US20200062848A1 - Human monoclonal antibodies to programmed death ligand 1 (pd-l1) - Google Patents

Human monoclonal antibodies to programmed death ligand 1 (pd-l1) Download PDF

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Publication number
US20200062848A1
US20200062848A1 US16/448,721 US201916448721A US2020062848A1 US 20200062848 A1 US20200062848 A1 US 20200062848A1 US 201916448721 A US201916448721 A US 201916448721A US 2020062848 A1 US2020062848 A1 US 2020062848A1
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antibody
seq
human
variable region
chain variable
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US16/448,721
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Alan J. Korman
Mark J. Selby
Changyu Wang
Mohan Srinivasan
David B. Passmore
Haichun Huang
Haibin Chen
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US16/448,721 priority Critical patent/US20200062848A1/en
Publication of US20200062848A1 publication Critical patent/US20200062848A1/en
Priority to US17/842,540 priority patent/US20230061544A1/en
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Definitions

  • PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA.
  • Two cell surface glycoprotein ligands for PD-1 have been identified, PD-L1 and PD-L2, and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1 (Freeman et al.
  • Both PD-L1 (B7-H1) and PD-L2 (B7-DC) are B7 homologs that bind to PD-1, but do not bind to other CD28 family members (Blank et al. (2004). Expression of PD-L1 on the cell surface has also been shown to be upregulated through IFN- ⁇ stimulation.
  • PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. (2002) PNAS 99: 12293-7; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53).
  • PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. (2002) Nat Med 8:793-800). It has also been suggested that PD-L1 might be involved in intestinal mucosal inflammation and inhibition of PD-L1 suppresses wasting disease associated with colitis (Kanai et al. (442003) J Immunol 171:4156-63).
  • the present invention provides isolated monoclonal antibodies, in particular human monoclonal antibodies that bind to PD-L1 and exhibit numerous desirable properties. These properties include high affinity binding to human PD-L1. Still further, antibodies of the invention have been shown to increase T-cell proliferation, IFN- ⁇ secretion, and IL-2 secretion in a mixed lymphocyte reaction.
  • the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody exhibits at least one of the following properties:
  • the antibody binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, or binds to human PD-L1 with a K D of between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, wherein the antibody cross-competes for binding to PD-L1 with a reference antibody comprising:
  • the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-18 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-69 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-3 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product, of or derived from a human V H 3-9 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L15 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K A27 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L18 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
  • the antibodies additionally comprise at least one of the following properties:
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
  • antibodies, or antigen-binding portions thereof are provided that compete for binding to PD-L1 with any of the aforementioned antibodies.
  • the antibodies of the instant disclosure can be, for example, full-length antibodies, for example of an IgG1 or IgG4 isotype.
  • the antibodies can be antibody fragments, such as Fab or Fab′2 fragments, or single chain antibodies.
  • the instant disclosure also provides an immunoconjugate comprising an antibody of the invention, or antigen-binding portion thereof, linked to a therapeutic agent, such as a cytotoxin or a radioactive isotope.
  • a therapeutic agent such as a cytotoxin or a radioactive isotope.
  • the invention also provides a bispecific molecule comprising an antibody, or antigen-binding portion thereof, of the invention, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.
  • compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule of the instant disclosure and a pharmaceutically acceptable carrier are also provided.
  • Nucleic acid molecules encoding the antibodies, or antigen-binding portions thereof, of the invention are also encompassed by the invention, as well as expression vectors comprising such nucleic acids and host cells comprising such expression vectors.
  • the invention provides a transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses an antibody of the invention, as well as hybridomas prepared from such a mouse, wherein the hybridoma produces the antibody of the invention.
  • the invention provides a method of modulating an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modulated.
  • the antibody of the invention enhances, stimulates or increases the immune response in the subject.
  • the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.
  • the antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention).
  • a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of inhibiting tumor growth.
  • the invention provides a method of treating an infectious disease in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.
  • the antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention).
  • a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of treating an infectious disease.
  • the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced.
  • the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
  • the antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention).
  • a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of enhancing an immune response to an antigen in a subject.
  • the invention also provides methods for making “second generation” anti-PD-L1 antibodies based on the sequences of the anti-PD-L1 antibodies provided herein.
  • the invention provides a method for preparing an anti-PD-L1 antibody comprising:
  • FIG. 1A shows the nucleotide sequence (SEQ ID NO:81) and amino acid sequence (SEQ ID NO:1) of the heavy chain variable region of the 3G10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:21), CDR2 (SEQ ID NO:31) and CDR3 (SEQ ID NO:41) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 1B shows the nucleotide sequence (SEQ ID NO:91) and amino acid sequence (SEQ ID NO:11) of the light chain variable region of the 3G10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:51), CDR2 (SEQ ID NO:61) and CDR3 (SEQ ID NO:71) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2A shows the nucleotide sequence (SEQ ID NO:82) and amino acid sequence (SEQ ID NO:2) of the heavy chain variable region of the 12A4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:22), CDR2 (SEQ ID NO:32) and CDR3 (SEQ ID NO:42) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2B shows the nucleotide sequence (SEQ ID NO:92) and amino acid sequence (SEQ ID NO:12) of the tight chain variable region of the 12A4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:52), CDR2 (SEQ ID NO:62) and CDR3 (SEQ ID NO:72) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3A shows the nucleotide sequence (SEQ ID NO:83) and amino acid sequence (SEQ ID NO:3) of the heavy chain variable region of the 10A5 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:23), CDR2 (SEQ ID NO:33) and CDR3 (SEQ ID NO:43) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3B shows the nucleotide sequence (SEQ ID NO:93) and amino acid sequence (SEQ ID NO:13) of the light chain variable region of the 10A5 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:53), CDR2 (SEQ ID NO:63) and CDR3 (SEQ ID NO:73) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4A shows the nucleotide sequence (SEQ ID NO:84) and amino acid sequence (SEQ ID NO:4) of the heavy chain variable region of the 5F8 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:24), CDR2 (SEQ ID NO:34) and CDR3 (SEQ ID NO:44) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4B shows the nucleotide sequence (SEQ ID NO:94) and amino acid sequence (SEQ ID NO:14) of the light chain variable region of the 5F8 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:54), CDR2 (SEQ ID NO:64) and CDR3 (SEQ ID NO:74) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5A shows the nucleotide sequence (SEQ ID NO:85) and amino acid sequence (SEQ ID NO:5) of the heavy chain variable region of the 10H10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:25), CDR2 (SEQ ID NO:35) and CDR3 (SEQ ID NO:45) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5B shows the nucleotide sequence (SEQ ID NO:95) and amino acid sequence (SEQ ID NO:15) of the light chain variable region of the 10H10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:55), CDR2 (SEQ ID NO:65) and CDR3 (SEQ ID NO:75) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6A shows the nucleotide sequence (SEQ ID NO:86) and amino acid sequence (SEQ ID NO:6) of the heavy chain variable region of the 1B12 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:26), CDR2 (SEQ ID NO:36) and CDR3 (SEQ ID NO:46) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6B shows the nucleotide sequence (SEQ ID NO:96) and amino acid sequence (SEQ ID NO:16) of the light chain variable region of the 1B12 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:56), CDR2 (SEQ ID NO:66) and CDR3 (SEQ ID NO:76) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7A shows the nucleotide sequence (SEQ ID NO:87) and amino acid sequence (SEQ ID NO:7) of the heavy chain variable region of the 7H1 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:27), CDR2 (SEQ ID NO:37) and CDR3 (SEQ ID NO:47) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7B shows the nucleotide sequence (SEQ ID NO:97) and amino acid sequence (SEQ ID NO:17) of the light chain variable region of the 7H1 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:57), CDR2 (SEQ ID NO:67) and CDR3 (SEQ ID NO:77) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8A shows the nucleotide sequence (SEQ ID NO:88) and amino acid sequence (SEQ ID NO:8) of the heavy chain variable region of the 11E6 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:28), CDR2 (SEQ ID NO:38) and CDR3 (SEQ ID NO:48) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8B shows the nucleotide sequence (SEQ ID NO:98) and amino acid sequence (SEQ ID NO:18) of the light chain variable region of the 11E6 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:58), CDR2 (SEQ ID NO:68) and CDR3 (SEQ ID NO:78) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9A shows the nucleotide sequence (SEQ ID NO:89) and amino acid sequence (SEQ ID NO:9) of the heavy chain variable region of the 12B7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:29), CDR2 (SEQ ID NO:39) and CDR3 (SEQ ID NO:49) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9B shows the nucleotide sequence (SEQ ID NO:99) and amino acid sequence (SEQ ID NO:19) of the light chain variable region of the 12B7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:59), CDR2 (SEQ ID NO:69) and CDR3 (SEQ ID NO:79) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10A shows the nucleotide sequence (SEQ ID NO:90) and amino acid sequence (SEQ ID NO:10) of the heavy chain variable region of the 13G4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:30), CDR2 (SEQ ID NO:40) and CDR3 (SEQ ID NO:50) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10B shows the nucleotide sequence (SEQ ID NO:100) and amino acid sequence (SEQ ID NO:20) of the light chain variable region of the 13G4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:60), CDR2 (SEQ ID NO:70) and CDR3 (SEQ ID NO:80) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 11 shows the alignment of the amino acid sequence of the heavy chain variable region of 3G10 with the human germline V H 1-18 amino acid sequence (SEQ ID NO:101).
  • FIG. 12 shows the alignment of the amino acid sequence of the heavy chain variable region of 12A4 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 13 shows the alignment of the amino acid sequence of the heavy chain variable region of 10A5 with the human germline V H 1-3 amino acid sequence (SEQ ID NO:103).
  • FIG. 14 shows the alignment of the amino acid sequence of the heavy chain variable region of 5F8 with the human germane V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 15 shows the alignment of the amino acid sequence of the heavy chain variable region of 10H10 with the human germline V H 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 16 shows the alignment of the amino acid sequence of the heavy chain variable region of 1B12 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 17 shows the alignment of the amino acid sequence of the heavy chain variable region of 7H1 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 18 shows the alignment of the amino acid sequence of the heavy chain variable region of 11E6 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 19 shows the alignment of the amino acid sequence of the heavy chain variable region of 12B7 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 20 shows the alignment of the amino acid sequence of the heavy chain variable region of 13G4 with the human germline V H 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 21 shows the alignment of the amino acid sequence of the light chain variable region of 3G10 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 22 shows the alignment of the amino acid sequence of the light chain variable region of 12A4 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 23 shows the alignment of the amino acid sequence of the light chain variable region of 10A5 with the human germline V k L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 24 shows the alignment of the amino acid sequence of the light chain variable region of 5F8 with the human germline V k A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 25 shows the alignment of the amino acid sequence of the light chain variable region of 10H10 with the human germline V k L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 26 shows the alignment of the amino acid sequence of the light chain variable region of 1B12 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 27 shows the alignment of the amino acid sequence of the light chain variable region of 7H1 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 28 shows the alignment of the amino acid sequence of the light chain variable region of 11E6 with the human germline V k A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 29 shows the alignment of the amino acid sequence of the light chain variable region of 11E6a (SEQ ID NO:109) with the human germline V k A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 30 shows the alignment of the amino acid sequence of the light chain variable region of 12B7 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 31 shows the alignment of the amino acid sequence of the light chain variable region of 13G4 with the human germline V k L18 amino acid sequence (SEQ ID NO:108).
  • FIGS. 32A-C show the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1.
  • A Flow cytometry plot for 3G10
  • B Flow cytometry plot for 10A5
  • C Flow cytometry plot for 12A4.
  • FIG. 33 shows the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1 in a concentration dependent manner.
  • FIG. 34 shows the results of ELISA experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1-Fc fusion protein.
  • FIG. 35 shows the results of experiments demonstrating HuMab titration on stimulated human CD4+ T cells.
  • FIG. 36 shows the results of experiments demonstrating HuMab titration on stimulated cynomolgus PBMC.
  • FIGS. 37A-C shows the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1 on the cell surface of activated T cells.
  • A Flow cytometry plot for 3G10
  • B Flow cytometry plot for 10A5
  • C Flow cytometry plot for 12A4.
  • FIG. 38 demonstrates binding of HuMabs to ES-2 cells.
  • FIGS. 39A-D shows the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation, IFN- ⁇ secretion and IL-2 secretion in a mixed lymphocyte reaction assay.
  • FIG. 39A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5;
  • FIG. 39B is a bar graph showing concentration dependent IFN- ⁇ secretion using HuMAb 10A5;
  • FIG. 39C is a bar graph showing IFN- ⁇ secretion using HuMAbs 3G10 and 12A4;
  • FIG. 39D is a bar graph showing concentration dependent IL-2 secretion using HuMAb 10A5.
  • FIG. 40 demonstrates the effect of human anti-PD-L1 antibody on proliferation and IFN- ⁇ secretion in the MLR using allogeneic dendritic cells and T cells (CD4+ effector T cells) Dendritic Cells.
  • FIGS. 41A-B shows the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation and IFN- ⁇ secretion in MLR containing T regulatory cells.
  • FIG. 41A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5;
  • FIG. 41B is a bar graph showing concentration dependent IFN- ⁇ secretion using HuMAb 10A5.
  • FIG. 42 demonstrates the results of anti-PD-L1 antibodies on cell proliferation in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 43 demonstrates the results of anti-PD-L1 antibodies on cytokine production in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 44 demonstrates the results of anti-PD-L1 antibodies on CMV lysate stimulated human PBMC IFN- ⁇ secretion.
  • FIG. 45 shows the results of flow cytometry experiments demonstrating that human monoclonal antibodies against human PD-L1 block the binding of PD-L1 to CHO transfected cells expressing PD-1.
  • FIG. 46 shows that anti-PD-L1 antibodies block binding of PD-1 to IFN ⁇ treated ES-2 cells.
  • FIG. 47 shows the effect of anti-PD-L1 antibodies on tumor growth in vivo.
  • the present disclosure relates to isolated monoclonal antibodies, particularly human monoclonal antibodies that bind specifically to PD-L1.
  • the antibodies of the invention exhibit one or more desirable functional properties, such as high affinity binding to PD-L1, the ability to augment T cell proliferation, IFN- ⁇ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of PD-L1 to the PD-1 receptor, the ability to stimulate antibody responses and/or the ability to reverse the suppressive function of T regulatory cells.
  • the antibodies of the invention are derived from particular heavy and light chain germline sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences.
  • the instant disclosure provides, for example, isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunoconjugates or bispecific molecules of the invention.
  • the disclosure pertains to methods of inhibiting growth of tumor cells in a subject using anti-PD-L1 antibodies.
  • the invention also relates to methods of using the antibodies to modify an immune response, as well as to treat diseases such as cancer or infectious disease, or to stimulate a protective autoimmune response or to stimulate antigen-specific immune responses (e.g., by coadministration of anti-PD-L1 with an antigen of interest).
  • immune response refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell.
  • the phrase “cell surface receptor” includes, for example, molecules and complexes of molecules capable of receiving a signal and the transmission of such a signal across the plasma membrane of a cell.
  • An example of a “cell surface receptor” of the present invention is the PD-L1 receptor.
  • antibody as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains thereof.
  • An “antibody” refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, C H1 , C H2 and C H3 .
  • Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the light chain constant region is comprised of one domain, C L .
  • the V H and V L regions can be further subdivided into regions of hypervariability, termed complementarily determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarily determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • antibody portion refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PD-L1). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V L , V H , C L and C H1 domains; (ii) a F(ab′) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V H and C H1 domains; (iv) a Fv fragment consisting of the V L and V H domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a V H domain; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the V L , V H , C L and C H1 domains
  • F(ab′) 2 fragment a bivalent fragment comprising two
  • the two domains of the Fv fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody.
  • an “isolated antibody,” as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-L1).
  • An isolated antibody that specifically binds PD-L1 may, however, have cross-reactivity to other antigens, such as PD-L1 molecules from other species.
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • human antibody is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term “human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • human monoclonal antibody refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences.
  • the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), (b) antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • isotype refers to the antibody class (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • an antibody recognizing an antigen and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”
  • human antibody derivatives refers to any modified form of the human antibody, e.g., a conjugate of the antibody and another agent or antibody.
  • humanized antibody is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences.
  • chimeric antibody is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • an antibody that “specifically binds to human PD-L1” is intended to refer to an antibody that binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 7 M or less, more preferably 5 ⁇ 10 ⁇ 8 M or less, more preferably 1 ⁇ 10 ⁇ 8 M or less, more preferably 5 ⁇ 10 ⁇ 9 M or less, even more preferably between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M or less.
  • K assoc or “K a ,” as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction
  • K dis or “K d ,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction
  • K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e., K d /K a ) and is expressed as a molar concentration (M).
  • K D values for antibodies can be determined using methods well established in the art. A preferred method for determining the K D of an antibody is by using surface plasmon resonance, preferably using a biosensor system such as a Biacore® system.
  • high affinity for an IgG antibody refers to an antibody having a K D of 10 ⁇ 8 M or less, more preferably 10 ⁇ 9 M or less and even more preferably 10 ⁇ 10 M or less for a target antigen.
  • “high affinity” binding can vary for other antibody isotypes.
  • “high affinity” binding for an IgM isotype refers to an antibody having a K D of 10 ⁇ 7 M or less, more preferably 10 ⁇ 8 M or less, even more preferably 10 ⁇ 9 M or less.
  • the term “subject” includes any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the antibodies of the invention are characterized by particular functional features or properties of the antibodies.
  • the antibodies bind specifically to human PD-L1.
  • an antibody of the invention binds to PD-L1 with high affinity, for example with a K D of 1 ⁇ 10 ⁇ 7 M or less.
  • the anti-PD-L1 antibodies of the invention preferably exhibit one or more of the following characteristics:
  • the antibody binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, binds to human PD-L1 with a K D of 4 ⁇ 10 ⁇ 9 M or less, binds to human PD-L1 with a K D of 2 ⁇ 10 ⁇ 9 M or less, or binds to human PD-L1 with a K D of between 1 ⁇ 10 ⁇ 9 M and 1 ⁇ 10 ⁇ 10 M or less.
  • Standard assays to evaluate the binding ability of the antibodies toward PD-L1 are known in the art, including for example, ELISAs, Western blots and RIAs. Suitable assays are described in detail in the Examples.
  • the binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore® analysis.
  • Preferred antibodies of the invention are the human monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, isolated and structurally characterized as described in Examples 1 and 2.
  • the V H amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, respectively.
  • V L amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, respectively.
  • V H and V L sequences can be “mixed and matched” to create other anti-PD-L1 binding molecules of the invention.
  • PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs).
  • a V H sequence from a particular V H /V L pairing is replaced with a structurally similar V H sequence.
  • a V L sequence from a particular V H /V L pairing is replaced with a structurally similar V L sequence.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • the invention provides antibodies that comprise the heavy chain and light chain CDR1s, CDR2s and CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, or combinations thereof.
  • the amino acid sequences of the V H CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.
  • the amino acid sequences of the V H CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, respectively.
  • the amino acid sequences of the V H CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively.
  • the amino acid sequences of the V k CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, respectively.
  • the amino acid sequences of the V k CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, respectively.
  • the amino acid sequences of the V k CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, respectively.
  • the CDR regions are delineated using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • V H CDR1, CDR2, and CDR3 sequences and V k CDR1 CDR2, and CDR3 sequences can be “mixed and matched” (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a V H CDR1, CDR2, and CDR3 and a V k CDR1, CDR2, and CDR3) to create other anti-PD-L1 binding molecules of the invention.
  • PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs, Biacore analysis).
  • the CDR1, CDR2 and/or CDR3 sequence from a particular V H sequence is replaced with a structurally similar CDR sequence(s).
  • V k CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular V k sequence preferably is replaced with a structurally similar CDR sequence(s).
  • V H and V L sequences can be created by substituting one or more V H and/or V L CDR region sequences with structurally similar sequences from the CDR sequences disclosed herein for monoclonal antibodies antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70;
  • the CDR3 domain independently from the CDR1 and/or CDR2 domain(s), alone can determine the binding specificity of an antibody for a cognate antigen and that multiple antibodies can predictably be generated having the same binding specificity based on a common CDR3 sequence. See, for example, Klimka et al., British J. of Cancer 83(2):252-260 (2000) (describing the production of a humanized anti-CD30 antibody using only the heavy chain variable domain CDR3 of murine anti-CD30 antibody Ki-4); Beiboer et al., J. Mol. Biol.
  • the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody, such as a mouse or rat antibody, wherein the monoclonal antibody is capable of specifically binding to PD-L1.
  • inventive antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental non-human antibody.
  • the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a first human antibody, such as, for example, a human antibody obtained from a non-human animal, wherein the first human antibody is capable of specifically binding to PD-L1 and wherein the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for PD-L1 to generate a second human antibody that is capable of specifically binding to PD-L1.
  • a first human antibody such as, for example, a human antibody obtained from a non-human animal
  • the first human antibody is capable of specifically binding to PD-L1
  • the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for PD-L1 to generate a second human antibody that is capable of specifically binding to PD-L1.
  • antibodies of the instant disclosure comprising one or more heavy and/or light chain CDR3 domain from the first human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental first human antibody.
  • an antibody of the invention comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-18 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-69 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-3 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 3-9 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L15 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K A27 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L18 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody:
  • An example of an antibody having V H and V K of V H 1-18 and V K L6, respectively, is 3G10.
  • An example of an antibody having V H and V K of V H 1-3 and V K L15, respectively, is 10A5.
  • Examples of antibodies having V H and V K of V H 1-69 and V K A27, respectively, are 5F8, 11E6 and 11E6a.
  • An example of an antibody having V H and V K of V H 3-9 and V K L15, respectively, is 10H10.
  • An example of an antibody having V H and V K of V H 1-3 and V K L15, respectively, is 10A5.
  • An example of an antibody having V H and V K of V H 3-9 and V K L18, respectively, is 13G4.
  • a human antibody comprises heavy or light chain variable regions that is “the product of” or “derived from” a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes.
  • Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest.
  • a human antibody that is “the product of” or “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody.
  • a human antibody that is “the product of” or “derived from” a particular human germline immunoglobulin sequence may contain amino acid differences as compared to the germane sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation.
  • a selected human antibody is generally at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences).
  • a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene.
  • a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene.
  • the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
  • an antibody of the invention comprises heavy and light chain variable regions comprising amino acid sequences that are homologous to the amino acid sequences of the preferred antibodies described herein, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
  • the V H and/or V L amino acid sequences may be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above.
