and suitable contents are well known to those skilled in the art.
  • the culture medium used for human IL1RAcP 293T cells was DMEM + 10% FBS + 0.1 ⁇ g/ml puromycin; the culture medium for HEK293-LUC cells was MEM + 10% FBS + 1 ⁇ g/ml puromycin, and the experimental culture medium was MEM + 10% FBS; the culture medium for A431 cells was DMEM + 10% FBS; the culture medium for HUVEC cells was VEGF Cell Culture Medium+ VEGF, experimental culture medium is M199+10% FBS+5% L-Gln.
  • Antigen (hIL1RAP-his or cIL1RAP-his) was diluted in Qbuffer starting at 200 nM and diluted in a 2-fold dilution series for a total of seven steps. All antibody samples were adjusted to a concentration of 10 ⁇ g/ml and diluted in Qbuffer, with 200 ⁇ l per well and 2 ml per sample. BLI detection was performed on a Gator Prime instrument using a Protein A probe to capture the antibody as the stationary phase and the diluted antigen as the mobile phase.
  • HEK293-AP1-NFkB-Luc-9 (hereinafter referred to as HEK293-LUC) cell line was plated, with 1x104 cells per well of a 96-well flat-bottom plate, and incubated overnight at 37°C and 5% CO2 ; the test antibody was diluted with HEK293-LUC culture medium, and the diluted antibody solution was added to the corresponding well plate, followed by the addition of IL-1 ⁇ factor (IL-1 ⁇ working concentration was 0.3ng/ml), and incubated at 37°C and 5% CO2 for 6 hours; then 25ul of cell lysis buffer (5X Passive Lysis Buffer) was added to each well, and after thorough mixing, 20ul was aspirated from each well and placed in a white-bottomed 96-well plate. 60ul of Luciferase Assay System was added to each well, and luminescence detection was performed on a multifunctional microplate reader.
  • IL-1 ⁇ factor IL-1 ⁇ working concentration was 0.3ng/ml
  • HEK293-AP1-NFkB-Luc-9 (hereinafter referred to as HEK293-LUC) cell line was plated, with 1x104 cells per well of a 96-well flat-bottom plate, and incubated overnight at 37°C and 5% CO2 .
  • the antibody to be tested was serially diluted with culture medium and added to the corresponding wells of the plate.
  • IL-1 ⁇ factor was then added (the working concentration of IL-1 ⁇ was 0.3ng/ml), and the cells were incubated at 37°C and 5% CO2 for 6 hours. 25ul of cell lysis buffer (5X Passive Lysis Buffer) was then added to each well.
  • HUVEC cells were plated, with 4,000 cells per well of a 96-well flat-bottom plate, and incubated at 37°C, 5% CO2 for 4 hours.
  • the antibody to be tested was serially diluted in HUVEC cell culture medium, and the diluted antibody solution was added to the corresponding wells of the plate.
  • IL33 factor (IL33 working concentration was 4 ng/ml) was then added and incubated at 37°C, 5% CO2 for 24 hours. The cell supernatant was then collected and IL8 secretion was detected by ELISA.
  • A431 cells were plated at 1x104 cells per well of a 96-well flat-bottom plate and incubated overnight at 37°C and 5% CO2 .
  • the antibody to be tested was serially diluted in A431 cell culture medium and added to the corresponding wells of the plate.
  • IL36 ⁇ factor working concentration of IL36 ⁇ was 40 ng/ml
  • the cell supernatant was then collected and IL8 secretion was detected by ELISA.
  • PBMCs were counted, centrifuged, resuspended, and adjusted to a density of 1 ⁇ 106 cells/ml. 1 ⁇ 106 cells were plated into a 96-well flat-bottom plate. Cytokines IL-12 and IL-33 were diluted in the same tube of complete culture medium to a final concentration of 40 ng/ml for IL-12 and 100 ng/ml for IL-33. 50 ⁇ l of these dilutions were added to the 96-well flat-bottom plate at a rate of 50 ⁇ l/well, mixed with the PBMCs, and incubated at 37°C, 5% CO2 for 15 min.
  • PBMCs were plated in the same manner.
  • IL1 ⁇ was diluted in a separate centrifuge tube to a final concentration of 4 ng/ml.
  • the diluted factor solution was added to a 96-well flat-bottom plate at a rate of 50 ⁇ l/well, mixed with the PBMCs, and incubated at 37°C, 5% CO2 for 15 minutes.
  • the test antibody was diluted in complete culture medium, with eight 10-fold dilutions starting at 50 ⁇ g/mL.
  • the diluted antibody was added to the incubated 96-well flat-bottom plate, gently mixed, and incubated at 37°C, 5% CO2 for 48 hours. After incubation, the supernatant was collected and assayed for IL6 and IL8 secretion by ELISA.
  • PBMC recovery place them in a 37°C, 5% CO2 incubator and culture overnight.
  • Collect target cells wash them once with complete culture medium, adjust the target cell density to 1 ⁇ 10 6 cells/ml, take an appropriate amount of target cells according to the plating design and place them in a new 15ml centrifuge tube, add an appropriate amount of DELFIA BATDA, and incubate them in a 37°C, 5% CO2 incubator for 10-25 minutes. Wash with PBS, centrifuge at 1200rpm for 4 minutes at room temperature, and repeat the wash 3-5 times. Discard the supernatant, resuspend the target cells in complete culture medium (containing 2-5mM probenecid), count again, and adjust the cell density to 2 ⁇ 10 5 cells/ml.
  • test antibodies were serially diluted in complete culture medium (containing 2-5 mM probenecid) and added to the plate at 50 ⁇ l/well. Incubate at 37°C, 5% CO2 for 15 minutes.
  • PBMCs peripheral blood mononuclear cells
  • PBMCs peripheral blood mononuclear cells