  • An antibody having V H and V L regions having high (i.e., 80% or greater) homology to the V H and V L regions of the sequences set forth above can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs:25, 26, 27, 28, 29, and 30, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • mutagenesis e.g., site-directed or PCR-mediated mutagenesis
  • the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
  • the percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller ( Comput. Appl. Biosci., 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch ( J. Mol. Biol.
  • the protein sequences of the present disclosure can be further used as a “query sequence” to perform a search against public databases to, for example, identify related sequences.
  • Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10.
  • Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402.
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • an antibody of the invention comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on the preferred antibodies described herein (e.g., 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4), or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
  • the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof.
  • the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • conservative sequence modifications is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art.
  • amino acids with basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
  • one or more amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • the invention provides antibodies that bind to the same epitope on human PD-L1 as any of the PD-L1 monoclonal antibodies of the invention (i.e., antibodies that have the ability to cross-compete for binding to PD-L1 with any of the monoclonal antibodies of the invention).
  • the reference antibody for cross-competition studies can be the monoclonal antibody 3G10 (having V H and V L sequences as shown in SEQ ID NOs:1 and 11, respectively), or the monoclonal antibody 12A4 (having V H and V L sequences as shown in SEQ ID NOs:2 and 12, respectively), or the monoclonal antibody 10A5 (having V H and V L sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 10A5 (having V H and V L sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 5F8 (having V H and V L sequences as shown in SEQ ID NOs:4 and 14, respectively), or the monoclonal antibody 10H10 (having V H and V L sequences as shown in SEQ ID NOs:5 and 15, respectively), or the monoclonal antibody 1B12 (having V H and V L sequences as shown in SEQ ID NOs:6 and 16, respectively), or
  • cross-competing antibodies can be identified based on their ability to cross-compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 in standard PD-L1 binding assays.
  • BIAcore analysis, ELISA assays or flow cytometry may be used to demonstrate cross-competition with the antibodies of the current invention.
  • test antibody to inhibit the binding of, for example, 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4, to human PD-L1 demonstrates that the test antibody can compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 for binding to human PD-L1 and thus binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4.
  • the antibody that binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 is a human monoclonal antibody.
  • human monoclonal antibodies can be prepared and isolated as described in the Examples.
  • An antibody of the invention further can be prepared using an antibody having one or more of the V H and/or V L sequences disclosed herein as starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody.
  • An antibody can be engineered by modifying one or more residues within one or both variable regions (i.e., V H and/or V L ), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant region(s), for example to alter the effector function(s) of the antibody.
  • CDR grafting One type of variable region engineering that can be performed is CDR grafting.
  • Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al. (1998) Nature 332:323-327; Jones, P. et al.
  • another embodiment of the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and SEQ ID NOs:71, 72, 73, 74, 75, 76,
  • such antibodies contain the V H and V L CDR sequences of monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H11, 11E6, 12B7 or 3G4 yet may contain different framework sequences from these antibodies.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • germline DNA sequences for human heavy and light chain variable region genes can be found in the “VBase” human germline sequence database (available on the Internet at www.mrc-cpe.cam.ac.uk/vbase), as well as in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al.
  • Antibody protein sequences are compared against a compiled protein sequence database using one of the sequence similarity searching methods called the Gapped BLAST (Altschul et al. (1997) Nucleic Acids Research 25:3389-3402), which is well known to those skilled in the art.
  • BLAST is a heuristic algorithm in that a statistically significant alignment between the antibody sequence and the database sequence is likely to contain high-scoring segment pairs (HSP) of aligned words. Segment pairs whose scores cannot be improved by extension or trimming is called a hit.
  • HSP high-scoring segment pairs
  • nucleotide sequences of VBASE origin are translated and the region between and including FR1 through FR3 framework region is retained.
  • the database sequences have an average length of 98 residues. Duplicate sequences which are exact matches over the entire length of the protein are removed.
  • the nucleotide sequences are translated in all six frames and the frame with no stop codons in the matching segment of the database sequence is considered the potential hit. This is in turn continued using the BLAST program tblastx. This translates the antibody sequence in all six frames and compares those translations to the VBASE nucleotide sequences dynamically translated in all six frames.
  • the identities are exact amino acid matches between the antibody sequence and the protein database over the entire length of the sequence.
  • the positives are not identical but amino acid substitutions guided by the BLOSUM62 substitution matrix. If the antibody sequence matches two of the database sequences with same identity, the hit with most positives would be decided to be the matching sequence hit.
  • Preferred framework sequences for use in the antibodies of the invention are those that are structurally similar to the framework sequences used by selected antibodies of the invention, e.g., similar to the V H 1-18 framework sequences (SEQ ID NO:101) and/or the V H 1-69 framework sequences (SEQ ID NO:102) and/or the V H 1-3 framework sequences (SEQ ID NO:103) and/or the V H 3-9 framework sequences (SEQ ID NO:104) and/or the V K L6 framework sequences (SEQ ID NO:105) and/or the V K L15 framework sequences (SEQ ID NO:106) and/or the V K (A27 framework sequences (SEQ ID NO:107) and/or the V K L18 framework sequences (SEQ ID NO:107) used by preferred monoclonal antibodies of the invention.
  • V H CDR1, CDR2, and CDR3 sequences can be grafted onto framework regions that have the identical sequence as that found in the germline immunoglobulin gene from which the framework sequence derive, or the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences.
  • variable region modification is to mutate amino acid residues within the V H and/or V K CDR1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest.
  • Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutation(s) and the effect on antibody binding, or other functional property of interest, can be evaluated in in vitro or in vivo assays as described herein and provided in the Examples.
  • Preferably conservative modifications are introduced.
  • the mutations may be amino acid substitutions, additions or deletions, but are preferably substitutions.
  • typically no more than one, two, three, four or five residues within a CDR region are altered.
  • the invention provides isolated anti-PD-L1 monoclonal antibodies, or antigen binding portions thereof, comprising a heavy chain variable region comprising: (a) a V H CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; (b) a V H CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; (c) a V H CDR3 region comprising an amino acid sequence
  • Engineered antibodies of the invention include those in which modifications have been made to framework residues within V H and/or V K , e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to “backmutate” one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived.
  • the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis.
  • the alignment of the V H region for 3G10 against the parent germline V H 1-18 sequence is shown in FIG. 11 .
  • the alignment of the V H region for 12A4 against the parent germline V H 1-69 sequence is shown in FIG. 12 .
  • the alignment of the V H region for 10A5 against the parent germline V H 1-3 sequence is shown in FIG. 13 .
  • the alignment of the V H region for 5F8 against the parent germline V H 1-69 sequence is shown in FIG. 14 .
  • the alignment of the V H region for 10H10 against the parent germline V H 3-9 sequence is shown in FIG. 15 .
  • the alignment of the V H region for 1B12 against the parent germline V H 1-69 sequence is shown in FIG. 16 .
  • the alignment of the V H region for 7H1 against the parent germline V H 1-69 sequence is shown in FIG. 17 .
  • the alignment of the V H region for 11E6 against the parent germline V H 1-69 sequence is shown in FIG. 18 .
  • the alignment of the V H region for 12B7 against the parent germline V H 1-69 sequence is shown in FIG. 19 .
  • the alignment of the V H region for 13G4 against the parent germline V H 3-9 sequence is shown in FIG. 20 .
  • amino acid residue #79 (within FR3) of V H is a valine whereas this residue in the corresponding V H 1-18 germline sequence is an alanine.
  • the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis (e.g., residue #79 (residue #13 of FR3) of the V H of 3G10 can be “backmutated” from valine to alanine).
  • amino acid residue #24 (within FR1) of V H is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 12A4 can be “backmutated” from threonine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #27 (within FR1) of V H is an aspartic acid whereas this residue in the corresponding V H 1-69 germline sequence is a glycine.
  • residue #27 of the V H of 12A4 can be “backmutated” from aspartic acid to glycine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #95 (within FR3) of V H is a phenylalanine whereas this residue in the corresponding V H 1-69 germline sequence is a tyrosine.
  • residue #95 (residue #29 of FR3) of the V H of 12A4 can be “backmutated” from phenylalanine to tyrosine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 5F8 can be “backmutated” from valine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #28 (within FR1) is an isoleucine whereas this residue in the corresponding V H 1-69 germline sequence is an threonine.
  • residue #28 of the V H of 5F8 can be “backmutated” from isoleucine to threonine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding V H 3-9 germline sequence is an alanine.
  • residue #24 of the V H of 10H10 can be “backmutated” from valine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • an amino acid can be inserted following amino acid residue #97 (within FR3).
  • This amino acid is a valine.
  • the inserted amino acid following residue #97 of the V H of 10H10 can be “backmutated” to delete this valine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 1B12 can be “backmutated” from threonine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #27 (within FR1) is an aspartic acid whereas this residue in the corresponding V H 1-69 germline sequence is an glycine.
  • residue #27 of the V H of 1B12 can be “backmutated” from aspartic acid to glycine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #95 (within FR3) is a phenylalanine whereas this residue in the corresponding V H 1-69 germline sequence is an tyrosine.
  • residue #95 residue #29 of FR3
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 7H1 can be “backmutated” from threonine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #77 (within FR3) is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is a serine.
  • residue #72 residue #11 of FR3 of the V H of 7H1 can be “backmutated” from threonine to serine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #78 (within FR3) is an alanine whereas this residue in the corresponding V H 1-69 germline sequence is a threonine.
  • residue #78 residue 12 of FR3 of the V H of 11E6 can be “backmutated” from alanine to threonine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #13 (within FR1) is a glutamic acid whereas this residue in the corresponding V H 1-69 germline sequence is an lysine.
  • residue #13 of the V H of 12B7 can be “backmutated” glutamic acid to lysine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #30 (within FR1) is an asparagine whereas this residue in the corresponding V H 1-69 germline sequence is an serine.
  • residue #30 of the V H of 12B7 can be “backmutated” from asparagine to serine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #77 (within FR3) is an asparagine whereas this residue in the corresponding V H 1-69 germline sequence is an serine.
  • residue #377 residue 11 of FR3 of the V H of 12B7 can be “backmutated” from asparagine to serine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #82 (within FR3) is an aspartic acid whereas this residue in the corresponding V H 1-69 germline sequence is a glutamic acid.
  • residue #82 (residue #16 of FR3) of the V H of 12B7 can be “backmutated” from aspartic acid to glutamic acid.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #27 (within FR1) is an isoleucine whereas this residue in the corresponding V H 1-69 germline sequence is an phenylalanine.
  • residue #27 of the V H of 12B7 can be “backmutated” from isoleucine to phenylalanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No. 20030153043 by Carr et al.
  • antibodies of the invention may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • an antibody of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody.
  • the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased.
  • This approach is described further in U.S. Pat. No. 5,677,425 by Bodmer et al.
  • the number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • the Fc hinge region of an antibody is mutated to decrease the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • the antibody is modified to increase its biological half life.
  • Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to Ward.
  • the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody.
  • one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
  • one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al.
  • the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fc ⁇ receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439.
  • ADCC antibody dependent cellular cytotoxicity
  • the glycosylation of an antibody is modified.
  • an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation).
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen.
  • carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation may increase the affinity of the antibody for antigen.
  • an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures.
  • altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation.
  • the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (alpha (1,6) fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates.
  • the Ms704, Ms705, and Ms709 FUT8 ⁇ / ⁇ cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 by Yamane et al. and Yamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22).
  • EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the alpha 1,6 bond-related enzyme.
  • Hanai et al. also describe cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662).
  • PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lec13 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R. L. et al. (2002) J. Biol. Chem. 277:26733-26740).
  • PCT Publication WO 99/54342 by Umana et al.
  • glycoprotein-modifying glycosyl transferases e.g., beta(1,4)-N-acetylglucosaminyltransferase III (GnTIII)
  • GnTIII glycoprotein-modifying glycosyl transferases
  • the fucose residues of the antibody may be cleaved off using a fucosidase enzyme.
  • the fucosidase alpha-L-fucosidase removes fucosyl residues from antibodies (Tarentino, A. L. et al. (1975) Biochem. 14:5516-23).
  • an antibody can be pegylated to, for example, increase the biological (e.g., serum) half life of the antibody.
  • the antibody, or fragment thereof typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment.
  • PEG polyethylene glycol
  • the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer).
  • polyethylene glycol is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide.
  • the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.
  • the anti-PD-L1 antibodies having V H and V K sequences disclosed herein can be used to create new anti-PD-L1 antibodies by modifying the VH and/or V K sequences, or the constant region(s) attached thereto.
  • the structural features of an anti-PD-L1 antibody of the invention e.g. 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, or 13G4, are used to create structurally related anti-PD-L1 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to human PD-L1.
  • one or more CDR regions of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H11, 11E6, 12B7, or 13G4 or mutations thereof can be combined recombinantly with known framework regions and/or other CDRs to create additional, recombinantly-engineered, anti-PD-L1 antibodies of the invention, as discussed above.
  • Other types of modifications include those described in the previous section.
  • the starting material for the engineering method is one or more of the V H and/or V K sequences provided herein, or one or more CDR regions thereof.
  • the engineered antibody it is not necessary to actually prepare (i.e., express as a protein) an antibody having one or more of the V H and/or V K sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequence(s) is used as the starting material to create a “second generation” sequence(s) derived from the original sequence(s) and then the “second generation” sequence(s) is prepared and expressed as a protein.
  • the invention provides a method for preparing an anti-PD-L1 antibody comprising:
  • Standard molecular biology techniques can be used to prepare and express the altered antibody sequence.
  • the antibody encoded by the altered antibody sequence(s) is one that retains one, some or all of the functional properties of the anti-PD-L1 antibodies described herein, which functional properties include, hut are not limited to:
  • the functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein, such as those set forth in the Examples (e.g., flow cytometry, binding assays).
  • mutations can be introduced randomly or selectively along all or part of an anti-PD-L1 antibody coding sequence and the resulting modified anti-PD-L1 antibodies can be screened for binding activity and/or other functional properties as described herein.
  • Mutational methods have been described in the art.
  • PCT Publication WO 02/092780 by Short describes methods for creating and screening antibody mutations using saturation mutagenesis, synthetic ligation assembly, or a combination thereof.
  • PCT Publication WO 03/074679 by Lazar et al. describes methods of using computational screening methods to optimize physiochemical properties of antibodies.
  • nucleic acid molecules that encode the antibodies of the invention.
  • the nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form.
  • a nucleic acid is “isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York.
  • a nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences.
  • the nucleic acid is a cDNA molecule.
  • Nucleic acids of the invention can be obtained using standard molecular biology techniques.
  • hybridomas e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below
  • cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques.
  • nucleic acid encoding the antibody can be recovered from the library.
  • Preferred nucleic acids molecules of the invention are those encoding the VH and VL sequences of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, monoclonal antibodies.
  • DNA sequences encoding the VH sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:81, 82, 83, 84, 85, 86, 87, 88, 89 and 90, respectively.
  • DNA sequences encoding the VL sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:91, 92, 93, 94, 95, 96, 97, 98, 99 and 100, respectively.
  • VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene.
  • a VL- or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
  • the term “operatively linked,” as used in this context, is intended to mean that the two INA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • the isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3).
  • heavy chain constant regions CH1, CH2 and CH3
  • the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgG1 or IgG4 constant region.
  • the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CH1 constant region.
  • the isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
  • the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 , such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 42:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., (1990) Nature 348:552-554).
  • a flexible linker e.g., encoding the amino acid sequence (Gly 4 -Ser) 3
  • Monoclonal antibodies (mAbs) of the present invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein (1975) Nature 256: 495. Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibody can be employed e.g., viral or oncogenic transformation of B lymphocytes.
  • hybridomas The preferred animal system for preparing hybridomas is the murine system.
  • Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.
  • Chimeric or humanized antibodies of the present invention can be prepared based on the sequence of a murine monoclonal antibody prepared as described above.
  • DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques.
  • the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.).
  • the murine CDR regions can be inserted into a human framework using methods known in the art (see e.g., U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.).
  • the antibodies of the invention are human monoclonal antibodies.
  • Such human monoclonal antibodies directed against PD-L1 can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system.
  • transgenic and transchromosomic mice include mice referred to herein as HuMAb mice and KM MiceTM, respectively, and are collectively referred to herein as “human Ig mice.”
  • the HuMAb Mouse® (Medarex, Inc.) contains human immunoglobulin gene miniloci that encode unrearranged human heavy ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain, loci (see e.g., Lonberg, et al. (1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or ⁇ , and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG ⁇ monoclonal (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N.
  • human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes, such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome.
  • KM MiceTM are described in detail in PCT Publication WO 02/43478 to Ishida et al.
  • transgenic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-PD-L1 antibodies of the invention.
  • an alternative transgenic system referred to as the Xenomouse (Abgenix, Inc.) can be used; such mice are described in, for example, U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584 and 6,162,963 to Kucherlapati et al.
  • mice carrying both a human heavy chain transchromosome and a human light chain transchromosome referred to as “TC mice” can be used; such mice are described in Tomizuka et al. (2000) Proc. Natl. Acad. Sci. USA 97:722-727.
  • cows carrying human heavy and light chain transchromosomes have been described in the art (Kuroiwa et al. (2002) Nature Biotechnology 20:889-894) and can be used to raise anti-PD-L1 antibodies of the invention.
  • Human monoclonal antibodies of the invention can also be prepared using phage display methods for screening libraries of human immunoglobulin genes. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698 to Ladner et al.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat. Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos. 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 to Griffiths et al.
  • Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization.
  • SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization.
  • Such mice are described in, for example, U.S. Pat. Nos. 5,476,996 and 5,698,767 to Wilson et al.
  • mice When human Ig mice are used to raise human antibodies of the invention, such mice can be immunized with a purified or enriched preparation of PD-L1 antigen and/or recombinant PD-L1, or an PD-L1 fusion protein, as described by Lonberg, N. et al. (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851; and PCT Publication WO 98/24884 and WO 01/14424.
  • the mice will be 6-16 weeks of age upon the first infusion.
  • a purified or recombinant preparation (5-50 ⁇ g) of PD-L1 antigen can be used to immunize the human Ig mice intraperitoneally.
  • Example 1 Detailed procedures to generate fully human monoclonal antibodies to PD-L1 are described in Example 1 below. Cumulative experience with various antigens has shown that the transgenic mice respond when initially immunized intraperitoneally (IP) with antigen in complete Freund's adjuvant, followed by every other week IP immunizations (up to a total of 6) with antigen in incomplete Freund's adjuvant. However, adjuvants other than Freund's are also found to be effective. In addition, whole cells in the absence of adjuvant are found to be highly immunogenic. The immune response can be monitored over the course of the immunization protocol with plasma samples being obtained by retroorbital bleeds.
  • mice with sufficient titers of anti-PD-L1 human immunoglobulin can be used for fusions.
  • Mice can be boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. It is expected that 2-3 fusions for each immunization may need to be performed. Between 6 and 24 mice are typically immunized for each antigen.
  • HCo7 and HCo12 strains are used.
  • both HCo7 and HCo12 transgene can be bred together into a single mouse having two different human heavy chain transgenes (HCo7/HCo12).
  • the KM MouseTM strain can be used, as described in Example 1.
  • splenocytes and/or lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line.
  • an appropriate immortalized cell line such as a mouse myeloma cell line.
  • the resulting hybridomas can be screened for the production of antigen-specific antibodies.
  • single cell suspensions of splenic lymphocytes from immunized mice can be fused to one-sixth the number of P3X63-Ag8.653 nonsecreting mouse myeloma cells (ATCC, CRL 1580) with 50% PEG.
  • Cells are plated at approximately 2 ⁇ 10 5 in flat bottom microtiter plate, followed by a two week incubation in selective medium containing 20% fetal Clone Serum, 18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin, 50 mg/ml streptomycin, 50 mg/ml gentamycin and 1 ⁇ HAT (Sigma; the HAT is added 24 hours after the fusion). After approximately two weeks, cells can be cultured in medium in which the HAT is replaced with HT.
  • selective medium containing 20% fetal Clone Serum, 18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin
  • selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification.
  • Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.).
  • Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity.
  • the buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient.
  • the monoclonal antibodies can be aliquoted and stored at ⁇ 80° C.
  • Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202).
  • DNAs encoding partial or full-length light and heavy chains can be obtained by standard molecular biology techniques (e.g., PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
  • operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
  • the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
  • the light and heavy chain variable regions of the antibodies described herein can be used to create full-length antibody genes of any antibody isotype by inserting them into expression vectors already, encoding heavy chain constant and light chain constant regions of the desired isotype such that the V H segment is operatively linked to the C H segment(s) within the vector and the V K segment is operatively linked to the C L segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
  • the term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990)). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • nonviral regulatory sequences may be used, such as the ubiquitin promoter or ⁇ -globin promoter.
  • regulatory elements composed of sequences from different sources such as the SR ⁇ promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y. et al. (1988) Mol. Cell. Biol. 8:466-472).
  • the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
  • Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr ⁇ host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
  • the various forms of the term “transfection” are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr ⁇ CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
  • Chinese Hamster Ovary CHO cells
  • dhfr ⁇ CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621
  • NSO myeloma cells
  • another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841.
  • the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown.
  • Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Antibodies of the invention can be tested for binding to PD-L1 by, for example, standard ELISA. Briefly, microtiter plates are coated with purified PD-L1 at 0.25 ⁇ g/ml in PBS, and then blocked with 5% bovine serum albumin in PBS. Dilutions of antibody (e.g., dilutions of plasma from PD-L1-immunized mice) are added to each well and incubated for 1-2 hours at 37° C.
  • the plates are washed with PBS/Tween and then incubated with secondary reagent (e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent) conjugated to alkaline phosphatase for 1 hour at 37° C. After washing, the plates are developed with pNPP substrate (1 mg/ml), and analyzed at OD of 405-650. Preferably, mice which develop the highest titers will be used for fusions.
  • secondary reagent e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent conjugated to alkaline phosphatase for 1 hour at 37° C.
  • secondary reagent e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent conjugated to alkaline phosphatase for 1 hour at 37° C.
  • secondary reagent e.g., for human antibodies,
  • An ELISA assay as described above can also be used to screen for hybridomas that show positive reactivity with PD-L1 immunogen.
  • Hybridomas that bind with high avidity to PD-L1 are subcloned and further characterized.
  • One clone from each hybridoma, which retains the reactivity of the parent cells (by ELISA) can be chosen for making a 5-10 vial cell bank stored at ⁇ 140° C., and for antibody purification.
  • selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification.
  • Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.). Fluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity.
  • the buffer solution can be exchanged into PBS, and the concentration can be determined by OD 280 using 1.43 extinction coefficient.