  • the cells were resuspended in complete culture medium (containing 2-5 mM probenecid) and added to the plate at the designed effector-target ratio (1:40). Incubate at 37°C, 5% CO2 for 4 hours. After incubation, the cell plate was centrifuged at 500 g for 5 minutes. Transfer the sample supernatant to a DELFIA assay plate at 20 ⁇ l/well, add 200 ⁇ l/well of the DELFIA Europium solution, and incubate on a shaker at room temperature for 15 minutes.
  • the EDTA anticoagulated rabbit whole blood was added to a centrifuge tube containing Ficoll, centrifuged, and the middle white film layer containing lymphocytes and monocytes was taken to a new centrifuge tube, and the PBMC cells were obtained by centrifugation. Labeled antibodies and fluorescent labeled proteins were added to the separated PBMC cells for incubation, the cells were washed by centrifugation, and resuspended in PBS. Single B cells were sorted using a flow cytometer. The sorted antigen-specific memory B cells were stimulated and cultured in vitro, and the culture supernatant was taken for ELISA, FACS and cell activity detection.
  • the chimeric antibodies were tested for their inhibitory activity using IL1 ⁇ pathway blocking assays based on HEK293-AP1-NFkB-Luc-9 reporter cells, IL1 ⁇ pathway blocking assays based on HEK293-AP1-NFkB-Luc-9 reporter cells, IL33 pathway blocking assays based on HUVEC cells, IL36 ⁇ pathway blocking assays based on A431 cells, IL36 ⁇ pathway blocking assays based on A431 cells, and IL36 ⁇ pathway blocking assays based on A431 cells.
  • the CDR sequences of the above antibodies numbered according to the Kabat system are shown in Table 3, and the sequence information of the heavy chain variable region (VH), light chain variable region (VL), heavy chain (HC) and light chain (LC) are shown in Table 4.
  • the amino acid encoding for each antibody's CDR and framework regions was performed according to the Kabat system.
  • NO.58afu is a defucosylated version of NO.58 with a wild-type human IgG constant region, which is defucosylated at the Asn amino acid position 297.
  • the only difference between NO.58afu mIgG and NO.58afu is that it uses the mouse IgG constant region.
  • the CDR sequences of humanized antibodies No. 1-30, 44-47, 49-60, and 62-70 are consistent with those of the parent antibody.
  • the amino acid at the last position of HCDR2 in humanized antibodies No. 32 to No. 43 was changed (from G to R) during CDR grafting.
  • Their CDR sequences, numbered according to the Kabat system, are as follows:
  • the binding ability of the antibody samples to overexpressed human IL1RAcP 293T was measured using the PE channel of a flow cytometer, and EC50 values were calculated from the MFI binding curve. The results showed that the R0322, R0366, R0415, and R0433 parental antibodies and their humanized counterparts all exhibited high binding ability to human IL1RAcP 293T (Tables 6-9).
  • Table 8 Humanized antibody binding assay results using R0415 as a parent
  • Example 5 HEK293-AP1-NFkB-Luc-9 cells verify that humanized antibodies block IL-1 ⁇ pathway function
  • IL-1 ⁇ stimulates the HEK293-LUC reporter cell line to produce fluorescence.
  • the final fluorescence value of the luminescence assay was used to confirm whether the antibody blocked the IL-1 ⁇ stimulation of HEK293-LUC cells.
  • the antibody was diluted using a 1 ⁇ g/ml 5-fold serial dilution method, with a total of 5 concentration points.
  • the IC50 value of the curve was calculated (Sx is the sample reading, M is the negative control, and M' is the positive control).
  • Example 6 A431 cell screening verifies that humanized antibodies block the IL36 ⁇ pathway function
  • IL36 ⁇ stimulates IL8 secretion from A431 cells, and antibodies inhibit IL36 ⁇ stimulation of A431 cells.
  • ELISA was used to measure IL8 secretion in the cell culture supernatant to confirm the inhibitory activity of the antibodies.
  • the test antibody was diluted fivefold starting at 1 ⁇ g/ml, with a total of five concentration gradients.
  • a stimulation experiment using IL36 ⁇ was first performed. Three sets of humanized antibodies based on R0322, R0415, and R0433 were tested. The inhibitory activity of the antibodies was characterized by measuring IL8 secretion in the A431 cell supernatant after treatment with each sample.
  • the antibody group with R0322 as the parent showed blocking activity on the IL36 pathway, and among them, humanized antibodies No. 2, No. 6, No. 13, No. 16, No. 17, No. 21 and No. 23 inhibited IL8 secretion on A431 cells more effectively than the parent (Table 13).
  • the antibody group using R0433 as the parental antibody demonstrated blocking activity against the IL-36 pathway, and humanized antibodies No. 62, No. 63, No. 64, No. 65, No. 66, No. 67, and No. 68 exhibited stronger inhibition of IL-8 secretion on A431 cells than the parental antibody (Table 15). Based on the previous results of blocking the IL-1 ⁇ pathway, humanized antibodies No. 63, No. 65, No. 67, No. 68, and No. 69 were further selected from this group for subsequent functional experiments.
  • Example 7 HEK293-AP1-NFkB-Luc-9 cells verify that humanized antibodies block IL-1 ⁇ / ⁇ pathway function
  • the selected molecules were tested for IL1 ⁇ / ⁇ blocking activity.
  • Example 9 HUVEC cell detection of humanized antibodies blocking the IL33 pathway
  • IL33 blocking activity was tested.
  • IL33 stimulates HUVEC cells to secrete IL8.
  • An IL8 ELISA kit was used to measure IL8 secretion levels in the cell supernatant to confirm the antibody's inhibitory effect on IL33-stimulated HUVEC cells.
  • the test antibody was diluted 8-fold starting at 50 ⁇ g/ml, with a total of 10 concentration gradients.