  • the monoclonal antibodies can be aliquoted and stored at ⁇ 80° C.
  • each antibody can be biotinylated using commercially available reagents (Pierce, Rockford, Ill.). Competition studies using unlabeled monoclonal antibodies and biotinylated monoclonal antibodies can be performed using PD-L1 coated-ELISA plates as described above. Biotinylated mAb binding can be detected with a strep-avidin-alkaline phosphatase probe.
  • isotype ELISAs can be performed using reagents specific for antibodies of a particular isotype. For example, to determine the isotype of a human monoclonal antibody, wells of microtiter plates can be coated with 1 ⁇ g/ml of anti-human immunoglobulin overnight at 4° C. After blocking with 1% BSA, the plates are reacted with 1 ⁇ g/ml or less of test monoclonal antibodies or purified isotype controls, at ambient temperature for one to two hours. The wells can then be reacted with either human IgG1 or human IgM-specific alkaline phosphatase-conjugated probes. Plates are developed and analyzed as described above.
  • Anti-PD-L1 human IgGs can be farther tested for reactivity with PD-L1 antigen by Western blotting. Briefly, PD-L1 can be prepared and subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis. After electrophoresis, the separated antigens are transferred to nitrocellulose membranes, blocked with 10% fetal calf serum, and probed with the monoclonal antibodies to be tested. Human IgG binding can be detected using anti-human IgG alkaline phosphatase and developed with BCIP/NBT substrate tablets (Sigma Chem. Co., St. Louis, Mo.).
  • the antibodies of the present invention may be further characterized by the various physical properties of the anti-PD-L1 antibodies.
  • Various assays may be used to detect and/or differentiate different classes of antibodies based on these physical properties.
  • antibodies of the present invention may contain one or more glycosylation sites in either the light or heavy chain variable region.
  • the presence of one or more glycosylation sites in the variable region may result in increased immunogenicity of the antibody or an alteration of the pK of the antibody due to altered antigen binding (Marshall et al (1972) Annu Rev Biochem 41:673-702; Gala F A and Morrison S L (2004) J Immunol 172:5489-94; Wallick et al (1988) J Exp Med 168:1099-109; Spiro R G (2002) Glycobiology 12:43R-56R; Parekh et al (1985) Nature 316:452-7; Mimura et al.
  • variable region glycosylation may be tested using a Glycoblot assay, which cleaves the antibody to produce a Fab, and then tests for glycosylation using an assay that measures periodate oxidation and Schiff base formation.
  • variable region glycosylation may be tested using Dionex light chromatography (Dionex-LC), which cleaves saccharides from a Fab into monosaccharides and analyzes the individual saccharide content.
  • Dionex-LC Dionex light chromatography
  • the antibodies of the present invention do not contain asparagine isomerism sites.
  • a deamidation or isoaspartic acid effect may occur on N-G or D-G sequences, respectively.
  • the deamidation or isoaspartic acid effect results in the creation of isoaspartic acid which decreases the stability of an antibody by creating a kinked structure off a side chain carboxy terminus rather than the main chain.
  • the creation of isoaspartic acid can be measured using an iso-quant assay, which uses a reverse-phase HPLC to test for isoaspartic acid.
  • Each antibody will have a unique isoelectric point (pI), but generally antibodies will fall in the pH range of between 6 and 9.5.
  • the pI for an IgG1 antibody typically falls within the pH range of 7-9.5 and the pI for an IgG4 antibody typically falls within the pH range of 6-8.
  • Antibodies may have a pI that is outside this range. Although the effects are generally unknown, there is speculation that antibodies with a pI outside the normal range may have some unfolding and instability under in vivo conditions.
  • the isoelectric point may be tested using a capillary isoelectric focusing assay, which creates a pH gradient and may utilize laser focusing for increased accuracy (Janini et al (2002) Electrophoresis 23:1605-11; Ma et al.
  • an anti-PD-L1 antibody that contains a pI value that falls in the normal range. This can be achieved either by selecting antibodies with a pI in the normal range, or by mutating charged surface residues using standard techniques well known in the art.
  • each antibody will have a melting temperature that is indicative of thermal stability (Krishnamurthy R and Manning M C (2002) Curr Pharm Biotechnol 3:361-71). A higher thermal stability indicates greater overall antibody stability in vivo.
  • the melting point of an antibody may be measure using techniques such as differential scanning calorimetry (Chen et al (2003) Pharm Res 20:1952-60; Ghirlando et al (1999) Immunol Lett 68:47-52).
  • T M1 indicates the temperature of the initial unfolding of the antibody.
  • T M2 indicates the temperature of complete unfolding of the antibody.
  • the T M1 of an antibody of the present invention is greater than 60° C., preferably greater than 65° C., even more preferably greater than 70° C.
  • the thermal stability of an antibody may be measure using circular dichroism (Murray et al. (2002) J. Chromatogr Sci 40:343-9).
  • Table 1 The thermal stability of anti-PD-L1 antibodies disclosed herein is summarized in
  • antibodies are selected that do not rapidly degrade. Fragmentation of an anti-PD-L1 antibody may be measured using capillary electrophoresis (CE) and MALDI-MS, as is well understood in the art (Alexander A J and Hughes D E (1995) Anal Chem 67:3626-32).
  • CE capillary electrophoresis
  • MALDI-MS MALDI-MS
  • antibodies are selected that have minimal aggregation effects. Aggregation may lead to triggering of an unwanted immune response and/or altered or unfavorable pharmacokinetic properties. Generally, antibodies are acceptable with aggregation of 25% or less, preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less and even more preferably 5% or less. Aggregation may be measured by several techniques well known in the art, including size-exclusion column (SEC) high performance liquid chromatography (HPLC), and light scattering to identify monomers, dimers, trimers or multimers.
  • SEC size-exclusion column
  • HPLC high performance liquid chromatography
  • the present invention features an anti-PD-L1 antibody, or a fragment thereof, conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin.
  • a therapeutic moiety such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin.
  • conjugates are referred to herein as “immunoconjugates”.
  • Immunoconjugates that include one or more cytotoxins are referred to as “immunotoxins.”
  • a cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells.
  • Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.
  • Therapeutic agents also include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vin
  • An example of a calicheamicin antibody conjugate is commercially available (MylotargTM; Wyeth-Ayerst).
  • Cytotoxins can be conjugated to antibodies of the invention using linker technology available in the art.
  • linker types that have been used to conjugate a cytotoxin to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers.
  • a linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D).
  • Antibodies of the present invention also can be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates.
  • radioactive isotopes that can be conjugated to antibodies for use diagnostically or therapeutically include, but are not limited to, iodine 131 , indium 111 , yttrium 90 and lutetium 177 .
  • Method for preparing radioimmunconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including ZevalinTM (IDEC Pharmaceuticals) and BexxarTM (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention.
  • the antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety is not to be construed as limited to classical chemical therapeutic agents.
  • the drug moiety may be a protein or polypeptide possessing a desired biological activity.
  • proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, Pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon- ⁇ ; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • IL-1 interleukin-1
  • IL-2 interleukin-2
  • IL-6 interleukin-6
  • the present invention features bispecific molecules comprising an anti-PD-L1 antibody, or a fragment thereof, of the invention.
  • An antibody of the invention, or antigen-binding portions thereof can be derivatized or linked to another functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules.
  • the antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multispecific molecules that bind to more than two different binding sites and/or target molecules; such multispecific molecules are also intended to be encompassed by the term “bispecific molecule” as used herein.
  • an antibody of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results.
  • the present invention includes bispecific molecules comprising at least one first binding specificity for PD-L1 and a second binding specificity for a second target epitope.
  • the second target epitope is an Fc receptor, e.g., human Fc ⁇ RI (CD64) or a human Fc ⁇ receptor (CD89). Therefore, the invention includes bispecific molecules capable of binding both to Fc ⁇ R or Fc ⁇ R expressing effector cells (e.g., monocytes, macrophages or polymorphonuclear cells (PMNs)), and to target cells expressing PD-L1.
  • bispecific molecules target PD-L1 expressing cells to effector cell and trigger Fc receptor-mediated effector cell activities, such as phagocytosis of an PD-L1 expressing cells, antibody dependent cell-mediated cytotoxicity (ADCC), cytokine release, or generation of superoxide anion.
  • ADCC antibody dependent cell-mediated cytotoxicity
  • the molecule can further include a third binding specificity, in addition to an anti-Fc binding specificity and an anti-PD-L1 binding specificity.
  • the third binding specificity is an anti-enhancement factor (EF) portion, e.g., a molecule which binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell.
  • EF anti-enhancement factor
  • the “anti-enhancement factor portion” can be an antibody, functional antibody fragment or a ligand that binds to a given molecule, e.g., an antigen or a receptor, and thereby results in an enhancement of the effect of the binding determinants for the F c receptor or target cell antigen.
  • the “anti-enhancement factor portion” can bind an F c receptor or a target cell antigen.
  • the anti-enhancement factor portion can bind to an entity that is different from the entity to which the first and second binding specificities bind.
  • the anti-enhancement factor portion can bind a cytotoxic T-cell (e.g. via CD2, CD3, CD8, CD28, CD4, CD40, ICAM-1 or other immune cell that results in an increased immune response against the target cell).
  • the bispecific molecules of the invention comprise as a binding specificity at least one antibody, or an antibody fragment thereof, including, e.g., an Fab, Fab′, F(ab′) 2 , Fv, or a single chain Fv.
  • the antibody may also be a light chain or heavy chain dimer, or any minimal fragment thereof such as a Fv or a single chain construct as described in Ladner et al. U.S. Pat. No. 4,946,778, the contents of which is expressly incorporated by reference.
  • the binding specificity for an Fc ⁇ receptor is provided by a monoclonal antibody, the binding of which is not blocked by human immunoglobulin G (IgG).
  • IgG receptor refers to any of the eight ⁇ -chain genes located on chromosome 1. These genes encode a total of twelve transmembrane or soluble receptor isoforms which are grouped into three Fc ⁇ receptor classes: Fc ⁇ RI (CD64), Fc ⁇ RII (CD32), and Fc ⁇ RIII (CD16).
  • the Fc ⁇ receptor a human high affinity Fc ⁇ RI.
  • the human Fc ⁇ RI is a 72 kDa molecule, which shows high affinity for monomeric IgG (10 8 -10 9 M ⁇ 1 ).
  • the hybridoma producing mAb 32 is available from the American Type Culture Collection, ATCC Accession No. HB9469.
  • the anti-Fc ⁇ receptor antibody is a humanized form of monoclonal antibody 22 (H22).
  • H22 monoclonal antibody 22
  • the production and characterization of the H22 antibody is described in Graziano, R. F. et al. (1995) J. Immunol 155 (10): 4996-5002 and PCT Publication WO 94/10332.
  • the H22 antibody producing cell line was deposited at the American Type Culture Collection under the designation HA022CL1 and has the accession no. CRL 11177.
  • the binding specificity for an Fc receptor is provided by an antibody that binds to a human IgA receptor, e.g., an Fc-alpha receptor (Fc ⁇ RI (CD89)), the binding of which is preferably not blocked by human immunoglobulin A (IgA).
  • IgA receptor is intended to include the gene product of one ⁇ -gene (Fc ⁇ RI) located on chromosome 19. This gene is known to encode several alternatively spliced transmembrane isoforms of 55 to 110 kDa.
  • Fc ⁇ RI (CD89) is constitutively expressed on monocytes/macrophages, eosinophilic, and neutrophilic granulocytes, but not on non-effector cell populations.
  • Fc ⁇ RI has medium affinity ( ⁇ 5 ⁇ 10 7 M ⁇ 1 ) for both IgA1 and IgA2, which is increased upon exposure to cytokines such as G-CSF or GM-CSF (Morton, H. C. et al. (1996) Critical Reviews in Immunology 16:423-440).
  • cytokines such as G-CSF or GM-CSF
  • Fc ⁇ RI and Fc ⁇ RI are preferred trigger receptors for use in the bispecific molecules of the invention because they are (1) expressed primarily on immune effector cells, e.g., monocytes, PMNs, macrophages and dendritic cells; (2) expressed at high levels 5,000-100,000 per cell); (3) mediators of cytotoxic activities (e.g., ADCC, phagocytosis); (4) mediate enhanced antigen presentation of antigens, including self-antigens, targeted to them.
  • immune effector cells e.g., monocytes, PMNs, macrophages and dendritic cells
  • mediators of cytotoxic activities e.g., ADCC, phagocytosis
  • human monoclonal antibodies are preferred, other antibodies which can be employed in the bispecific molecules of the invention are murine, chimeric and humanized monoclonal antibodies.
  • the bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, e.g., the anti-FcR and anti-PD-L1 binding specificities, using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation.
  • cross-linking agents examples include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-1-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al. (1984) J. Exp. Med.
  • Preferred conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).
  • the binding specificities are antibodies, they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains.
  • the hinge region is modified to contain an odd number of sulfhydryl residues, preferably one, prior to conjugation.
  • both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell.
  • This method is particularly useful where the bispecific molecule is a mAb ⁇ mAb, mAb ⁇ Fab, Fab ⁇ F(ab′) 2 or ligand ⁇ Fab fusion protein.
  • a bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants.
  • Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Pat. Nos. 5,260,203; 5,455,030; 4,881,175; 5,132,405; 5,091,513; 5,476,786; 5,013,653; 5,258,498; and 5,482,858.
  • Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • FACS fluorescence-activated cell sorting
  • bioassay e.g., growth inhibition
  • Western Blot assay Western Blot assay.
  • Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest.
  • a labeled reagent e.g., an antibody
  • the FcR-antibody complexes can be detected using e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody-FcR complexes.
  • the antibody can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein).
  • RIA radioimmunoassay
  • the radioactive isotope can be detected by such means as the use of a ⁇ counter or a scintillation counter or by autoradiography.
  • the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding portion(s) thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target antigen or that have complementary activities.
  • compositions of the invention also can be administered in combination therapy, i.e., combined with other agents.
  • the combination therapy can include an anti-PD-L1 antibody of the present invention combined with at least one other anti-inflammatory or immunosuppressant agent. Examples of therapeutic agents that can be used in combination therapy are described in greater detail below in the section on uses of the antibodies of the invention.
  • “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound i.e., antibody, immunoconjugate, or bispecific molecule
  • the active compound i.e., antibody, immunoconjugate, or bispecific molecule, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
  • the pharmaceutical compounds of the invention may include one or mere pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66:1-19). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • a pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant.
  • pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical faint may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization micro filtration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent of active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight.
  • dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg.
  • An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • Preferred dosage regimens for an anti-PD-L1 antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.
  • two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated.
  • Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 ⁇ g/ml and in some methods about 25-300 ⁇ g/ml.
  • antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending, on the half-life of the antibody in the patient. In general, human antibodies show the longest half life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a “therapeutically effective dosage” of an anti-PD-L1 antibody of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a “therapeutically effective dosage” preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
  • the ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors.
  • this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner.
  • a therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
  • a composition of the present invention can be administered via one or more routes of administration using one or more of a variety of methods known in the art.
  • routes and/or mode of administration will vary depending upon the desired results.
  • Preferred routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • an antibody of the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • a non-parenteral route such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems , J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • compositions can be administered with medical devices known in the art.
  • a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. No. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in U.S. Pat. No. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
  • Examples of well-known implants and modules useful in the present invention include: U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Pat
  • the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo.
  • the blood-brain barrier excludes many highly hydrophilic compounds.
  • the therapeutic compounds of the invention cross the BBB (if desired)
  • they can be formulated, for example, in liposomes.
  • liposomes For methods of manufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and 5,399,331.
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin. Pharmacol. 29:685).
  • Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357:140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233:134); p120 (Schreier et al. (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273.
  • the antibodies, antibody compositions and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of PD-L1 or enhancement of immune response by blockade of PD-L1.
  • the antibodies of the present invention are human antibodies.
  • these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in a variety of situations.
  • the invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modified.
  • the response is enhanced, stimulated or up-regulated.
  • the term “subject” is intended to include human and non-human animals.
  • Non-human animals includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses.
  • Preferred subjects include human patients in need of enhancement of an immune response.
  • the methods are particularly suitable for treating human patients having a disorder that can be treated by augmenting the T-cell mediated immune response.
  • the methods are particularly suitable for treatment of cancer cells in vivo.
  • the anti-PD-L1 antibodies can be administered together with an antigen of interest. When antibodies to PD-L1 are administered together with another agent, the two can be administered in either order or simultaneously.
  • the invention further provides methods for detecting the presence of human PD-L1 antigen in a sample, or measuring the amount of human PD-L1 antigen, comprising contacting the sample, and a control sample, with a human monoclonal antibody, or an antigen binding portion thereof, which specifically hinds to human PD-L1, under conditions that allow for formation of a complex between the antibody or portion thereof and human PD-L1. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of human PD-L1 antigen in the sample.
  • Blockade of PD-L1 by antibodies can enhance the immune response to cancerous cells in the patient.
  • PD-L1 is not expressed in normal human cells, but is abundant in a variety of human cancers (Dong et al. (2002) Nat Med 8:787-9).
  • the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2004) Cancer Immunol. Immunother . [epub]; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100).
  • Immune suppression can be reversed by inhibiting the local interaction of PD-L1 to PD-1 and the effect is additive when the interaction of PD-L2 to PD-1 is blocked as well (Iwai et al. (2002) PNAS 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).
  • An anti-PD-L1 antibody may be used alone to inhibit the growth of cancerous tumors.
  • an anti-PD-L1 antibody may be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies, as described below.
  • the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.
  • the antibody is a human anti-PD-L1 antibody (such as any of the human anti-human PD-L1 antibodies described herein). Additionally or alternatively, the antibody may be a chimeric or humanized anti-PD-L1 antibody.
  • Preferred cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy.
  • preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer.
  • cancers examples include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid
  • antibodies to PD-L1 can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
  • tumors have been shown to be immunogenic such as melanomas. It is anticipated that by raising the threshold of T cell activation by PD-L1 blockade, we may expect to activate tumor responses in the host.
  • PD-L1 blockade is likely to be most effective when combined with a vaccination protocol.
  • Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition).
  • a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
  • tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host.
  • PD-L1 blockade may be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins.
  • the tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means).
  • Tumor antigen may also be “neo-antigens” expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e. bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
  • tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
  • HPV Human Papilloma Viruses
  • HBV Hepatitis Viruses
  • KHSV Kaposi's Herpes Sarcoma Virus
  • Another form of tumor specific antigen which may be used in conjunction with PD-1 blockade is purified heat shock proteins (HSP) isolated from the rumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).
  • HSP heat shock proteins
  • DC Dendritic cells
  • DC's can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs may also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization may be effectively combined with PD-L1 blockade to activate more potent anti-tumor responses.
  • PD-L1 blockade may also be combined with standard cancer treatments. PD-L1 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304).
  • An example of such a combination is an anti-PD-L1 antibody in combination with decarbazine for the treatment of melanoma.
  • Another example of such a combination is an anti-PD-L1 antibody in combination with interleukin-2 (IL-2) for the treatment of melanoma.
  • IL-2 interleukin-2
  • PD-L1 blockade The scientific rationale behind the combined use of PD-L1 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
  • Other combination therapies that may result in synergy with PD-L1 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
  • Angiogenesis inhibitors may also be combined with PD-L1 blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
  • PD-L1 blocking antibodies can also be used in combination with bispecific antibodies that target Fc alpha or Fc ⁇ receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243).
  • Bispecific antibodies can be used to target two separate antigens.
  • anti-Fc receptor/anti tumor antigen e.g., Her-2/neu
  • bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses.
  • the T cell arm of these responses would by augmented by the use of PD-L1 blockade.
  • antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
  • Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365). Antibodies to each of these entities may be used in combination with anti-PD-L1 to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
  • Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in conjunction with PD-L1 antibodies (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40).
  • Activating antibodies to T cell costimulatory molecules such as OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al.
  • Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses.
  • PD-L1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
  • another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-PD-L1 antibody, or antigen-binding portion thereof, such that the subject is treated for the infectious disease.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein).
  • the antibody can be a chimeric or humanized antibody.
  • antibody mediated PD-L1 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens.
  • pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, C), Influenza, Herpes, Giardia , Malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa .
  • PD-L1 blockade is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of anti-human PD-L1 administration, thus provoking a strong T cell response that is not dampened by negative signals through PD-L1.
  • pathogenic viruses causing infections treatable by methods of the invention include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
  • adenovirus e.g., influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie
  • pathogenic bacteria causing infections treatable by methods of the invention include Chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and Gonococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella , diphtheria, Salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • pathogenic fungi causing infections treatable by methods of the invention include Candida ( albicans, krusei, glabrata, tropicalis , etc.), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , etc.), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • pathogenic parasites causing infections treatable by methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.
  • PD-L1 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci . USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).
  • cytokine treatment e.g., interferons, GM-CSF, G-CSF, IL-2
  • bispecific antibody therapy which provides for enhanced presentation of tumor antigens
  • Anti-PD-L1 antibodies may provoke and amplify autoimmune responses. Indeed, induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities (depigmentation observed in anti-CTLA-4+GM-CSF-modified B16 melanoma in van Elsas et al. supra; depigmentation in Trp-2 vaccinated mice (Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96: 2982-2987); autoimmune prostatitis evoked by TRAMP tumor cell vaccines (Hurwitz, A. (2000) supra), melanoma peptide antigen vaccination and vitilago observed in human clinical trials (Rosenberg, S A and White, D E (1996) J. Immunother Emphasis Tumor Immunol 19 (1): 81-4).
  • anti-PD-L1 blockade in conjunction with various self proteins in order to devise vaccination protocols to efficiently generate immune responses against these self proteins for disease treatment.
  • Alzheimer's disease involves inappropriate accumulation of A ⁇ peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).
  • Analogous methods as described above for the use of anti-PD-L1 antibody can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNF ⁇ , and IgE.
  • Anti-PD-L1 antibodies may be used to stimulate antigen-specific immune responses by coadministration of an anti-PD-L1 antibody with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
  • antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
  • Anti-PD-L1 antibodies may also be used to abrogate secondary effects associated with diseases such as T cell suppressed wasting disease with colitis (Kauai et al. (2003) J. Immunol. 171:4156-63). Accordingly, in another aspect the invention provides a method of abrogating leukocyte infiltration, decreasing production of IFN- ⁇ , IL-2, and IFN- ⁇ by T cells.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Anti-PD-L1 antibodies may also be used to treat diseases such as chronic inflammatory diseases, such as lichen planus, a T-cell mediated chronic inflammatory mucocutaneous disease (Youngnak-Piboonratanakit et al. (2004) Immunol Letters 94:215-22). Accordingly, in another aspect the invention provides a method of abrogating chronic inflammatory disease by T cells.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Suitable routes of administering the antibody compositions e.g., human monoclonal antibodies, multispecific and bispecific molecules and immunoconjugates
  • the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous).
  • Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.
  • human anti-PD-L1 antibodies of the invention can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent.
  • the antibody can be linked to the agent (as an immunocomplex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation.
  • Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
  • anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
  • Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days.
  • Co-administration of the human anti-PD-L1 antibodies, or antigen binding fragments thereof, of the present invention with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
  • kits comprising the antibody compositions of the invention (e.g., human antibodies, bispecific or multispecific molecules, or immunoconjugates) and instructions for use.
  • the kit can further contain a least one additional reagent, or one or more additional human antibodies of the invention (e.g., a human antibody having a complementary activity which binds to an epitope in PD-L1 antigen distinct from the first human antibody).
  • Kits typically include a label indicating the intended use of the contents of the kit.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • Immunization protocols utilized as antigen both (i) a recombinant fusion protein comprising the extracellular portion of PD-L1, and (ii) membrane bound full-length PD-L1. Both antigens were generated by recombinant transfection methods in a CHO cell line.
  • Fully human monoclonal antibodies to PD-L1 were prepared using the KM strain of transgenic transchromosomic mice, which expresses human antibody genes.
  • the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820 and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of PCT Publication WO 01/09187.
  • this mouse strain carries a human kappa light chain transgene, KCo5, as described in Fishwild et al. (1996) Nature Biotechnology 14:845-851, and a SC20 transchromosome as described in PCT Publication WO 02/43478.
  • mice of the KM-Mouse® strain were immunized with purified recombinant PD-L1-Ig and PD-L1-transfected CHO cells as antigen.
  • General immunization schemes for HuMab mice are described in Lonberg, N. et al (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851 and PCT Publication WO 98/24884.
  • the mice were 6-16 weeks of age upon the first infusion of antigen.
  • a purified recombinant preparation (5-50 ⁇ g) of PD-L1-Ig antigen and 5-10 ⁇ 10 6 cells were used to immunize the HuMab mice intraperitonealy (IP), subcutaneously (Sc) or via footpad injection.
  • mice were immunized twice with antigen in complete Freund's adjuvant or Ribi adjuvant IP, followed by 3-21 days IP (up to a total of 11 immunizations) with the antigen in incomplete Freund's or Ribi adjuvant.
  • the immune response was monitored by retroorbital bleeds.
  • the plasma was screened by ELISA (as described below), and mice with sufficient titers of anti-PD-L1 human immunoglobulin were used for fusions.
  • Mice were boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. Typically, 10-35 fusions for each antigen were performed. Several dozen mice were immunized for each antigen.
  • mice producing antibodies that bound PD-L1 sera from immunized mice were tested by ELISA as described by Fishwild, D. et al. (1996). Briefly, microtiter plates were coated with purified recombinant PD-L1 fusion protein from transfected CHO cells at 1-2 ⁇ g/ml in PBS, 100 ⁇ l/wells incubated 4° C. overnight then blocked with 200 ⁇ l/well of 5% fetal bovine serum in PBS/Tween (0.05%). Dilutions of sera from PD-L1-immunized mice were added to each well and incubated for 1-2 hours at ambient temperature.
  • the plates were washed with PBS/Tween and then incubated with a goat-anti-human IgG polyclonal antibody conjugated with horseradish peroxidase (HRP) for 1 hour at room temperature. After washing, the plates were developed with ABTS substrate (Sigma, A-1888, 0.22 mg/ml) and analyzed by spectrophotometer at OD 415-495. Mice that developed the highest titers of anti-PD-L1 antibodies were used for fusions. Fusions were performed as described below and hybridoma supernatants were tested for anti-PD-L1 activity by ELISA.
  • HRP horseradish peroxidase
  • mice The mouse splenocytes, isolated from a KM mouse, were fused with PEG to a mouse myeloma cell line based upon standard protocols. The resulting hybridomas were then screened for the production of antigen-specific antibodies. Single cell suspensions of splenocytes from immunized mice were fused to one-fourth the number of SP2/0 nonsecreting mouse myeloma cells (ATCC, CRL 1581) with 50% PEG (Sigma).
  • Cells were plated at approximately 1 ⁇ 10 5 /well in flat bottom microtiter plate, followed by about two week incubation in selective medium containing 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditioned medium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose, L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 mg/ml gentamycin and 1 ⁇ HAT (Sigma, CRL P-7185). After 1-2 weeks, cells were cultured in medium in which the HAT was replaced with HT.
  • selective medium containing 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditioned medium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose, L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.05
  • Hybridoma clones 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 were selected for further analysis.
  • the cDNA sequences encoding the heavy and light chain variable regions of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 monoclonal antibodies were obtained from the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 hybridomas, respectively, using standard PCR techniques and were sequenced using standard DNA sequencing techniques.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 3G10 are shown in FIG. 1A and in SEQ ID NO:81 and 1, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 3G10 are shown in FIG. 1B and in SEQ ID NO:91 and 11, respectively.
  • Further analysis of the 3G10 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 1A and 11 , and in SEQ ID NOs:21, 31 and 41, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 12A4 are shown in FIG. 2A and in SEQ ID NO:82 and 2, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 12A4 are shown in FIG. 2B and in SEQ ID NO:92 and 12, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 10A5 are shown in FIG. 3A and in SEQ ID NO:83 and 3, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 10A5 are shown in FIG. 3B and in SEQ ID NO:93 and 13, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 5F8 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 5F8 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 10H10 are shown in FIG. 5A and in SEQ ID NO:85 and 5, respectively.
  • nucleotide and amino acid sequences of the light chain variable region of 10H10 are shown in FIG. 5B and in SEQ ID NO:95 and 15, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 1B12 are shown in FIG. 6A and in SEQ ID NO:86 and 6, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 1B12 are shown in FIG. 6B and in SEQ ID NO:96 and 16, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 7H1 are shown in FIG. 7A and in SEQ ID NO:87 and 7, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 7H1 are shown in FIG. 7B and in SEQ ID NO:97 and 17, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 11E6 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 11E6 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 12B7 are shown in FIG. 9A and in SEQ ID NO:89 and 9, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 12B7 are shown in FIG. 9B and in SEQ ID NO:99 and 19, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 13G4 are shown in FIG. 10A and in SEQ ID NO:90 and 10, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 13G4 are shown in FIG. 10B and in SEQ ID NO:100 and 20, respectively.
  • binding affinity and binding kinetics of anti-PD-L1 antibodies were examined by Biacore analysis. Binding specificity, and cross-competition were examined by flow cytometry.
  • Anti-PD-L1 antibodies were characterized for affinities and binding kinetics by Biacore analysis (Biacore AB, Uppsala, Sweden). Purified recombinant human PD-L1 fusion protein was covalently linked to a CM5 chip (carboxy methyl dextran coated chip) via primary amines, using standard amine coupling chemistry and kit provided by Biacore, to a density of 562 RUs. Binding was measured by flowing the antibodies in HBS EP buffer (provided by Biacore AB) at a concentration of 133 nM at a flow rate of 50 ⁇ l/min. The antigen-antibody association kinetics was followed for 1 minute and the dissociation kinetics was followed for 1 minute.
  • Biacore AB Biacore AB
  • association and dissociation curves were fit to a 1:1 Langmuir binding model using BIAevaluation software (Biacore AB). To minimize the effects of avidity in the estimation of the binding constants, only the initial segment of data corresponding to association and dissociation phases were used for fitting.
  • the K D , k on and k off values that were determined are shown in Table 2.
  • CHO cell lines that: express recombinant human PD-L1 at the cell surface were developed and used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry.
  • CHO cells were transfected with expression plasmids containing full length cDNA encoding transmembrane forms of PD-L1. Binding of the 3G10, 10A5, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the transfected cells with the anti-PD-L1 human monoclonal antibody. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab.
  • FIGS. 32A Human 3G10
  • 32 B HumanMAb 10A5
  • 32 C HumanMAb 12A4
  • Binding was also tested using varying concentrations of an anti-PD-L1 antibody.
  • FIG. 33 The anti-PD-L1 human monoclonal antibodies 3G10, 10A5, and 12A4 bound to the CHO cells transfected with PD-L1 in a concentration dependent manner.
  • the specificity of the anti-PD-L1 monoclonal antibodies was determined using a standard ELISA assay for binding to a human PD-L1 fusion to an immunoglobulin Fc region.
  • An Fc-fusion protein of human PD-L1 was tested for binding against the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5. Standard ELISA procedures were performed. The anti-PD-L1 human monoclonal antibodies were added at different concentrations. Goat-anti-human IgG (kappa chain-specific) polyclonal antibody conjugated with horseradish peroxidase (HRP) was used as secondary antibody. The results are shown in FIG. 34 . Each of the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5 bound with high specificity to PD-L1.
  • Anti-PD-L1 antibodies were tested by flow cytometry for binding to activated human or cynomolgus monkey T cells expressing PD-L1 on their surface.
  • Human or monkey T cells were activated by anti-CD3 antibody to induce PD-L1 expression prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 1B12, 13G4, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated cells with serial dilutions of the anti-PD-L1 human monoclonal antibodies. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human Ig-kappa light chain Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.).
  • the results are shown in FIGS. 35 and 36 .
  • Anti-PD-L1 antibodies were tested for binding to activated human T cells expressing PD-L1 on their cell surface by flow cytometry.
  • Human T cells were activated by anti-CD3 antibody to induce PD-L1 expression on T cells prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 10A5 and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated T cells with the anti-PD-L1 human monoclonal antibodies at a concentration of 20 ⁇ g/ml. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometry (Becton Dickinson, San Jose, Calif.). The results are shown in FIGS.
  • the ES-2 human ovarian carcinoma cell line that expresses human PD-L1 at the cell surface was used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry.
  • ES-2 cells were treated overnight with 500 IU/mL of recombinant hIFN- ⁇ to increase PD-L1 expression over the basal level.
  • Binding of the 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 anti-PD-L1 human monoclonal antibodies was assessed by incubating the induced cells with serial dilutions of the anti-PD-L1 human monoclonal antibody.
  • the cells were washed and binding was detected with a PE-labeled anti-human IgG Ab.
  • Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The binding was compared to isotype control antibody. The results are shown in FIG. 38 .
  • the anti-PD-L1 human monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 bound to the hIFN- ⁇ -induced ES-2 cells in a concentration dependent manner.
  • a mixed lymphocyte reaction was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway to lymphocyte effector cells.
  • T cells in the assay were tested for proliferation, IFN- ⁇ secretion and IL-2 secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ positive selection kit (Dynal Biotech).
  • Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days.
  • Monocytes were prepared using a monocyte negative selection kig (Mitenyi Biotech).
  • Each culture contained 10 5 purified T-cells and 10 4 allogeneic dendritic cells in a total volume of 200 ⁇ l.
  • Anti-PD-L1 monoclonal antibody 10A5, 12A4, or 3G10 was added to each culture at different antibody concentrations. Either no antibody or an isotype control antibody was used as a negative control.
  • the cells were cultured for 5 days at 37° C. After day 5, 100 ⁇ l of medium was taken from each culture for cytokine measurement. The levels of IFN- ⁇ and IL-2 were measured using OptEIA ELISA kits (BD Biosciences). The cells were labeled with 3 H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIGS. 39A (T cell proliferation), 39 B (IFN- ⁇ secretion using HuMAb 10A5), 39 C (IFN- ⁇ secretion using HuMAb 12A4 or 3G10) and 39 D (IL-2 secretion).
  • the anti-PD-L1 human monoclonal antibody 10A5 promotes T-cell proliferation, IFN- ⁇ secretion and IL-2 secretion in a concentration dependent manner.
  • the anti-PD-L1 human monoclonal antibodies 12A4 and 3G10 also showed an increase in IFN- ⁇ secretion.
  • cultures containing the control antibody did not show an increase in T cell proliferation, IFN- ⁇ or IL-2 secretion.
  • an allogeneic mixed lymphocyte reaction was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway in lymphocyte effector cells.
  • T cells in the assay were tested for proliferation and IFN- ⁇ secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody or isotype control antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ negative selection kit (Miltenyi). Monocytes were prepared using a monocyte negative selection kit (Mitenyi Biotech). Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days. Each MLR culture contained 10 5 purified T-cells and 10 4 allogeneic dendritic cells in a total volume of 200 ⁇ l. Anti-PD-L1 monoclonal antibody 12A4, 11E6, 3G10, 13G4, 1B12, 10A5, and 12B7 were added to each culture at different antibody concentrations.
  • Either no antibody or an isotype control antibody was used as a negative control.
  • the cells were cultured for 5 days at 37° C. On day 5, 50 ⁇ l of medium was taken from each culture for cytokine measurement and replaced with an equal volume of culture medium containing 1 ⁇ Ci of 3 H-thymidine.
  • the cells were cultured for another 18 hours, harvested, and analyzed for cell proliferation.
  • the levels of IFN- ⁇ in the culture fluid were measured using an OptEIA hIFN- ⁇ ELISA kit (BD Biosciences). The results are shown in FIG. 40 .
  • the anti-PD-L1 human monoclonal antibodies promote T-cell proliferation and IFN- ⁇ secretion in a concentration-dependent manner. In contrast, cultures containing the control antibody did not show an increase in T cell proliferation or IFN- ⁇ secretion.
  • T regulatory cells are lymphocytes that suppress the immune response. The effect of the addition of T regulatory cells on proliferation and IFN- ⁇ secretion in the allogeneic dendritic cell and T cell MLR in the presence or absence of an anti-PD-L1 human monoclonal antibody was tested.
  • T regulatory cells were purified from PBMC using a CD4+CD25+ regulatory T cell isolation kit (Miltenyi Biotec). T regulatory cells were added into a mixed lymphocyte reaction (see above) containing purified CD4+CD25 ⁇ T cells and allogeneic dendritic cells in a 2:1 ratio of CD4+CD25 ⁇ to T regulatory cells.
  • Anti-PD-L1 monoclonal antibody 10A5 was added to each culture at a concentration of 10 ⁇ g/ml. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. at which time the supernatants were analyzed for IFN- ⁇ secretion using a Beadlyte cytokine detection system (Upstate).
  • the cells were labeled with 3 H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIGS. 41A (T cell proliferation) and 41 B (IFN- ⁇ secretion).
  • T cell proliferation T cell proliferation
  • 41 B IFN- ⁇ secretion
  • the addition of anti-PD-L1 human monoclonal antibody 10A5 promotes both T cell proliferation and IFN- ⁇ secretion in cell cultures of allogeneic dendritic cells, T cells and T regulatory cells, indicating that anti-PD-L1 antibodies can reverse the effect of T regulatory cells in the allogeneic DC—T cell-MLR
  • CMV antigen-responsive human PBMC (Astarte Biologics, Redmond, Wash.) were cultured at 2e5 cells/well in flat bottom TC-treated 96 well plates, in the presence of 0.5 ug/ml CMV lysate (Astarte Biologics)+/ ⁇ titrated anti-PD-L1 antibodies.
  • AIM-V medium Invitrogen
  • FBS heat-inactivated FBS
  • the results are shown in FIG. 44 .
  • the anti-PD-L1 human monoclonal antibodies promote IFN- ⁇ secretion by CMV-specific T-cells in a dose-dependent manner.
  • the most robust response was generated by antibodies 13G4, 1B12, and 12A4 compared to isotype control.
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of the ligand PD-L1 to PD-1 expressed on transfected CHO cells by using a cell cytometry assay.
  • PD-1 expressing CHO cells were suspended in FACS buffer (PBS with 4% fetal calf serum).
  • FACS buffer PBS with 4% fetal calf serum.
  • Various concentrations of the anti-PD-L1 HuMAbs 3G10, 10A5 or 12A4 was added to the cell suspension tubes at 4° C. for 30 minutes, followed by addition FITC-labeled PD-L1 fused to an immunoglobulin Fc-region.
  • Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are depicted in FIG. 45 .
  • the anti-PD-L1 monoclonal antibodies 3G10, 10A5, and 12A4 blocked binding of PD-L1 to CHO cells transfected with human PD-1, as measured by the mean fluorescent intensity (MFI) of staining.
  • MFI mean fluorescent intensity
  • Example 11 Inhibition of the Binding of Soluble PD-1 to Cell-Surface PD-L1 Human Anti-PD-L1 Antibodies
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of a soluble dimeric version of the PD-1 receptor (PD-1-hFc) to PD-L1 expressed on hIFN- ⁇ -induced ES-2 human ovarian carcinoma cells using a flow cytometry assay. The blocking was compared to isotype control antibody.
  • PD-1-hFc soluble dimeric version of the PD-1 receptor
  • ES-2 cells were induced overnight with 500 IU/mL of hIFN- ⁇ to upregulate hPD-L1 cell surface expression. Induced cells were suspended in FACS buffer. Serial dilutions of the anti-PD-L1 HuMAbs 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 were added to the cell suspension tubes at 4° C. for 30 minutes, followed by two washes to remove unbound antibody. Next PD-1-hFc protein was added at a constant 2 ug/mL to all wells at 4° C. for 30 minutes, followed by two washes to remove unbound PD-1-hFc.
  • the anti-PD-L1 monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 blocked binding of PD-1 to ES-2 cells that express human PD-L1, as measured by the geometric mean fluorescent intensity (GMFI) of staining.
  • GMFI geometric mean fluorescent intensity
  • mice implanted with a cancerous tumor are treated in viva with anti-PD-L1 antibodies to examine the in vivo effect of the antibodies on tumor growth.
  • Female AJ mice between 6-8 weeks of age are randomized by weight into 6 groups.
  • the mice are implanted subcutaneously in the right flank with 2 ⁇ 10 6 SA1/N fibrosarcoma cells dissolved in 200 ⁇ l of DMEM media on day 0.
  • the mice are treated with PBS vehicle, or anti-PD-L1 antibodies at 10 mg/kg.
  • the animals are dosed by intraperitoneal injection with approximately 200 ⁇ l of PBS containing antibody or vehicle on days 1, 4, 3 and 11.
  • Each group contains 10 animals and the groups consist of: (i) a vehicle group, (ii) control mouse IgG, and (iii) an anti-PD-L1 antibody.
  • the mice are monitored twice weekly for tumor growth for approximately 6 weeks. Using an electronic caliper, the tumors are measured three dimensionally (height ⁇ width ⁇ length) and tumor volume is calculated. Mice are euthanized when the tumors reached tumor end point (1500 mm 3 ) or show greater than 15% weight loss.
  • Example 13 In Vivo Efficacy of Combination Therapy (Anti-CTLA-4 and Anti-PD-L1 Antibodies) on Tumor Establishment and Growth
  • MC38 colorectal cancer cells (available from Dr. N. Restifo, National Cancer Institute, Bethesda, Md.; or Jeffrey Schlom, National Institutes of Health, Bethesda, Md.) were implanted in C57BL/6 mice (2 ⁇ 10 6 cells/mouse) and selected for treatment when tumors reached a size of 100-200 mm 3 ).
  • IP intraperitoneally
  • each of four groups of 10 mice each was injected intraperitoneally (IP) with one of the following: (1) 10 mg/kg mouse IgG and 10 mg/kg of rat IgG (control), (2) 10 mg/kg anti-CTLA-4 monoclonal antibody 9D9 (mouse anti-mouse CTLA-4, obtained from J.
  • Snap frozen and OCT embedded normal and tumor tissues were purchased from Cooperative Human Tissue Network (Philadelphia, Pa.) or National Disease Research Institute (Philadelphia, Pa.). Cryostat sections at 5 ⁇ m were fixed with acetone for 10 min at room temperature, and stored at ⁇ 80° C. until use. A Medarex developed immunohistochemistry protocol was performed using unmodified HuMab anti-PD-L1 by pre-complex of the primary antibodies (12A4, 13G4, 3G10 and 12B7) and secondary antibody (FITC conjugated Fab fragment of goat anti-Hu-IgG. Jackson ImmunoResearch Laboratories. West Grove, Pa.) before applying onto the sections.
  • HuMabs There was overall less intense staining by HuMabs, especially for the staining in the germinal centers. In spleen, diffuse weak immunoreactivity in red pulp was slightly above the background staining. In addition, weak to moderate staining was displayed in Kupffer-like cells in liver and scattered cells in Peyer's patch, as well as in scattered macrophage-like cells and fibroblasts mainly in focal region of the muscularis externa of small intestine.
  • VH CDR2 a.a. 3G10 32 VH CDR2 a.a. 12A4 33 VH CDR2 a.a. 10A5 34 VH CDR2 a.a. 5F8 35 VH CDR2 a.a. 10H10 36 VH CDR2 a.a. 1B12 37 VH CDR2 a.a. 7H1 38 VH CDR2 a.a. 11E6 39 VH CDR2 a.a. 12B7 40 VH CDR2 a.a. 13G4 41 VH CDR3 a.a. 3G10 42 VH CDR3 a.a. 12A4 43 VH CDR3 a.a.
  • VH CDR3 a.a. 5F8 45 VH CDR3 a.a. 10H10 46 VH CDR3 a.a. 1B12 47 VH CDR3 a.a. 7H1 48 VH CDR3 a.a. 11E6 49 VH CDR3 a.a. 12B7 50 VH CDR3 a.a. 13G4 51 VK CDR1 a.a. 3G10 52 VK CDR1 a.a. 12A4 53 VK CDR1 a.a. 10A5 54 VK CDR1 a.a. 5F8 55 VK CDR1 a.a. 10H10 56 VK CDR1 a.a.
  • VH n.t. 10A5 84 VH n.t. 5F8 85 VH n.t. 10H10 86 VH n.t. 1B12 87 VH n.t. 7H1 88 VH n.t. 11E6 89 VH n.t. 12B7 90 VH n.t. 13G4 91 VK n.t. 3G10 92 VK n.t. 12A4 93 VK n.t. 10A5 94 VK n.t. 5F8 95 VK n.t. 10H10 96 VK n.t. 1B12 97 VK n.t. 7H1 98 VK n.t.

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Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-L1 antibodies.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Patent Application No. 60/696,426, filed Jul. 1, 2005, which is incorporated herein by reference in its entirety.