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Abstract

L'invention concerne un anticorps anti-IL1RAP ou un fragment de liaison à l'antigène de celui-ci, un acide nucléique codant pour l'anticorps, un vecteur comprenant l'acide nucléique, et une cellule hôte comprenant l'acide nucléique ou le vecteur. L'invention concerne en outre une composition pharmaceutique et un conjugué comprenant l'anticorps, et une méthode de traitement utilisant l'anticorps.
PCT/CN2025/085730 2024-03-29 2025-03-28 Anticorps anti-il1rap et son utilisation Pending WO2025201513A1 (fr)

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Citations (7)

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Publication number Priority date Publication date Assignee Title
CN103459424A (zh) * 2011-01-19 2013-12-18 坎塔吉亚有限责任公司 抗il1rap抗体及其治疗人类的用途
WO2014100772A1 (fr) * 2012-12-21 2014-06-26 Cellerant Therapeutics, Inc. Anticorps qui se fixent à il1 rap lié à la membrane
CN106459195A (zh) * 2014-03-05 2017-02-22 坎塔吉亚有限责任公司 抗人白介素‑1受体辅助蛋白(il1 rap)抗体及其用途
CN107074946A (zh) * 2014-08-06 2017-08-18 坎塔吉亚有限责任公司 新型抗体及其用途
CN108431042A (zh) * 2015-11-02 2018-08-21 詹森药业有限公司 抗-il1rap抗体，结合il1rap和cd3的双特异性抗原结合分子及其用途
CN110997725A (zh) * 2017-06-12 2020-04-10 蓝鳍生物医药公司 抗-il1rap抗体和抗体药物缀合物
CN116724055A (zh) * 2020-12-23 2023-09-08 坎塔吉亚有限责任公司 抗il1rap抗体

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103459424A (zh) * 2011-01-19 2013-12-18 坎塔吉亚有限责任公司 抗il1rap抗体及其治疗人类的用途
WO2014100772A1 (fr) * 2012-12-21 2014-06-26 Cellerant Therapeutics, Inc. Anticorps qui se fixent à il1 rap lié à la membrane
CN106459195A (zh) * 2014-03-05 2017-02-22 坎塔吉亚有限责任公司 抗人白介素‑1受体辅助蛋白(il1 rap)抗体及其用途
CN107074946A (zh) * 2014-08-06 2017-08-18 坎塔吉亚有限责任公司 新型抗体及其用途
CN108431042A (zh) * 2015-11-02 2018-08-21 詹森药业有限公司 抗-il1rap抗体，结合il1rap和cd3的双特异性抗原结合分子及其用途
CN110997725A (zh) * 2017-06-12 2020-04-10 蓝鳍生物医药公司 抗-il1rap抗体和抗体药物缀合物
CN116724055A (zh) * 2020-12-23 2023-09-08 坎塔吉亚有限责任公司 抗il1rap抗体

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