    • BACKGROUND
  • Programmed death 1 (PD-1) is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. The initial members of the family, CD28 and ICOS, were discovered by functional effect on augmenting T cell proliferation following the addition of monoclonal antibodies (Hutloff et al. (1999) Nature 397:263-266; Hansen et al. (1980) Immunogenics 10:247-260). Two cell surface glycoprotein ligands for PD-1 have been identified, PD-L1 and PD-L2, and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192:1027-34; Latchman et al. (2001) Nat Immunol 2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53). Both PD-L1 (B7-H1) and PD-L2 (B7-DC) are B7 homologs that bind to PD-1, but do not bind to other CD28 family members (Blank et al. (2004). Expression of PD-L1 on the cell surface has also been shown to be upregulated through IFN-γ stimulation.
  • PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. (2002) PNAS 99: 12293-7; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53). PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. (2002) Nat Med 8:793-800). It has also been suggested that PD-L1 might be involved in intestinal mucosal inflammation and inhibition of PD-L1 suppresses wasting disease associated with colitis (Kanai et al. (442003) J Immunol 171:4156-63).
    • SUMMARY
  • The present invention provides isolated monoclonal antibodies, in particular human monoclonal antibodies that bind to PD-L1 and exhibit numerous desirable properties. These properties include high affinity binding to human PD-L1. Still further, antibodies of the invention have been shown to increase T-cell proliferation, IFN-γ secretion, and IL-2 secretion in a mixed lymphocyte reaction.
  • In one aspect, the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody exhibits at least one of the following properties:
      • (a) binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (c) increases interferon-γ production in an MLR assay;
      • (d) increases IL-2 secretion in an MLR assay;
      • (e) stimulates antibody responses; or
      • (f) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
        Preferably the antibody is a human antibody, although in alternative embodiments the antibody can be, for example, a murine antibody, a chimeric antibody or humanized antibody.
  • In particular embodiments, the antibody binds to human PD-L1 with a KD of 5×10−8 M or less, binds to human PD-L1 with a KD of 1×10−8 M or less, binds to human PD-L1 with a KD of 5×10−9 M or less, binds to human PD-L1 with a KD of 5×10−9 M or less, or binds to human PD-L1 with a KD of between 1×10−8M and 1×10−10 M.
  • In another embodiment, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, wherein the antibody cross-competes for binding to PD-L1 with a reference antibody comprising:
      • (a) the human heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
      • (b) the human light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
        In various embodiments, the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:11;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:12;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:13;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14:
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:15;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:16;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:17;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:18;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • In another aspect, the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-18 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-69 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-3 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product, of or derived from a human VH 3-9 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L6 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L15 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK A27 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L18 gene, wherein the antibody specifically binds PD-L1.
  • In a particularly preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-18 gene; and
      • (b) a light chain variable region of a human VK L6 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-69 gene; and
      • (b) a light chain variable region of a human VK L6 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-3 gene; and
      • (b) a light chain variable region of a human VK L15 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-69 gene; and
      • (b) a light chain variable region of a human VK A27 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 3-9 gene; and
      • (b) a light chain variable region of a human VK L15 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 3-9 gene; and
      • (b) a light chain variable region of a human VK L18 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
      • a heavy chain variable region that comprises CDR1, CDR2, and CDR3 sequences; and a light chain variable region that comprises CDR1, CDR2, and CDR3 sequences, wherein:
      • (a) the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and conservative modifications thereof;
      • (b) the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, and conservative modifications thereof; and
      • (c) the antibody specifically binds to human PD-L1.
        Preferably, the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof. Preferably, the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • In yet another aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • (a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
      • (b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and
      • (c) the antibody binds to human PD-L1 with a KD of 1×10−7M or less.
  • In a preferred embodiment, the antibodies additionally comprise at least one of the following properties:
      • (a) the antibody increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (b) the antibody increases interferon-γ production in an MLR assay; or
      • (c) the antibody increases IL-2 secretion in an MLR assay.
  • In preferred embodiments, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
      • (a) a heavy chain variable region CDR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;
      • (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40;
      • (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50;
      • (d) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;
      • (e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and
      • (f) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
      • wherein the antibody specifically binds PD-L1.
        A preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:21;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:31;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:41;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:51;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:61; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:71.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:22;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:32;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:42;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:52;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:62; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:72.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:23;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:33;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:43;
      • (d) a light chain variable region. CDR1 comprising SEQ ID NO:53;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:63; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:73.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:24;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:34;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:44;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:54;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:64; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:74.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:25;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:35;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:45;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:55;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:65; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:75.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:26;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:36;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:46;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:56;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:66; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:76.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:27;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:37;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:47;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:57;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:67; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:77.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:28;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:38;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:48;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:58;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:68; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:78.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:29;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:39;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:49;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:59;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:69; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:79.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:30;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:40;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:50;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:60;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:70; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:80.
        Other preferred antibodies of the invention, or antigen binding portions thereof comprise:
      • (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
      • (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;
      • wherein the antibody specifically binds PD-L1.
        A preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:11.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:12.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:13.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:15.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:16.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:17.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:18.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • In another aspect of the instant disclosure, antibodies, or antigen-binding portions thereof, are provided that compete for binding to PD-L1 with any of the aforementioned antibodies.
  • The antibodies of the instant disclosure can be, for example, full-length antibodies, for example of an IgG1 or IgG4 isotype. Alternatively, the antibodies can be antibody fragments, such as Fab or Fab′2 fragments, or single chain antibodies.
  • The instant disclosure also provides an immunoconjugate comprising an antibody of the invention, or antigen-binding portion thereof, linked to a therapeutic agent, such as a cytotoxin or a radioactive isotope. The invention also provides a bispecific molecule comprising an antibody, or antigen-binding portion thereof, of the invention, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.
  • Compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule of the instant disclosure and a pharmaceutically acceptable carrier are also provided.
  • Nucleic acid molecules encoding the antibodies, or antigen-binding portions thereof, of the invention are also encompassed by the invention, as well as expression vectors comprising such nucleic acids and host cells comprising such expression vectors. Moreover, the invention provides a transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses an antibody of the invention, as well as hybridomas prepared from such a mouse, wherein the hybridoma produces the antibody of the invention.
  • In yet another aspect, the invention provides a method of modulating an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modulated. Preferably, the antibody of the invention enhances, stimulates or increases the immune response in the subject.
  • In a further aspect, the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof. The antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention). For example, a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of inhibiting tumor growth.
  • In a further aspect, the invention provides a method of treating an infectious disease in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof. The antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention). For example, a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of treating an infectious disease.
  • Still further, the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen. The antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention). For example, a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of enhancing an immune response to an antigen in a subject.
  • The invention also provides methods for making “second generation” anti-PD-L1 antibodies based on the sequences of the anti-PD-L1 antibodies provided herein. For example, the invention provides a method for preparing an anti-PD-L1 antibody comprising:
      • (a) providing: (i) a heavy chain variable region antibody sequence comprising a CDR1 sequence that is selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, a CDR2 sequence that is selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; and a CDR3 sequence that is selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; or (ii) a light chain variable region antibody sequence comprising a CDR1 sequence that is selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, a CDR2 sequence that is selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and a CDR3 sequence that is selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
      • (b) altering at least one amino acid residue within at least one variable region antibody sequence, said sequence being selected from the heavy chain variable region antibody sequence and the light chain variable region antibody sequence, to create at least one altered antibody sequence; and
      • (c) expressing the altered antibody sequence as a protein.
  • Other features and advantages of the instant invention will be apparent from the following detailed description and examples which should not be construed as limiting. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1A shows the nucleotide sequence (SEQ ID NO:81) and amino acid sequence (SEQ ID NO:1) of the heavy chain variable region of the 3G10 human monoclonal antibody. The CDR1 (SEQ ID NO:21), CDR2 (SEQ ID NO:31) and CDR3 (SEQ ID NO:41) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 1B shows the nucleotide sequence (SEQ ID NO:91) and amino acid sequence (SEQ ID NO:11) of the light chain variable region of the 3G10 human monoclonal antibody. The CDR1 (SEQ ID NO:51), CDR2 (SEQ ID NO:61) and CDR3 (SEQ ID NO:71) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2A shows the nucleotide sequence (SEQ ID NO:82) and amino acid sequence (SEQ ID NO:2) of the heavy chain variable region of the 12A4 human monoclonal antibody. The CDR1 (SEQ ID NO:22), CDR2 (SEQ ID NO:32) and CDR3 (SEQ ID NO:42) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2B shows the nucleotide sequence (SEQ ID NO:92) and amino acid sequence (SEQ ID NO:12) of the tight chain variable region of the 12A4 human monoclonal antibody. The CDR1 (SEQ ID NO:52), CDR2 (SEQ ID NO:62) and CDR3 (SEQ ID NO:72) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3A shows the nucleotide sequence (SEQ ID NO:83) and amino acid sequence (SEQ ID NO:3) of the heavy chain variable region of the 10A5 human monoclonal antibody. The CDR1 (SEQ ID NO:23), CDR2 (SEQ ID NO:33) and CDR3 (SEQ ID NO:43) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3B shows the nucleotide sequence (SEQ ID NO:93) and amino acid sequence (SEQ ID NO:13) of the light chain variable region of the 10A5 human monoclonal antibody. The CDR1 (SEQ ID NO:53), CDR2 (SEQ ID NO:63) and CDR3 (SEQ ID NO:73) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4A shows the nucleotide sequence (SEQ ID NO:84) and amino acid sequence (SEQ ID NO:4) of the heavy chain variable region of the 5F8 human monoclonal antibody. The CDR1 (SEQ ID NO:24), CDR2 (SEQ ID NO:34) and CDR3 (SEQ ID NO:44) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4B shows the nucleotide sequence (SEQ ID NO:94) and amino acid sequence (SEQ ID NO:14) of the light chain variable region of the 5F8 human monoclonal antibody. The CDR1 (SEQ ID NO:54), CDR2 (SEQ ID NO:64) and CDR3 (SEQ ID NO:74) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5A shows the nucleotide sequence (SEQ ID NO:85) and amino acid sequence (SEQ ID NO:5) of the heavy chain variable region of the 10H10 human monoclonal antibody. The CDR1 (SEQ ID NO:25), CDR2 (SEQ ID NO:35) and CDR3 (SEQ ID NO:45) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5B shows the nucleotide sequence (SEQ ID NO:95) and amino acid sequence (SEQ ID NO:15) of the light chain variable region of the 10H10 human monoclonal antibody. The CDR1 (SEQ ID NO:55), CDR2 (SEQ ID NO:65) and CDR3 (SEQ ID NO:75) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6A shows the nucleotide sequence (SEQ ID NO:86) and amino acid sequence (SEQ ID NO:6) of the heavy chain variable region of the 1B12 human monoclonal antibody. The CDR1 (SEQ ID NO:26), CDR2 (SEQ ID NO:36) and CDR3 (SEQ ID NO:46) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6B shows the nucleotide sequence (SEQ ID NO:96) and amino acid sequence (SEQ ID NO:16) of the light chain variable region of the 1B12 human monoclonal antibody. The CDR1 (SEQ ID NO:56), CDR2 (SEQ ID NO:66) and CDR3 (SEQ ID NO:76) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7A shows the nucleotide sequence (SEQ ID NO:87) and amino acid sequence (SEQ ID NO:7) of the heavy chain variable region of the 7H1 human monoclonal antibody. The CDR1 (SEQ ID NO:27), CDR2 (SEQ ID NO:37) and CDR3 (SEQ ID NO:47) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7B shows the nucleotide sequence (SEQ ID NO:97) and amino acid sequence (SEQ ID NO:17) of the light chain variable region of the 7H1 human monoclonal antibody. The CDR1 (SEQ ID NO:57), CDR2 (SEQ ID NO:67) and CDR3 (SEQ ID NO:77) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8A shows the nucleotide sequence (SEQ ID NO:88) and amino acid sequence (SEQ ID NO:8) of the heavy chain variable region of the 11E6 human monoclonal antibody. The CDR1 (SEQ ID NO:28), CDR2 (SEQ ID NO:38) and CDR3 (SEQ ID NO:48) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8B shows the nucleotide sequence (SEQ ID NO:98) and amino acid sequence (SEQ ID NO:18) of the light chain variable region of the 11E6 human monoclonal antibody. The CDR1 (SEQ ID NO:58), CDR2 (SEQ ID NO:68) and CDR3 (SEQ ID NO:78) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9A shows the nucleotide sequence (SEQ ID NO:89) and amino acid sequence (SEQ ID NO:9) of the heavy chain variable region of the 12B7 human monoclonal antibody. The CDR1 (SEQ ID NO:29), CDR2 (SEQ ID NO:39) and CDR3 (SEQ ID NO:49) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9B shows the nucleotide sequence (SEQ ID NO:99) and amino acid sequence (SEQ ID NO:19) of the light chain variable region of the 12B7 human monoclonal antibody. The CDR1 (SEQ ID NO:59), CDR2 (SEQ ID NO:69) and CDR3 (SEQ ID NO:79) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10A shows the nucleotide sequence (SEQ ID NO:90) and amino acid sequence (SEQ ID NO:10) of the heavy chain variable region of the 13G4 human monoclonal antibody. The CDR1 (SEQ ID NO:30), CDR2 (SEQ ID NO:40) and CDR3 (SEQ ID NO:50) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10B shows the nucleotide sequence (SEQ ID NO:100) and amino acid sequence (SEQ ID NO:20) of the light chain variable region of the 13G4 human monoclonal antibody. The CDR1 (SEQ ID NO:60), CDR2 (SEQ ID NO:70) and CDR3 (SEQ ID NO:80) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 11 shows the alignment of the amino acid sequence of the heavy chain variable region of 3G10 with the human germline VH 1-18 amino acid sequence (SEQ ID NO:101).
  • FIG. 12 shows the alignment of the amino acid sequence of the heavy chain variable region of 12A4 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 13 shows the alignment of the amino acid sequence of the heavy chain variable region of 10A5 with the human germline VH 1-3 amino acid sequence (SEQ ID NO:103).
  • FIG. 14 shows the alignment of the amino acid sequence of the heavy chain variable region of 5F8 with the human germane VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 15 shows the alignment of the amino acid sequence of the heavy chain variable region of 10H10 with the human germline VH 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 16 shows the alignment of the amino acid sequence of the heavy chain variable region of 1B12 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 17 shows the alignment of the amino acid sequence of the heavy chain variable region of 7H1 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 18 shows the alignment of the amino acid sequence of the heavy chain variable region of 11E6 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 19 shows the alignment of the amino acid sequence of the heavy chain variable region of 12B7 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 20 shows the alignment of the amino acid sequence of the heavy chain variable region of 13G4 with the human germline VH 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 21 shows the alignment of the amino acid sequence of the light chain variable region of 3G10 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 22 shows the alignment of the amino acid sequence of the light chain variable region of 12A4 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 23 shows the alignment of the amino acid sequence of the light chain variable region of 10A5 with the human germline Vk L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 24 shows the alignment of the amino acid sequence of the light chain variable region of 5F8 with the human germline Vk A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 25 shows the alignment of the amino acid sequence of the light chain variable region of 10H10 with the human germline Vk L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 26 shows the alignment of the amino acid sequence of the light chain variable region of 1B12 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 27 shows the alignment of the amino acid sequence of the light chain variable region of 7H1 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 28 shows the alignment of the amino acid sequence of the light chain variable region of 11E6 with the human germline Vk A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 29 shows the alignment of the amino acid sequence of the light chain variable region of 11E6a (SEQ ID NO:109) with the human germline Vk A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 30 shows the alignment of the amino acid sequence of the light chain variable region of 12B7 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 31 shows the alignment of the amino acid sequence of the light chain variable region of 13G4 with the human germline Vk L18 amino acid sequence (SEQ ID NO:108).
  • FIGS. 32A-C show the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1. (A) Flow cytometry plot for 3G10 (B) Flow cytometry plot for 10A5 (C) Flow cytometry plot for 12A4.
  • FIG. 33 shows the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1 in a concentration dependent manner.
  • FIG. 34 shows the results of ELISA experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1-Fc fusion protein.
  • FIG. 35 shows the results of experiments demonstrating HuMab titration on stimulated human CD4+ T cells.
  • FIG. 36 shows the results of experiments demonstrating HuMab titration on stimulated cynomolgus PBMC.
  • FIGS. 37A-C shows the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1 on the cell surface of activated T cells. (A) Flow cytometry plot for 3G10 (B) Flow cytometry plot for 10A5 (C) Flow cytometry plot for 12A4.
  • FIG. 38 demonstrates binding of HuMabs to ES-2 cells.
  • FIGS. 39A-D shows the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation, IFN-γ secretion and IL-2 secretion in a mixed lymphocyte reaction assay. FIG. 39A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5; FIG. 39B is a bar graph showing concentration dependent IFN-γ secretion using HuMAb 10A5; FIG. 39C is a bar graph showing IFN-γ secretion using HuMAbs 3G10 and 12A4; FIG. 39D is a bar graph showing concentration dependent IL-2 secretion using HuMAb 10A5.
  • FIG. 40 demonstrates the effect of human anti-PD-L1 antibody on proliferation and IFN-γ secretion in the MLR using allogeneic dendritic cells and T cells (CD4+ effector T cells) Dendritic Cells.
  • FIGS. 41A-B shows the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation and IFN-γ secretion in MLR containing T regulatory cells. FIG. 41A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5; FIG. 41B is a bar graph showing concentration dependent IFN-γ secretion using HuMAb 10A5.
  • FIG. 42 demonstrates the results of anti-PD-L1 antibodies on cell proliferation in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 43 demonstrates the results of anti-PD-L1 antibodies on cytokine production in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 44 demonstrates the results of anti-PD-L1 antibodies on CMV lysate stimulated human PBMC IFN-γ secretion.
  • FIG. 45 shows the results of flow cytometry experiments demonstrating that human monoclonal antibodies against human PD-L1 block the binding of PD-L1 to CHO transfected cells expressing PD-1.
  • FIG. 46 shows that anti-PD-L1 antibodies block binding of PD-1 to IFNγ treated ES-2 cells.
  • FIG. 47 shows the effect of anti-PD-L1 antibodies on tumor growth in vivo.
    •  DETAILED DESCRIPTION
  • In one aspect, the present disclosure relates to isolated monoclonal antibodies, particularly human monoclonal antibodies that bind specifically to PD-L1. In certain embodiments, the antibodies of the invention exhibit one or more desirable functional properties, such as high affinity binding to PD-L1, the ability to augment T cell proliferation, IFN-γ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of PD-L1 to the PD-1 receptor, the ability to stimulate antibody responses and/or the ability to reverse the suppressive function of T regulatory cells. Additionally or alternatively, the antibodies of the invention are derived from particular heavy and light chain germline sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences.
  • The instant disclosure provides, for example, isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunoconjugates or bispecific molecules of the invention.
  • In another aspect, the disclosure pertains to methods of inhibiting growth of tumor cells in a subject using anti-PD-L1 antibodies. The invention also relates to methods of using the antibodies to modify an immune response, as well as to treat diseases such as cancer or infectious disease, or to stimulate a protective autoimmune response or to stimulate antigen-specific immune responses (e.g., by coadministration of anti-PD-L1 with an antigen of interest).
  • In order that the present disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.
  • The term “immune response” refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • A “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. As used herein, the phrase “cell surface receptor” includes, for example, molecules and complexes of molecules capable of receiving a signal and the transmission of such a signal across the plasma membrane of a cell. An example of a “cell surface receptor” of the present invention is the PD-L1 receptor.
  • The term “antibody” as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains thereof. An “antibody” refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarily determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • The term “antigen-binding portion” of an antibody (or simply “antibody portion”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PD-L1). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within 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 bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. These antibody fragments are 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.
  • An “isolated antibody,” as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-L1). An isolated antibody that specifically binds PD-L1 may, however, have cross-reactivity to other antigens, such as PD-L1 molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • The terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • The term “human antibody,” as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody,” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • The term “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • The term “recombinant human antibody,” as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), (b) antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • As used herein, “isotype” refers to the antibody class (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • The phrases “an antibody recognizing an antigen” and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”
  • The term “human antibody derivatives” refers to any modified form of the human antibody, e.g., a conjugate of the antibody and another agent or antibody.
  • The term “humanized antibody” is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences.
  • The term “chimeric antibody” is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • As used herein, an antibody that “specifically binds to human PD-L1” is intended to refer to an antibody that binds to human PD-L1 with a KD of 1×10−7 M or less, more preferably 5×10−8 M or less, more preferably 1×10−8 M or less, more preferably 5×10−9 M or less, even more preferably between 1×10−8 M and 1×10−10 M or less.
  • The term “Kassoc” or “Ka,” as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction, whereas the term “Kdis” or “Kd,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term “KD,” as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd/Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A preferred method for determining the KD of an antibody is by using surface plasmon resonance, preferably using a biosensor system such as a Biacore® system.
  • As used herein, the term “high affinity” for an IgG antibody refers to an antibody having a KD of 10−8 M or less, more preferably 10−9M or less and even more preferably 10−10 M or less for a target antigen. However, “high affinity” binding can vary for other antibody isotypes. For example, “high affinity” binding for an IgM isotype refers to an antibody having a KD of 10−7 M or less, more preferably 10−8 M or less, even more preferably 10−9 M or less.
  • As used herein, the term “subject” includes any human or nonhuman animal. The term “nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • Various aspects of the disclosure are described in further detail in the following subsections.
    • Anti-PD-L1 Antibodies
  • The antibodies of the invention are characterized by particular functional features or properties of the antibodies. For example, the antibodies bind specifically to human PD-L1. Preferably, an antibody of the invention binds to PD-L1 with high affinity, for example with a KD of 1×10−7 M or less. The anti-PD-L1 antibodies of the invention preferably exhibit one or more of the following characteristics:
      • (a) binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (c) increases interferon-γ production in an MLR assay;
      • (d) increases IL-2 secretion in an MLR assay
      • (e) stimulates antibody responses; and/or
      • (f) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • Preferably, the antibody binds to human PD-L1 with a KD of 5×10−8 M or less, binds to human PD-L1 with a KD of 1×10−8 M or less, binds to human PD-L1 with a KD of 5×10−9 M or less, binds to human PD-L1 with a KD of 4×10−9 M or less, binds to human PD-L1 with a KD of 2×10−9 M or less, or binds to human PD-L1 with a KD of between 1×10−9M and 1×10−10 M or less.
  • Standard assays to evaluate the binding ability of the antibodies toward PD-L1 are known in the art, including for example, ELISAs, Western blots and RIAs. Suitable assays are described in detail in the Examples. The binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore® analysis.
    • Monoclonal Antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4.
  • Preferred antibodies of the invention are the human monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, isolated and structurally characterized as described in Examples 1 and 2. The VH amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, respectively. The VL amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, respectively.
  • Given that each of these antibodies can bind to PD-L1, the VH and VL sequences can be “mixed and matched” to create other anti-PD-L1 binding molecules of the invention. PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs). Preferably, when VH and VL chains are mixed and matched, a VH sequence from a particular VH/VL pairing is replaced with a structurally similar VH sequence. Likewise, preferably a VL sequence from a particular VH/VL pairing is replaced with a structurally similar VL sequence.
  • Accordingly, in one aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
      • (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
      • (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;
      • wherein the antibody specifically binds PD-L1, preferably human PD-L1.
        Preferred heavy and light chain combinations include:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:11; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:12; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:13; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:15; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and (h) a light chain variable region comprising the amino acid sequence of SEQ ID NO:16; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:17; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:18; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • In another aspect, the invention provides antibodies that comprise the heavy chain and light chain CDR1s, CDR2s and CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, or combinations thereof. The amino acid sequences of the VH CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively. The amino acid sequences of the VH CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, respectively. The amino acid sequences of the VH CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively. The amino acid sequences of the Vk CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, respectively. The amino acid sequences of the Vk CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, respectively. The amino acid sequences of the Vk CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, respectively. The CDR regions are delineated using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • Given that each of these antibodies can bind to PD-L1 and that antigen-binding specificity is provided primarily by the CDR1, CDR2, and CDR3 regions, the VH CDR1, CDR2, and CDR3 sequences and Vk CDR1 CDR2, and CDR3 sequences can be “mixed and matched” (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a VH CDR1, CDR2, and CDR3 and a Vk CDR1, CDR2, and CDR3) to create other anti-PD-L1 binding molecules of the invention. PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs, Biacore analysis). Preferably, when VH CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence is replaced with a structurally similar CDR sequence(s). Likewise, when Vk CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular Vk sequence preferably is replaced with a structurally similar CDR sequence(s). It will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences can be created by substituting one or more VH and/or VL CDR region sequences with structurally similar sequences from the CDR sequences disclosed herein for monoclonal antibodies antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4.
  • Accordingly, in another aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
      • (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;
      • (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40;
      • (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50;
      • (d) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;
  • (e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and
      • (f) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
      • wherein the antibody specifically binds PD-L1, preferably human PD-L1.
        In a preferred embodiment, the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:21;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:31;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:41;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:51;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:61; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:71.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:22;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:32;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:42;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:52;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:62; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:72.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:23;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:33;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:43;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:53;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:63; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:73.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:24;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:34;
  • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:44;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:54;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:64; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:74.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:25;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:35;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:45;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:55;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:65; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:75.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:26;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:36;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:46;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:56;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:66; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:76.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:27;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:37;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:47;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:57;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:67; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:77.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:28;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:38;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:48;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:58;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:68; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:78.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:29;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:39;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:49;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:59;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:69; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:79.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:30;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:40;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:50;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:60;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:70; and
      • (f) a tight chain variable region CDR3 comprising SEQ ID NO:80.
  • It is well known in the art that the CDR3 domain, independently from the CDR1 and/or CDR2 domain(s), alone can determine the binding specificity of an antibody for a cognate antigen and that multiple antibodies can predictably be generated having the same binding specificity based on a common CDR3 sequence. See, for example, Klimka et al., British J. of Cancer 83(2):252-260 (2000) (describing the production of a humanized anti-CD30 antibody using only the heavy chain variable domain CDR3 of murine anti-CD30 antibody Ki-4); Beiboer et al., J. Mol. Biol. 296:833-849 (2000) (describing recombinant epithelial glycoprotein-2 (EGP-2) antibodies using only the heavy chain CDR3 sequence of the parental murine MOC-31 anti-EGP-2 antibody); Rader et al., Proc. Natl. Acad. Sci. U.S.A. 95:8910-8915 (1998) (describing a panel of humanized anti-integrin αvβ3 antibodies using a heavy and light chain variable CDR3 domain of a murine anti-integrin αvβ3 antibody LM609 wherein each member antibody, comprises a distinct sequence outside the CDR3 domain and capable of binding the same epitope as the parent muring antibody with affinities as high or higher than the parent murine antibody); Barbas et al., J. Am. Chem. Soc. 116:2161-2162 (1994) (disclosing that the CDR3 domain provides the most significant contribution to antigen binding); Barbas et al., Proc. Natl. Acad. Sci. U.S.A. 92:2529-2533 (1995) (describing the grafting of heavy chain CDR3 sequences of three Fabs (SI-1, SI-40, and SI-32) against human placental DNA onto the heavy chain of an anti-tetanus toxoid Fab thereby replacing the existing heavy chain CDR3 and demonstrating that the CDR3 domain alone conferred binding specificity); and Ditzel et al., J. Immunol. 157:739-749 (1996) (describing grafting studies wherein transfer of only the heavy chain CDR3 of a parent polyspecific Fab LNA3 to a heavy chain of a monospecific IgG tetanus toxoid-binding Fab p313 antibody was sufficient to retain binding specificity of the parent Fab). Each of these references is hereby incorporated by reference in its entirety.
  • Accordingly, within certain aspects, the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody, such as a mouse or rat antibody, wherein the monoclonal antibody is capable of specifically binding to PD-L1. Within some embodiments, such inventive antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental non-human antibody.
  • Within other aspects, the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a first human antibody, such as, for example, a human antibody obtained from a non-human animal, wherein the first human antibody is capable of specifically binding to PD-L1 and wherein the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for PD-L1 to generate a second human antibody that is capable of specifically binding to PD-L1. Within some embodiments, antibodies of the instant disclosure comprising one or more heavy and/or light chain CDR3 domain from the first human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental first human antibody.
    • Antibodies Having Particular Germline Sequences
  • In certain embodiments, an antibody of the invention comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.
  • For example, in a preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-18 gene, wherein the antibody specifically binds PD-L1. In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-69 gene, wherein the antibody specifically binds PD-L1. In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-3 gene, wherein the antibody specifically binds PD-L1. In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 3-9 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L6 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L15 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK A27 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L18 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody:
      • (a) comprises a heavy chain variable region that is the product of or derived from a human VH 1-18, 1-69, 1-3 or 3-9 gene (which encodes the amino acid sequences set forth in SEQ ID NOs:101, 102, 103 and 104, respectively);
      • (b) comprises a light chain variable region that is the product of or derived from a human VK L6, L15, A27 or L18 gene (which encodes the amino acid sequences set forth in SEQ ID NOs:105, 106, 107 and 108, respectively); and
      • (c) specifically binds to PD-L1, preferably human PD-L1.
  • An example of an antibody having VH and VK of VH 1-18 and VK L6, respectively, is 3G10. Examples of antibodies having VH and VK of VH 1-69 and VK L6, respectively, 12A4, 1B12, 7H1, and 12B7. An example of an antibody having VH and VK of VH 1-3 and VK L15, respectively, is 10A5. Examples of antibodies having VH and VK of VH 1-69 and VK A27, respectively, are 5F8, 11E6 and 11E6a. An example of an antibody having VH and VK of VH 3-9 and VK L15, respectively, is 10H10. An example of an antibody having VH and VK of VH 1-3 and VK L15, respectively, is 10A5. An example of an antibody having VH and VK of VH 3-9 and VK L18, respectively, is 13G4.
  • As used herein, a human antibody comprises heavy or light chain variable regions that is “the product of” or “derived from” a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes. Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest. A human antibody that is “the product of” or “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody. A human antibody that is “the product of” or “derived from” a particular human germline immunoglobulin sequence may contain amino acid differences as compared to the germane sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation. However, a selected human antibody is generally at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. In certain embodiments, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain other embodiments, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
    • Homologous Antibodies
  • In yet another embodiment, an antibody of the invention comprises heavy and light chain variable regions comprising amino acid sequences that are homologous to the amino acid sequences of the preferred antibodies described herein, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention.
  • For example, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • (a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
      • (b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;
      • (c) the antibody binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (d) the antibody increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (e) the antibody increases interferon-γ production in an MLR assay;
      • (f) the antibody increases IL-2 secretion in an MLR assay,
      • (g) the antibody stimulates antibody responses; and
      • (h) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • In other embodiments, the VH and/or VL amino acid sequences may be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above. An antibody having VH and VL regions having high (i.e., 80% or greater) homology to the VH and VL regions of the sequences set forth above, can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs:25, 26, 27, 28, 29, and 30, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • As used herein, the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology=# of identical positions/total # of positions×100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
  • The percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • In certain instances, the protein sequences of the present disclosure can be further used as a “query sequence” to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the antibody molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.
  • Antibodies with Conservative Modifications
  • In certain embodiments, an antibody of the invention comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on the preferred antibodies described herein (e.g., 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4), or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention. Accordingly, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
      • (a) the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and conservative modifications thereof;
      • (b) the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequence of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, and conservative modifications thereof;
      • (c) the antibody binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (d) the antibody increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (e) the antibody increases interferon-γ production in an MLR assay;
      • (f) the antibody increases IL-2 secretion in an MLR assay
      • (g) the antibody stimulates antibody responses; and
      • (h) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • In a preferred embodiment, the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof. In another preferred embodiment, the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • As used herein, the term “conservative sequence modifications” is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • Antibodies that Bind to the Same Epitope as Anti-PD-L1 Antibodies of the Invention
  • In another embodiment, the invention provides antibodies that bind to the same epitope on human PD-L1 as any of the PD-L1 monoclonal antibodies of the invention (i.e., antibodies that have the ability to cross-compete for binding to PD-L1 with any of the monoclonal antibodies of the invention). In preferred embodiments, the reference antibody for cross-competition studies can be the monoclonal antibody 3G10 (having VH and VL sequences as shown in SEQ ID NOs:1 and 11, respectively), or the monoclonal antibody 12A4 (having VH and VL sequences as shown in SEQ ID NOs:2 and 12, respectively), or the monoclonal antibody 10A5 (having VH and VL sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 10A5 (having VH and VL sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 5F8 (having VH and VL sequences as shown in SEQ ID NOs:4 and 14, respectively), or the monoclonal antibody 10H10 (having VH and VL sequences as shown in SEQ ID NOs:5 and 15, respectively), or the monoclonal antibody 1B12 (having VH and VL sequences as shown in SEQ ID NOs:6 and 16, respectively), or the monoclonal antibody 7H1 (having VH and VL sequences as shown in SEQ ID NOs:7 and 17, respectively), or the monoclonal antibody 11E6 (having VH and VL sequences as shown in SEQ ID NOs:8 and 18, respectively), or the monoclonal antibody 12B7 (having VH and VL sequences as shown in SEQ ID NOs:9 and 19, respectively), or the monoclonal antibody 13G4 (having VH and VL sequences as shown in SEQ ID NOs:10 and 20, respectively). Such cross-competing antibodies can be identified based on their ability to cross-compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 in standard PD-L1 binding assays. For example, BIAcore analysis, ELISA assays or flow cytometry may be used to demonstrate cross-competition with the antibodies of the current invention. The ability of a test antibody to inhibit the binding of, for example, 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4, to human PD-L1 demonstrates that the test antibody can compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 for binding to human PD-L1 and thus binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4. In a preferred embodiment, the antibody that binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 is a human monoclonal antibody. Such human monoclonal antibodies can be prepared and isolated as described in the Examples.
    • Engineered and Modified Antibodies
  • An antibody of the invention further can be prepared using an antibody having one or more of the VH and/or VL sequences disclosed herein as starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody. An antibody can be engineered by modifying one or more residues within one or both variable regions (i.e., VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant region(s), for example to alter the effector function(s) of the antibody.
  • One type of variable region engineering that can be performed is CDR grafting. Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al. (1998) Nature 332:323-327; Jones, P. et al. (1986) Nature 321:522-525; Queen, C. et al. (1989) Proc. Natl. Acad. See. U.S.A. 86:10029-10033; U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.)
  • Accordingly, another embodiment of the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, respectively. Thus, such antibodies contain the VH and VL CDR sequences of monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H11, 11E6, 12B7 or 3G4 yet may contain different framework sequences from these antibodies.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in the “VBase” human germline sequence database (available on the Internet at www.mrc-cpe.cam.ac.uk/vbase), as well as in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al. (1992) “The Repertoire of Human Germline Sequences Reveals about Fifty Groups of VH Segments with Different Hypervariable Loops” J. Mol. Biol. 227:776-798; and Cox, J. P. L. et al. (1994) “A Directory of Human Germ-line VH Segments Reveals a Strong Bias in their Usage” Eur. J. Immunol. 24:827-836; the contents of each of which are expressly incorporated herein by reference.
  • Antibody protein sequences are compared against a compiled protein sequence database using one of the sequence similarity searching methods called the Gapped BLAST (Altschul et al. (1997) Nucleic Acids Research 25:3389-3402), which is well known to those skilled in the art. BLAST is a heuristic algorithm in that a statistically significant alignment between the antibody sequence and the database sequence is likely to contain high-scoring segment pairs (HSP) of aligned words. Segment pairs whose scores cannot be improved by extension or trimming is called a hit. Briefly, the nucleotide sequences of VBASE origin (vbase.mrc-cpe.cam.ac.uk/vbase1/list2.php) are translated and the region between and including FR1 through FR3 framework region is retained. The database sequences have an average length of 98 residues. Duplicate sequences which are exact matches over the entire length of the protein are removed. A BLAST search for proteins using the program blastp with default, standard parameters except the low complexity filter which is turned off and the substitution matrix of BLOSUM62, filters for top 5 hits yielding sequence matches. The nucleotide sequences are translated in all six frames and the frame with no stop codons in the matching segment of the database sequence is considered the potential hit. This is in turn continued using the BLAST program tblastx. This translates the antibody sequence in all six frames and compares those translations to the VBASE nucleotide sequences dynamically translated in all six frames.
  • The identities are exact amino acid matches between the antibody sequence and the protein database over the entire length of the sequence. The positives (identities+ substitution match) are not identical but amino acid substitutions guided by the BLOSUM62 substitution matrix. If the antibody sequence matches two of the database sequences with same identity, the hit with most positives would be decided to be the matching sequence hit.
  • Preferred framework sequences for use in the antibodies of the invention are those that are structurally similar to the framework sequences used by selected antibodies of the invention, e.g., similar to the VH 1-18 framework sequences (SEQ ID NO:101) and/or the VH 1-69 framework sequences (SEQ ID NO:102) and/or the VH 1-3 framework sequences (SEQ ID NO:103) and/or the VH 3-9 framework sequences (SEQ ID NO:104) and/or the VK L6 framework sequences (SEQ ID NO:105) and/or the VK L15 framework sequences (SEQ ID NO:106) and/or the VK (A27 framework sequences (SEQ ID NO:107) and/or the VK L18 framework sequences (SEQ ID NO:107) used by preferred monoclonal antibodies of the invention. The VH CDR1, CDR2, and CDR3 sequences, and the VK CDR1, CDR2, and CDR3 sequences, can be grafted onto framework regions that have the identical sequence as that found in the germline immunoglobulin gene from which the framework sequence derive, or the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences. For example, it has been found that in certain instances it is beneficial to mutate residues within the framework regions to maintain or enhance the antigen binding ability of the antibody (see e.g., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al).
  • Another type of variable region modification is to mutate amino acid residues within the VH and/or VK CDR1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest. Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutation(s) and the effect on antibody binding, or other functional property of interest, can be evaluated in in vitro or in vivo assays as described herein and provided in the Examples. Preferably conservative modifications (as discussed above) are introduced. The mutations may be amino acid substitutions, additions or deletions, but are preferably substitutions. Moreover, typically no more than one, two, three, four or five residues within a CDR region are altered.
  • Accordingly, in another embodiment, the invention provides isolated anti-PD-L1 monoclonal antibodies, or antigen binding portions thereof, comprising a heavy chain variable region comprising: (a) a VH CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; (b) a VH CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; (c) a VH CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; (d) a VK CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, car an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60; (e) a VK CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and (f) a VK CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.
  • Engineered antibodies of the invention include those in which modifications have been made to framework residues within VH and/or VK, e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to “backmutate” one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived. For example, as described below, a number of amino acid changes in the framework regions of the anti-PD-L1 antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4 that differ from the parent germane sequence. To return the framework region sequences to their germline configuration, the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis. The alignment of the VH region for 3G10 against the parent germline VH 1-18 sequence is shown in FIG. 11. The alignment of the VH region for 12A4 against the parent germline VH 1-69 sequence is shown in FIG. 12. The alignment of the VH region for 10A5 against the parent germline VH 1-3 sequence is shown in FIG. 13. The alignment of the VH region for 5F8 against the parent germline VH 1-69 sequence is shown in FIG. 14. The alignment of the VH region for 10H10 against the parent germline VH 3-9 sequence is shown in FIG. 15. The alignment of the VH region for 1B12 against the parent germline VH 1-69 sequence is shown in FIG. 16. The alignment of the VH region for 7H1 against the parent germline VH 1-69 sequence is shown in FIG. 17. The alignment of the VH region for 11E6 against the parent germline VH 1-69 sequence is shown in FIG. 18. The alignment of the VH region for 12B7 against the parent germline VH 1-69 sequence is shown in FIG. 19. The alignment of the VH region for 13G4 against the parent germline VH 3-9 sequence is shown in FIG. 20.
  • For example, for 3G10, amino acid residue #79 (within FR3) of VH is a valine whereas this residue in the corresponding VH 1-18 germline sequence is an alanine. To return the framework region sequences to their germline configuration, the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis (e.g., residue #79 (residue #13 of FR3) of the VH of 3G10 can be “backmutated” from valine to alanine).
  • As another example, for 12A4, amino acid residue #24 (within FR1) of VH is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 12A4 can be “backmutated” from threonine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12A4, amino acid residue #27 (within FR1) of VH is an aspartic acid whereas this residue in the corresponding VH 1-69 germline sequence is a glycine. To return the framework region sequences to their germline configuration, for example, residue #27 of the VH of 12A4 can be “backmutated” from aspartic acid to glycine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12A4, amino acid residue #95 (within FR3) of VH is a phenylalanine whereas this residue in the corresponding VH 1-69 germline sequence is a tyrosine. To return the framework region sequences to their germline configuration, for example, residue #95 (residue #29 of FR3) of the VH of 12A4 can be “backmutated” from phenylalanine to tyrosine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 5F8, amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 5F8 can be “backmutated” from valine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 5F8, amino acid residue #28 (within FR1) is an isoleucine whereas this residue in the corresponding VH 1-69 germline sequence is an threonine. To return the framework region sequences to their germline configuration, for example, residue #28 of the VH of 5F8 can be “backmutated” from isoleucine to threonine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 10H10, amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding VH 3-9 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 10H10 can be “backmutated” from valine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 10H10, an amino acid can be inserted following amino acid residue #97 (within FR3). This amino acid is a valine. To return the framework region sequences to their germline configuration, for example, the inserted amino acid following residue #97 of the VH of 10H10 can be “backmutated” to delete this valine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 1B12, amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 1B12 can be “backmutated” from threonine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 1B12, amino acid residue #27 (within FR1) is an aspartic acid whereas this residue in the corresponding VH 1-69 germline sequence is an glycine. To return the framework region sequences to their germline configuration, for example, residue #27 of the VH of 1B12 can be “backmutated” from aspartic acid to glycine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 1B12, amino acid residue #95 (within FR3) is a phenylalanine whereas this residue in the corresponding VH 1-69 germline sequence is an tyrosine. To return the framework region sequences to their germline configuration, for example, residue #95 (residue #29 of FR3) of the VH of 1B12 can be “backmutated” from phenylalanine to tyrosine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 7H1, amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 7H1 can be “backmutated” from threonine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 7H1, amino acid residue #77 (within FR3) is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is a serine. To return the framework region sequences to their germline configuration, for example, residue #72 (residue #11 of FR3) of the VH of 7H1 can be “backmutated” from threonine to serine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 11E6, amino acid residue #78 (within FR3) is an alanine whereas this residue in the corresponding VH 1-69 germline sequence is a threonine. To return the framework region sequences to their germline configuration, for example, residue #78 (residue 12 of FR3) of the VH of 11E6 can be “backmutated” from alanine to threonine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #13 (within FR1) is a glutamic acid whereas this residue in the corresponding VH 1-69 germline sequence is an lysine. To return the framework region sequences to their germline configuration, for example, residue #13 of the VH of 12B7 can be “backmutated” glutamic acid to lysine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #30 (within FR1) is an asparagine whereas this residue in the corresponding VH 1-69 germline sequence is an serine. To return the framework region sequences to their germline configuration, for example, residue #30 of the VH of 12B7 can be “backmutated” from asparagine to serine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #77 (within FR3) is an asparagine whereas this residue in the corresponding VH 1-69 germline sequence is an serine. To return the framework region sequences to their germline configuration, for example, residue #377 (residue 11 of FR3) of the VH of 12B7 can be “backmutated” from asparagine to serine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #82 (within FR3) is an aspartic acid whereas this residue in the corresponding VH 1-69 germline sequence is a glutamic acid. To return the framework region sequences to their germline configuration, for example, residue #82 (residue #16 of FR3) of the VH of 12B7 can be “backmutated” from aspartic acid to glutamic acid. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 13G4, amino acid residue #27 (within FR1) is an isoleucine whereas this residue in the corresponding VH 1-69 germline sequence is an phenylalanine. To return the framework region sequences to their germline configuration, for example, residue #27 of the VH of 12B7 can be “backmutated” from isoleucine to phenylalanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No. 20030153043 by Carr et al.
  • In addition or alternative to modifications made within the framework or CDR regions, antibodies of the invention may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity. Furthermore, an antibody of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of residues in the Fc region is that of the EU index of Kabat.
  • In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Pat. No. 5,677,425 by Bodmer et al. The number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • In another embodiment, the Fc hinge region of an antibody is mutated to decrease the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding. This approach is described in further detail in U.S. Pat. No. 6,165,745 by Ward et al.
  • In another embodiment, the antibody is modified to increase its biological half life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to Ward. Alternatively, to increase the biological half life, the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.
  • In yet other embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
  • In another example, one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 by Idusogie et al.
  • In another example, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al.
  • In yet another example, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fcγ receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439. This approach is described further in PCT Publication WO 00/42072 by Presta. Moreover, the binding sites on human IgG1 for FcγR1, FcγRII, FcγRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R. L. et al. (2001) J. Biol. Chem. 270:6591-6604). Specific mutations at positions 256, 290, 298, 333, 334 and 339 were shown to improve binding to FcγRIII. Additionally, the following combination mutants were shown to improve FcγRIII binding: T256A/S298A, S298A/E333A, S298A/K224A and S298A/E333A/K334A.
  • In still another embodiment, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.
  • In certain other embodiments, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. For example, the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (alpha (1,6) fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates. The Ms704, Ms705, and Ms709 FUT8−/− cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 by Yamane et al. and Yamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22). As another example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the alpha 1,6 bond-related enzyme. Hanai et al. also describe cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662). PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lec13 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R. L. et al. (2002) J. Biol. Chem. 277:26733-26740). PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta(1,4)-N-acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech. 17:176-180). Alternatively, the fucose residues of the antibody may be cleaved off using a fucosidase enzyme. For example, the fucosidase alpha-L-fucosidase removes fucosyl residues from antibodies (Tarentino, A. L. et al. (1975) Biochem. 14:5516-23).
  • Another modification of the antibodies herein that is contemplated by the invention is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. Preferably, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.
    • Methods of Engineering Antibodies
  • As discussed above, the anti-PD-L1 antibodies having VH and VK sequences disclosed herein can be used to create new anti-PD-L1 antibodies by modifying the VH and/or VK sequences, or the constant region(s) attached thereto. Thus, in another aspect of the invention, the structural features of an anti-PD-L1 antibody of the invention, e.g. 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, or 13G4, are used to create structurally related anti-PD-L1 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to human PD-L1. For example, one or more CDR regions of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H11, 11E6, 12B7, or 13G4 or mutations thereof, can be combined recombinantly with known framework regions and/or other CDRs to create additional, recombinantly-engineered, anti-PD-L1 antibodies of the invention, as discussed above. Other types of modifications include those described in the previous section. The starting material for the engineering method is one or more of the VH and/or VK sequences provided herein, or one or more CDR regions thereof. To create the engineered antibody, it is not necessary to actually prepare (i.e., express as a protein) an antibody having one or more of the VH and/or VK sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequence(s) is used as the starting material to create a “second generation” sequence(s) derived from the original sequence(s) and then the “second generation” sequence(s) is prepared and expressed as a protein.
  • Accordingly, in another embodiment, the invention provides a method for preparing an anti-PD-L1 antibody comprising:
      • (a) providing: (i) a heavy chain variable region antibody sequence comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, a CDR2 sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; and/or (ii) a light chain variable region antibody sequence comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, a CDR2 sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
      • (b) altering at least one amino acid residue within the heavy chain variable region antibody sequence and/or the light chain variable region antibody sequence to create at least: one altered antibody sequence; and
      • (c) expressing the altered antibody sequence as a protein.
  • Standard molecular biology techniques can be used to prepare and express the altered antibody sequence.
  • Preferably, the antibody encoded by the altered antibody sequence(s) is one that retains one, some or all of the functional properties of the anti-PD-L1 antibodies described herein, which functional properties include, hut are not limited to:
      • (i) binds to human PD-L1 with KD of 1×10−7 M or less;
      • (ii) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (iii) increases interferon-γ production in an MLR assay;
      • (iv) increases LL-2 secretion in an MLR assay;
      • (v) stimulates antibody responses; and/or
      • (vi) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • The functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein, such as those set forth in the Examples (e.g., flow cytometry, binding assays).
  • In certain embodiments of the methods of engineering antibodies of the invention, mutations can be introduced randomly or selectively along all or part of an anti-PD-L1 antibody coding sequence and the resulting modified anti-PD-L1 antibodies can be screened for binding activity and/or other functional properties as described herein. Mutational methods have been described in the art. For example, PCT Publication WO 02/092780 by Short describes methods for creating and screening antibody mutations using saturation mutagenesis, synthetic ligation assembly, or a combination thereof. Alternatively, PCT Publication WO 03/074679 by Lazar et al. describes methods of using computational screening methods to optimize physiochemical properties of antibodies.
    • Nucleic Acid Molecules Encoding Antibodies of the Disclosure
  • Another aspect of the disclosure pertains to nucleic acid molecules that encode the antibodies of the invention. The nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form. A nucleic acid is “isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York. A nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences. In a preferred embodiment, the nucleic acid is a cDNA molecule.
  • Nucleic acids of the invention can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below), cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from an immunoglobulin gene library (e.g., using phage display techniques), nucleic acid encoding the antibody can be recovered from the library.
  • Preferred nucleic acids molecules of the invention are those encoding the VH and VL sequences of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, monoclonal antibodies. DNA sequences encoding the VH sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:81, 82, 83, 84, 85, 86, 87, 88, 89 and 90, respectively. DNA sequences encoding the VL sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:91, 92, 93, 94, 95, 96, 97, 98, 99 and 100, respectively.
  • Once DNA fragments encoding VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL- or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker. The term “operatively linked,” as used in this context, is intended to mean that the two INA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • The isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3). The sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgG1 or IgG4 constant region. For a Fab fragment heavy chain gene, the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CH1 constant region.
  • The isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
  • To create a scFv gene, the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 42:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., (1990) Nature 348:552-554).
    • Production of Monoclonal Antibodies of the Invention
  • Monoclonal antibodies (mAbs) of the present invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein (1975) Nature 256: 495. Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibody can be employed e.g., viral or oncogenic transformation of B lymphocytes.
  • The preferred animal system for preparing hybridomas is the murine system. Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.
  • Chimeric or humanized antibodies of the present invention can be prepared based on the sequence of a murine monoclonal antibody prepared as described above. DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques. For example, to create a chimeric antibody, the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.). To create a humanized antibody, the murine CDR regions can be inserted into a human framework using methods known in the art (see e.g., U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.).
  • In a preferred embodiment, the antibodies of the invention are human monoclonal antibodies. Such human monoclonal antibodies directed against PD-L1 can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system. These transgenic and transchromosomic mice include mice referred to herein as HuMAb mice and KM Mice™, respectively, and are collectively referred to herein as “human Ig mice.”
  • The HuMAb Mouse® (Medarex, Inc.) contains human immunoglobulin gene miniloci that encode unrearranged human heavy (μ and γ) and κ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous μ and κ chain, loci (see e.g., Lonberg, et al. (1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or κ, and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgGκ monoclonal (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. (1994) Handbook of Experimental Pharmacology 113:49-101; Lonberg, N. and Huszar, D. (1995) Intern. Rev. Immunol. 13: 65-93, and Harding, F. and Lonberg, N. (1995) Ann. N.Y. Acad. Sci. 764:536-546). The preparation and use of HuMAb mice, and the genomic modifications carried by such mice, is further described in Taylor, L. et al. (1992) Nucleic Acids Research 20:6287-6295; Chen, J. et al. (1993) International Immunology 5: 647-656; Tuaillon et al. (1993) Proc. Natl. Acad. Sci. USA 90:3720-3724; Choi et al. (1993) Nature Genetics 4:117-123; Chen, J. et al. (1993) EMBO J. 12: 821-830; Tuaillon et al. (1994) J. Immunol. 152:2912-2920; Taylor, L. et al. (1994) International Immunology 6: 579-591; and Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851, the contents of all of which are hereby specifically incorporated by reference in their entirety. See further, U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all to Lonberg and Kay; U.S. Pat. No. 5,545,807 to Surani et al.; PCT Publication Nos. WO 92/03918, WO 93/12227, WO 94/25585, WO 97/13852, WO 98/24884 and WO 99/45962, all to Lonberg and Kay; and PCT Publication No. WO 01/14424 to Korman et al.
  • In another embodiment, human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes, such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome. Such mice, referred to herein as “KM Mice™,” are described in detail in PCT Publication WO 02/43478 to Ishida et al.
  • Still further, alternative transgenic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-PD-L1 antibodies of the invention. For example, an alternative transgenic system referred to as the Xenomouse (Abgenix, Inc.) can be used; such mice are described in, for example, U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584 and 6,162,963 to Kucherlapati et al.
  • Moreover, alternative transchromosomic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-PD-L1 antibodies of the invention. For example, mice carrying both a human heavy chain transchromosome and a human light chain transchromosome, referred to as “TC mice” can be used; such mice are described in Tomizuka et al. (2000) Proc. Natl. Acad. Sci. USA 97:722-727. Furthermore, cows carrying human heavy and light chain transchromosomes have been described in the art (Kuroiwa et al. (2002) Nature Biotechnology 20:889-894) and can be used to raise anti-PD-L1 antibodies of the invention.
  • Human monoclonal antibodies of the invention can also be prepared using phage display methods for screening libraries of human immunoglobulin genes. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698 to Ladner et al.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat. Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos. 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 to Griffiths et al.
  • Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization. Such mice are described in, for example, U.S. Pat. Nos. 5,476,996 and 5,698,767 to Wilson et al.
    • Immunization of Human Ig Mice
  • When human Ig mice are used to raise human antibodies of the invention, such mice can be immunized with a purified or enriched preparation of PD-L1 antigen and/or recombinant PD-L1, or an PD-L1 fusion protein, as described by Lonberg, N. et al. (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851; and PCT Publication WO 98/24884 and WO 01/14424. Preferably, the mice will be 6-16 weeks of age upon the first infusion. For example, a purified or recombinant preparation (5-50 μg) of PD-L1 antigen can be used to immunize the human Ig mice intraperitoneally.
  • Detailed procedures to generate fully human monoclonal antibodies to PD-L1 are described in Example 1 below. Cumulative experience with various antigens has shown that the transgenic mice respond when initially immunized intraperitoneally (IP) with antigen in complete Freund's adjuvant, followed by every other week IP immunizations (up to a total of 6) with antigen in incomplete Freund's adjuvant. However, adjuvants other than Freund's are also found to be effective. In addition, whole cells in the absence of adjuvant are found to be highly immunogenic. The immune response can be monitored over the course of the immunization protocol with plasma samples being obtained by retroorbital bleeds. The plasma can be screened by ELISA (as described below), and mice with sufficient titers of anti-PD-L1 human immunoglobulin can be used for fusions. Mice can be boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. It is expected that 2-3 fusions for each immunization may need to be performed. Between 6 and 24 mice are typically immunized for each antigen. Usually both HCo7 and HCo12 strains are used. In addition, both HCo7 and HCo12 transgene can be bred together into a single mouse having two different human heavy chain transgenes (HCo7/HCo12). Alternatively or additionally, the KM Mouse™ strain can be used, as described in Example 1.
    • Generation of Hybridomas Producing Human Monoclonal Antibodies of the Disclosure
  • To generate hybridomas producing human monoclonal antibodies of the invention, splenocytes and/or lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line. The resulting hybridomas can be screened for the production of antigen-specific antibodies. For example, single cell suspensions of splenic lymphocytes from immunized mice can be fused to one-sixth the number of P3X63-Ag8.653 nonsecreting mouse myeloma cells (ATCC, CRL 1580) with 50% PEG. Cells are plated at approximately 2×105 in flat bottom microtiter plate, followed by a two week incubation in selective medium containing 20% fetal Clone Serum, 18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin, 50 mg/ml streptomycin, 50 mg/ml gentamycin and 1×HAT (Sigma; the HAT is added 24 hours after the fusion). After approximately two weeks, cells can be cultured in medium in which the HAT is replaced with HT. Individual wells can then be screened by ELISA for human monoclonal IgM and IgG antibodies. Once extensive hybridoma growth occurs, medium can be observed usually after 10-14 days. The antibody secreting hybridomas can be re-plated, screened again, and if still positive for human IgG, the monoclonal antibodies can be subcloned at least twice by limiting dilution. The stable subclones can then be cultured in vitro to generate small amounts of antibody in tissue culture medium for characterization.
  • To purify human monoclonal antibodies, selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification. Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.). Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be aliquoted and stored at −80° C.
    • Generation of Transfectomas Producing Monoclonal Antibodies of the Disclosure
  • Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202).
  • For example, to express the antibodies, or antibody fragments thereof, DNAs encoding partial or full-length light and heavy chains, can be obtained by standard molecular biology techniques (e.g., PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. In this context, the term “operatively linked” is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. The antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector. The antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present). The light and heavy chain variable regions of the antibodies described herein can be used to create full-length antibody genes of any antibody isotype by inserting them into expression vectors already, encoding heavy chain constant and light chain constant regions of the desired isotype such that the VH segment is operatively linked to the CH segment(s) within the vector and the VK segment is operatively linked to the CL segment within the vector. Additionally or alternatively, the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • In addition to the antibody chain genes, the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell. The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes. Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990)). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma. Alternatively, nonviral regulatory sequences may be used, such as the ubiquitin promoter or β-globin promoter. Still further, regulatory elements composed of sequences from different sources, such as the SRα promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y. et al. (1988) Mol. Cell. Biol. 8:466-472).
  • In addition to the antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.). For example, typically the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced. Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr− host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • For expression of the light and heavy chains, the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques. The various forms of the term “transfection” are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like. Although it is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells, and most preferably mammalian host cells, is the most preferred because such eukaryotic cells, and in particular mammalian cells, are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody. Prokaryotic expression of antibody genes has been reported to be ineffective for production of high yields of active antibody (Boss, M. A. and Wood, C. R. (1985) Immunology Today 6:12-13).
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr− CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells. In particular, for use with NSO myeloma cells, another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
    • Characterization of Antibody Binding to Antigen
  • Antibodies of the invention can be tested for binding to PD-L1 by, for example, standard ELISA. Briefly, microtiter plates are coated with purified PD-L1 at 0.25 μg/ml in PBS, and then blocked with 5% bovine serum albumin in PBS. Dilutions of antibody (e.g., dilutions of plasma from PD-L1-immunized mice) are added to each well and incubated for 1-2 hours at 37° C. The plates are washed with PBS/Tween and then incubated with secondary reagent (e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent) conjugated to alkaline phosphatase for 1 hour at 37° C. After washing, the plates are developed with pNPP substrate (1 mg/ml), and analyzed at OD of 405-650. Preferably, mice which develop the highest titers will be used for fusions.
  • An ELISA assay as described above can also be used to screen for hybridomas that show positive reactivity with PD-L1 immunogen. Hybridomas that bind with high avidity to PD-L1 are subcloned and further characterized. One clone from each hybridoma, which retains the reactivity of the parent cells (by ELISA), can be chosen for making a 5-10 vial cell bank stored at −140° C., and for antibody purification.
  • To purify anti-PD-L1 antibodies, selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification. Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.). Fluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be aliquoted and stored at −80° C.
  • To determine if the selected anti-PD-L1 monoclonal antibodies bind to unique epitopes, each antibody can be biotinylated using commercially available reagents (Pierce, Rockford, Ill.). Competition studies using unlabeled monoclonal antibodies and biotinylated monoclonal antibodies can be performed using PD-L1 coated-ELISA plates as described above. Biotinylated mAb binding can be detected with a strep-avidin-alkaline phosphatase probe.
  • To determine the isotype of purified antibodies, isotype ELISAs can be performed using reagents specific for antibodies of a particular isotype. For example, to determine the isotype of a human monoclonal antibody, wells of microtiter plates can be coated with 1 μg/ml of anti-human immunoglobulin overnight at 4° C. After blocking with 1% BSA, the plates are reacted with 1 μg/ml or less of test monoclonal antibodies or purified isotype controls, at ambient temperature for one to two hours. The wells can then be reacted with either human IgG1 or human IgM-specific alkaline phosphatase-conjugated probes. Plates are developed and analyzed as described above.
  • Anti-PD-L1 human IgGs can be farther tested for reactivity with PD-L1 antigen by Western blotting. Briefly, PD-L1 can be prepared and subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis. After electrophoresis, the separated antigens are transferred to nitrocellulose membranes, blocked with 10% fetal calf serum, and probed with the monoclonal antibodies to be tested. Human IgG binding can be detected using anti-human IgG alkaline phosphatase and developed with BCIP/NBT substrate tablets (Sigma Chem. Co., St. Louis, Mo.).
    • Antibody Physical Properties
  • The antibodies of the present invention may be further characterized by the various physical properties of the anti-PD-L1 antibodies. Various assays may be used to detect and/or differentiate different classes of antibodies based on these physical properties.
  • In some embodiments, antibodies of the present invention may contain one or more glycosylation sites in either the light or heavy chain variable region. The presence of one or more glycosylation sites in the variable region may result in increased immunogenicity of the antibody or an alteration of the pK of the antibody due to altered antigen binding (Marshall et al (1972) Annu Rev Biochem 41:673-702; Gala F A and Morrison S L (2004) J Immunol 172:5489-94; Wallick et al (1988) J Exp Med 168:1099-109; Spiro R G (2002) Glycobiology 12:43R-56R; Parekh et al (1985) Nature 316:452-7; Mimura et al. (2000) Mol Immunol 37:697-706). Glycosylation has been known to occur at motifs containing an N-X-S/T sequence. Variable region glycosylation may be tested using a Glycoblot assay, which cleaves the antibody to produce a Fab, and then tests for glycosylation using an assay that measures periodate oxidation and Schiff base formation. Alternatively, variable region glycosylation may be tested using Dionex light chromatography (Dionex-LC), which cleaves saccharides from a Fab into monosaccharides and analyzes the individual saccharide content. In some instances, it is preferred to have an anti-PD-L1 antibody that does not contain variable region glycosylation. This can be achieved either by selecting antibodies that do not contain the glycosylation motif in the variable region or by mutating residues within the glycosylation motif using standard techniques well known in the art.
  • In a preferred embodiment, the antibodies of the present invention do not contain asparagine isomerism sites. A deamidation or isoaspartic acid effect may occur on N-G or D-G sequences, respectively. The deamidation or isoaspartic acid effect results in the creation of isoaspartic acid which decreases the stability of an antibody by creating a kinked structure off a side chain carboxy terminus rather than the main chain. The creation of isoaspartic acid can be measured using an iso-quant assay, which uses a reverse-phase HPLC to test for isoaspartic acid.
  • Each antibody will have a unique isoelectric point (pI), but generally antibodies will fall in the pH range of between 6 and 9.5. The pI for an IgG1 antibody typically falls within the pH range of 7-9.5 and the pI for an IgG4 antibody typically falls within the pH range of 6-8. Antibodies may have a pI that is outside this range. Although the effects are generally unknown, there is speculation that antibodies with a pI outside the normal range may have some unfolding and instability under in vivo conditions. The isoelectric point may be tested using a capillary isoelectric focusing assay, which creates a pH gradient and may utilize laser focusing for increased accuracy (Janini et al (2002) Electrophoresis 23:1605-11; Ma et al. (2001) Chromatographia 53:S75-89; Hunt et al (1998) J Chromatogr A 800:355-67). In some instances, it is preferred to have an anti-PD-L1 antibody that contains a pI value that falls in the normal range. This can be achieved either by selecting antibodies with a pI in the normal range, or by mutating charged surface residues using standard techniques well known in the art.
  • Each antibody will have a melting temperature that is indicative of thermal stability (Krishnamurthy R and Manning M C (2002) Curr Pharm Biotechnol 3:361-71). A higher thermal stability indicates greater overall antibody stability in vivo. The melting point of an antibody may be measure using techniques such as differential scanning calorimetry (Chen et al (2003) Pharm Res 20:1952-60; Ghirlando et al (1999) Immunol Lett 68:47-52). TM1 indicates the temperature of the initial unfolding of the antibody. TM2 indicates the temperature of complete unfolding of the antibody. Generally, it is preferred that the TM1 of an antibody of the present invention is greater than 60° C., preferably greater than 65° C., even more preferably greater than 70° C. Alternatively, the thermal stability of an antibody may be measure using circular dichroism (Murray et al. (2002) J. Chromatogr Sci 40:343-9). The thermal stability of anti-PD-L1 antibodies disclosed herein is summarized in Table 1.
  • TABLE 1
    mAb Tm1 (° C.) Tm2 (° C.)
    3G10 70 75
    5F8 72 74
    11E6 64 73
    1B12 69 72
    12A4 68 72
    10A5 71
    12B7 70
    13G4 66 69
    10H10 69
  • In a preferred embodiment, antibodies are selected that do not rapidly degrade. Fragmentation of an anti-PD-L1 antibody may be measured using capillary electrophoresis (CE) and MALDI-MS, as is well understood in the art (Alexander A J and Hughes D E (1995) Anal Chem 67:3626-32).
  • In another preferred embodiment, antibodies are selected that have minimal aggregation effects. Aggregation may lead to triggering of an unwanted immune response and/or altered or unfavorable pharmacokinetic properties. Generally, antibodies are acceptable with aggregation of 25% or less, preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less and even more preferably 5% or less. Aggregation may be measured by several techniques well known in the art, including size-exclusion column (SEC) high performance liquid chromatography (HPLC), and light scattering to identify monomers, dimers, trimers or multimers.
    • Immunoconjugates
  • In another aspect, the present invention features an anti-PD-L1 antibody, or a fragment thereof, conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin. Such conjugates are referred to herein as “immunoconjugates”. Immunoconjugates that include one or more cytotoxins are referred to as “immunotoxins.” A cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents also include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).
  • Other preferred examples of therapeutic cytotoxins that can be conjugated to an antibody of the invention include duocarmycins, calicheamicins, maytansines and auristatins, and derivatives thereof. An example of a calicheamicin antibody conjugate is commercially available (Mylotarg™; Wyeth-Ayerst).
  • Cytotoxins can be conjugated to antibodies of the invention using linker technology available in the art. Examples of linker types that have been used to conjugate a cytotoxin to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers. A linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D).
  • For further discussion of types of cytotoxins, linkers and methods for conjugating therapeutic agents to antibodies, see also Saito, G. et al. (2003) Adv. Drug Deliv. Rev. 55:199-215; Trail, P. A. et al. (2003) Cancer Immunol. Immunother. 52:328-337; Payne, G. (2003) Cancer Cell 3:207-212; Allen, T. M. (2002) Nat. Rev. Cancer 2:750-763; Pastan, I. and Kreitman, R. J. (2002) Curr. Opin. Investig. Drugs 3:1089-1091; Senter, P. D. and Springer, C. J. (2001) Adv. Drug Deliv. Rev. 53:247-264.
  • Antibodies of the present invention also can be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates. Examples of radioactive isotopes that can be conjugated to antibodies for use diagnostically or therapeutically include, but are not limited to, iodine131, indium111, yttrium90 and lutetium177. Method for preparing radioimmunconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including Zevalin™ (IDEC Pharmaceuticals) and Bexxar™ (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention.
  • The antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, Pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon-γ; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy,” in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery,” in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,” in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy,” in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates,” Immunol. Rev., 62:119-58 (1982).
    • Bispecific Molecules
  • In another aspect, the present invention features bispecific molecules comprising an anti-PD-L1 antibody, or a fragment thereof, of the invention. An antibody of the invention, or antigen-binding portions thereof, can be derivatized or linked to another functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules. The antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multispecific molecules that bind to more than two different binding sites and/or target molecules; such multispecific molecules are also intended to be encompassed by the term “bispecific molecule” as used herein. To create a bispecific molecule of the invention, an antibody of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results.
  • Accordingly, the present invention includes bispecific molecules comprising at least one first binding specificity for PD-L1 and a second binding specificity for a second target epitope. In a particular embodiment of the invention, the second target epitope is an Fc receptor, e.g., human FcγRI (CD64) or a human Fcα receptor (CD89). Therefore, the invention includes bispecific molecules capable of binding both to FcγR or FcαR expressing effector cells (e.g., monocytes, macrophages or polymorphonuclear cells (PMNs)), and to target cells expressing PD-L1. These bispecific molecules target PD-L1 expressing cells to effector cell and trigger Fc receptor-mediated effector cell activities, such as phagocytosis of an PD-L1 expressing cells, antibody dependent cell-mediated cytotoxicity (ADCC), cytokine release, or generation of superoxide anion.
  • In an embodiment of the invention in which the bispecific molecule is multispecific, the molecule can further include a third binding specificity, in addition to an anti-Fc binding specificity and an anti-PD-L1 binding specificity. In one embodiment, the third binding specificity is an anti-enhancement factor (EF) portion, e.g., a molecule which binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell. The “anti-enhancement factor portion” can be an antibody, functional antibody fragment or a ligand that binds to a given molecule, e.g., an antigen or a receptor, and thereby results in an enhancement of the effect of the binding determinants for the Fc receptor or target cell antigen. The “anti-enhancement factor portion” can bind an Fc receptor or a target cell antigen. Alternatively, the anti-enhancement factor portion can bind to an entity that is different from the entity to which the first and second binding specificities bind. For example, the anti-enhancement factor portion can bind a cytotoxic T-cell (e.g. via CD2, CD3, CD8, CD28, CD4, CD40, ICAM-1 or other immune cell that results in an increased immune response against the target cell).
  • In one embodiment, the bispecific molecules of the invention comprise as a binding specificity at least one antibody, or an antibody fragment thereof, including, e.g., an Fab, Fab′, F(ab′)2, Fv, or a single chain Fv. The antibody may also be a light chain or heavy chain dimer, or any minimal fragment thereof such as a Fv or a single chain construct as described in Ladner et al. U.S. Pat. No. 4,946,778, the contents of which is expressly incorporated by reference.
  • In one embodiment, the binding specificity for an Fcγ receptor is provided by a monoclonal antibody, the binding of which is not blocked by human immunoglobulin G (IgG). As used herein, the term “IgG receptor” refers to any of the eight γ-chain genes located on chromosome 1. These genes encode a total of twelve transmembrane or soluble receptor isoforms which are grouped into three Fcγ receptor classes: FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). In one preferred embodiment, the Fcγ receptor a human high affinity FcγRI. The human FcγRI is a 72 kDa molecule, which shows high affinity for monomeric IgG (108-109 M−1).
  • The production and characterization of certain preferred anti-Fcγ monoclonal antibodies are described by Fanger et al. in PCT Publication WO 88/00052 and in U.S. Pat. No. 4,954,617, the teachings of which are fully incorporated by reference herein. These antibodies bind to an epitope of FcγRI, FcγRII or FcγRIII at a site which is distinct from the Fcγ binding site of the receptor and, thus, their binding is not blocked substantially by physiological levels of IgG. Specific anti-FcγRI antibodies useful in this invention are mAb 22, mAb 32, mAb 44, mAb 62 and mAb 197. The hybridoma producing mAb 32 is available from the American Type Culture Collection, ATCC Accession No. HB9469. In other embodiments, the anti-Fcγ receptor antibody is a humanized form of monoclonal antibody 22 (H22). The production and characterization of the H22 antibody is described in Graziano, R. F. et al. (1995) J. Immunol 155 (10): 4996-5002 and PCT Publication WO 94/10332. The H22 antibody producing cell line was deposited at the American Type Culture Collection under the designation HA022CL1 and has the accession no. CRL 11177.
  • In still other preferred embodiments, the binding specificity for an Fc receptor is provided by an antibody that binds to a human IgA receptor, e.g., an Fc-alpha receptor (FcαRI (CD89)), the binding of which is preferably not blocked by human immunoglobulin A (IgA). The term “IgA receptor” is intended to include the gene product of one α-gene (FcαRI) located on chromosome 19. This gene is known to encode several alternatively spliced transmembrane isoforms of 55 to 110 kDa. FcαRI (CD89) is constitutively expressed on monocytes/macrophages, eosinophilic, and neutrophilic granulocytes, but not on non-effector cell populations. FcαRI has medium affinity (≈5×107 M−1) for both IgA1 and IgA2, which is increased upon exposure to cytokines such as G-CSF or GM-CSF (Morton, H. C. et al. (1996) Critical Reviews in Immunology 16:423-440). Four FcαRI-specific monoclonal antibodies, identified as A3, A59, A62 and A77, which bind FcαRI outside the IgA ligand binding domain, have been described (Monteiro, R. C. et al. (1992) J. Immunol. 148:1764).
  • FcαRI and FcγRI are preferred trigger receptors for use in the bispecific molecules of the invention because they are (1) expressed primarily on immune effector cells, e.g., monocytes, PMNs, macrophages and dendritic cells; (2) expressed at high levels 5,000-100,000 per cell); (3) mediators of cytotoxic activities (e.g., ADCC, phagocytosis); (4) mediate enhanced antigen presentation of antigens, including self-antigens, targeted to them.
  • While human monoclonal antibodies are preferred, other antibodies which can be employed in the bispecific molecules of the invention are murine, chimeric and humanized monoclonal antibodies.
  • The bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, e.g., the anti-FcR and anti-PD-L1 binding specificities, using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation. Examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-1-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al. (1984) J. Exp. Med. 160:1686; Liu, M A et al. (1985) Proc. Natl. Acad. Sci. USA 82:8648). Other methods include those described in Paulus (1985) Behring Ins. Mitt. No. 78, 118-132; Brennan et al. (1985) Science 229:81-83), and Glennie et al. (1987) J. Immunol. 139: 2367-2375). Preferred conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).
  • When the binding specificities are antibodies, they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains. In a particularly preferred embodiment, the hinge region is modified to contain an odd number of sulfhydryl residues, preferably one, prior to conjugation.
  • Alternatively, both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell. This method is particularly useful where the bispecific molecule is a mAb×mAb, mAb×Fab, Fab×F(ab′)2 or ligand×Fab fusion protein. A bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Pat. Nos. 5,260,203; 5,455,030; 4,881,175; 5,132,405; 5,091,513; 5,476,786; 5,013,653; 5,258,498; and 5,482,858.
  • Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest. For example, the FcR-antibody complexes can be detected using e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody-FcR complexes. Alternatively, the complexes can be detected using any of a variety of other immunoassays. For example, the antibody can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a γ counter or a scintillation counter or by autoradiography.
    • Pharmaceutical Compositions
  • In another aspect, the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding portion(s) thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier. Such compositions may include one or a combination of (e.g., two or more different) antibodies, or immunoconjugates or bispecific molecules of the invention. For example, a pharmaceutical composition of the invention can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target antigen or that have complementary activities.
  • Pharmaceutical compositions of the invention also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include an anti-PD-L1 antibody of the present invention combined with at least one other anti-inflammatory or immunosuppressant agent. Examples of therapeutic agents that can be used in combination therapy are described in greater detail below in the section on uses of the antibodies of the invention.
  • As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, immunoconjugate, or bispecific molecule, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
  • The pharmaceutical compounds of the invention may include one or mere pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66:1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • A pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical faint may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization micro filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent of active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • For administration of the antibody, the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight. For example dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months. Preferred dosage regimens for an anti-PD-L1 antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.
  • In some methods, two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated. Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 μg/ml and in some methods about 25-300 μg/ml.
  • Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending, on the half-life of the antibody in the patient. In general, human antibodies show the longest half life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • A “therapeutically effective dosage” of an anti-PD-L1 antibody of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. For example, for the treatment of PD-L1+ tumors, a “therapeutically effective dosage” preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
  • A composition of the present invention can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. Preferred routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • Alternatively, an antibody of the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • Therapeutic compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. No. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules useful in the present invention include: U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Pat. No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.
  • In certain embodiments, the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin. Pharmacol. 29:685). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357:140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233:134); p120 (Schreier et al. (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273.
    • Uses and Methods of the Invention
  • The antibodies, antibody compositions and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of PD-L1 or enhancement of immune response by blockade of PD-L1. In a preferred embodiment, the antibodies of the present invention are human antibodies. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in a variety of situations. Accordingly, in one aspect, the invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modified. Preferably, the response is enhanced, stimulated or up-regulated.
  • As used herein, the term “subject” is intended to include human and non-human animals. Non-human animals includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses. Preferred subjects include human patients in need of enhancement of an immune response. The methods are particularly suitable for treating human patients having a disorder that can be treated by augmenting the T-cell mediated immune response. In a particular embodiment, the methods are particularly suitable for treatment of cancer cells in vivo. To achieve antigen-specific enhancement of immunity, the anti-PD-L1 antibodies can be administered together with an antigen of interest. When antibodies to PD-L1 are administered together with another agent, the two can be administered in either order or simultaneously.
  • The invention further provides methods for detecting the presence of human PD-L1 antigen in a sample, or measuring the amount of human PD-L1 antigen, comprising contacting the sample, and a control sample, with a human monoclonal antibody, or an antigen binding portion thereof, which specifically hinds to human PD-L1, under conditions that allow for formation of a complex between the antibody or portion thereof and human PD-L1. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of human PD-L1 antigen in the sample.
    • Cancer
  • Blockade of PD-L1 by antibodies can enhance the immune response to cancerous cells in the patient. PD-L1 is not expressed in normal human cells, but is abundant in a variety of human cancers (Dong et al. (2002) Nat Med 8:787-9). The interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2004) Cancer Immunol. Immunother. [epub]; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-L1 to PD-1 and the effect is additive when the interaction of PD-L2 to PD-1 is blocked as well (Iwai et al. (2002) PNAS 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). An anti-PD-L1 antibody may be used alone to inhibit the growth of cancerous tumors. Alternatively, an anti-PD-L1 antibody may be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies, as described below.
  • Accordingly, in one embodiment, the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof. Preferably, the antibody is a human anti-PD-L1 antibody (such as any of the human anti-human PD-L1 antibodies described herein). Additionally or alternatively, the antibody may be a chimeric or humanized anti-PD-L1 antibody.
  • Preferred cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer. Examples of other cancers that may be treated using the methods of the invention include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144).
  • Optionally, antibodies to PD-L1 can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
  • In humans, some tumors have been shown to be immunogenic such as melanomas. It is anticipated that by raising the threshold of T cell activation by PD-L1 blockade, we may expect to activate tumor responses in the host.
  • PD-L1 blockade is likely to be most effective when combined with a vaccination protocol. Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition). In one of these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
  • The study of gene expression and large scale gene expression patterns in various tumors has led to the definition of so-called tumor specific antigens (Rosenberg, S A (1999) Immunity 10: 281-7). In many cases, these tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host. PD-L1 blockade may be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins. These proteins are normally viewed by the immune system as self antigens and are therefore tolerant to them. The tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means). Tumor antigen may also be “neo-antigens” expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e. bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
  • Other tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). Another form of tumor specific antigen which may be used in conjunction with PD-1 blockade is purified heat shock proteins (HSP) isolated from the rumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).
  • Dendritic cells (DC) are potent antigen presenting cells that can be used to prime antigen-specific responses. DC's can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs may also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization may be effectively combined with PD-L1 blockade to activate more potent anti-tumor responses.
  • PD-L1 blockade may also be combined with standard cancer treatments. PD-L1 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). An example of such a combination is an anti-PD-L1 antibody in combination with decarbazine for the treatment of melanoma. Another example of such a combination is an anti-PD-L1 antibody in combination with interleukin-2 (IL-2) for the treatment of melanoma. The scientific rationale behind the combined use of PD-L1 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway. Other combination therapies that may result in synergy with PD-L1 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host. Angiogenesis inhibitors may also be combined with PD-L1 blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
  • PD-L1 blocking antibodies can also be used in combination with bispecific antibodies that target Fc alpha or Fc γ receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243). Bispecific antibodies can be used to target two separate antigens. For example anti-Fc receptor/anti tumor antigen (e.g., Her-2/neu) bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses. The T cell arm of these responses would by augmented by the use of PD-L1 blockade. Alternatively, antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
  • Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365). Antibodies to each of these entities may be used in combination with anti-PD-L1 to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
  • Other antibodies which may be used to activate host immune responsiveness can be used in combination with anti-PD-L1. These include molecules on the surface of dendritic cells which activate DC function and antigen presentation. Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in conjunction with PD-L1 antibodies (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40). Activating antibodies to T cell costimulatory molecules such as OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997), and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266) as well as antibodies which block the activity of negative costimulatory molecules such as CTLA-4 (e.g., U.S. Pat. No. 5,811,097) or BTLA (Watanabe, N. et al. (2003) Nat Immunol 4:670-9), B7-H4 (Sica, G L et al. (2003) Immunity 18:849-6 may also provide for increased levels of T cell activation.
  • Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses. PD-L1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
  • There are also several experimental treatment protocols that involve ex vivo activation and expansion of antigen specific T cells and adoptive transfer of these cells into recipients in order to antigen-specific T cells against tumor (Greenberg, R. & Riddell, S. (1999) Science 285: 546-51). These methods may also be used to activate T cell responses to infectious agents such as CMV. Ex vivo activation in the presence of anti-PD-L1 antibodies may be expected to increase the frequency and activity of the adoptively transferred T cells.
    • Infectious Diseases
  • Other methods of the invention are used to treat patients that have been exposed to particular toxins or pathogens. Accordingly, another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-PD-L1 antibody, or antigen-binding portion thereof, such that the subject is treated for the infectious disease. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Similar to its application to tumors as discussed above, antibody mediated PD-L1 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa. PD-L1 blockade is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of anti-human PD-L1 administration, thus provoking a strong T cell response that is not dampened by negative signals through PD-L1.
  • Some examples of pathogenic viruses causing infections treatable by methods of the invention include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • Some examples of pathogenic bacteria causing infections treatable by methods of the invention include Chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and Gonococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, diphtheria, Salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Some examples of pathogenic fungi causing infections treatable by methods of the invention include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Some examples of pathogenic parasites causing infections treatable by methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.
  • In all of the above methods, PD-L1 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).
    • Autoimmune Reactions
  • Anti-PD-L1 antibodies may provoke and amplify autoimmune responses. Indeed, induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities (depigmentation observed in anti-CTLA-4+GM-CSF-modified B16 melanoma in van Elsas et al. supra; depigmentation in Trp-2 vaccinated mice (Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96: 2982-2987); autoimmune prostatitis evoked by TRAMP tumor cell vaccines (Hurwitz, A. (2000) supra), melanoma peptide antigen vaccination and vitilago observed in human clinical trials (Rosenberg, S A and White, D E (1996) J. Immunother Emphasis Tumor Immunol 19 (1): 81-4).
  • Therefore, it is possible to consider using anti-PD-L1 blockade in conjunction with various self proteins in order to devise vaccination protocols to efficiently generate immune responses against these self proteins for disease treatment. For example, Alzheimer's disease involves inappropriate accumulation of Aβ peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).
  • Other self proteins may also be used as targets such as IgE for the treatment of allergy and asthma, and TNFα for rheumatoid arthritis. Finally, antibody responses to various hormones may be induced by the use of anti-PD-L1 antibody. Neutralizing antibody responses to reproductive hormones may be used for contraception. Neutralizing antibody response to hormones and other soluble factors that are required for the growth of particular tumors may also be considered as possible vaccination targets.
  • Analogous methods as described above for the use of anti-PD-L1 antibody can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including Aβ in Alzheimer's disease, cytokines such as TNFα, and IgE.
    • Vaccines
  • Anti-PD-L1 antibodies may be used to stimulate antigen-specific immune responses by coadministration of an anti-PD-L1 antibody with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen. Non-limiting examples of such antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
  • Anti-PD-L1 antibodies may also be used to abrogate secondary effects associated with diseases such as T cell suppressed wasting disease with colitis (Kauai et al. (2003) J. Immunol. 171:4156-63). Accordingly, in another aspect the invention provides a method of abrogating leukocyte infiltration, decreasing production of IFN-γ, IL-2, and IFN-α by T cells. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Anti-PD-L1 antibodies may also be used to treat diseases such as chronic inflammatory diseases, such as lichen planus, a T-cell mediated chronic inflammatory mucocutaneous disease (Youngnak-Piboonratanakit et al. (2004) Immunol Letters 94:215-22). Accordingly, in another aspect the invention provides a method of abrogating chronic inflammatory disease by T cells. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Suitable routes of administering the antibody compositions (e.g., human monoclonal antibodies, multispecific and bispecific molecules and immunoconjugates) of the invention in vivo and in vitro are well known in the art and can be selected by those of ordinary skill. For example, the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous). Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.
  • As previously described, human anti-PD-L1 antibodies of the invention can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent. The antibody can be linked to the agent (as an immunocomplex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation. Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient. Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days. Co-administration of the human anti-PD-L1 antibodies, or antigen binding fragments thereof, of the present invention with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
  • Also within the scope of the present invention are kits comprising the antibody compositions of the invention (e.g., human antibodies, bispecific or multispecific molecules, or immunoconjugates) and instructions for use. The kit can further contain a least one additional reagent, or one or more additional human antibodies of the invention (e.g., a human antibody having a complementary activity which binds to an epitope in PD-L1 antigen distinct from the first human antibody). Kits typically include a label indicating the intended use of the contents of the kit. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • The present invention is further illustrated by the following examples which should not be construed as further limiting. The contents of all figures and all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.
    • EXAMPLES Example 1: Generation of Human Monoclonal Antibodies Against PD-L1 Antigen
  • Immunization protocols utilized as antigen both (i) a recombinant fusion protein comprising the extracellular portion of PD-L1, and (ii) membrane bound full-length PD-L1. Both antigens were generated by recombinant transfection methods in a CHO cell line.
    • Transgenic Mice (KM-Mouse® Colony)
  • Fully human monoclonal antibodies to PD-L1 were prepared using the KM strain of transgenic transchromosomic mice, which expresses human antibody genes. In this mouse strain, the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820 and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of PCT Publication WO 01/09187. Furthermore, this mouse strain carries a human kappa light chain transgene, KCo5, as described in Fishwild et al. (1996) Nature Biotechnology 14:845-851, and a SC20 transchromosome as described in PCT Publication WO 02/43478.
    • KM-Mouse® Immunizations
  • To generate fully human monoclonal antibodies to PD-L1, a cohort of mice of the KM-Mouse® strain were immunized with purified recombinant PD-L1-Ig and PD-L1-transfected CHO cells as antigen. General immunization schemes for HuMab mice are described in Lonberg, N. et al (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851 and PCT Publication WO 98/24884. The mice were 6-16 weeks of age upon the first infusion of antigen. A purified recombinant preparation (5-50 μg) of PD-L1-Ig antigen and 5-10×106 cells were used to immunize the HuMab mice intraperitonealy (IP), subcutaneously (Sc) or via footpad injection.
  • Transgenic mice were immunized twice with antigen in complete Freund's adjuvant or Ribi adjuvant IP, followed by 3-21 days IP (up to a total of 11 immunizations) with the antigen in incomplete Freund's or Ribi adjuvant. The immune response was monitored by retroorbital bleeds. The plasma was screened by ELISA (as described below), and mice with sufficient titers of anti-PD-L1 human immunoglobulin were used for fusions. Mice were boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. Typically, 10-35 fusions for each antigen were performed. Several dozen mice were immunized for each antigen.
    • Selection of KM-Mouse® Producing Anti-PD-L1 Antibodies:
  • To select HuMab mice producing antibodies that bound PD-L1, sera from immunized mice were tested by ELISA as described by Fishwild, D. et al. (1996). Briefly, microtiter plates were coated with purified recombinant PD-L1 fusion protein from transfected CHO cells at 1-2 μg/ml in PBS, 100 μl/wells incubated 4° C. overnight then blocked with 200 μl/well of 5% fetal bovine serum in PBS/Tween (0.05%). Dilutions of sera from PD-L1-immunized mice were added to each well and incubated for 1-2 hours at ambient temperature. The plates were washed with PBS/Tween and then incubated with a goat-anti-human IgG polyclonal antibody conjugated with horseradish peroxidase (HRP) for 1 hour at room temperature. After washing, the plates were developed with ABTS substrate (Sigma, A-1888, 0.22 mg/ml) and analyzed by spectrophotometer at OD 415-495. Mice that developed the highest titers of anti-PD-L1 antibodies were used for fusions. Fusions were performed as described below and hybridoma supernatants were tested for anti-PD-L1 activity by ELISA.
    • Generation of Hybridomas Producing Human Monoclonal Antibodies to PD-L1:
  • The mouse splenocytes, isolated from a KM mouse, were fused with PEG to a mouse myeloma cell line based upon standard protocols. The resulting hybridomas were then screened for the production of antigen-specific antibodies. Single cell suspensions of splenocytes from immunized mice were fused to one-fourth the number of SP2/0 nonsecreting mouse myeloma cells (ATCC, CRL 1581) with 50% PEG (Sigma). Cells were plated at approximately 1×105/well in flat bottom microtiter plate, followed by about two week incubation in selective medium containing 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditioned medium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose, L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 mg/ml gentamycin and 1×HAT (Sigma, CRL P-7185). After 1-2 weeks, cells were cultured in medium in which the HAT was replaced with HT. Individual wells were then screened by ELISA (described above) for human anti-PD-L1 monoclonal IgG antibodies. Once extensive hybridoma growth occurred, medium was monitored usually after 10-14 days. The antibody-secreting hybridomas were re-plated, screened again and, if still positive for human IgG, anti-PD-L1 monoclonal antibodies were subcloned at least twice by limiting dilution. The stable subclones were then cultured in vitro to generate small amounts of antibody in tissue culture medium for further characterization.
  • Hybridoma clones 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 were selected for further analysis.
    • Example 2: Structural Characterization of Human Monoclonal Antibodies 3G10, 12A4, and 10A5
  • The cDNA sequences encoding the heavy and light chain variable regions of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 monoclonal antibodies were obtained from the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 hybridomas, respectively, using standard PCR techniques and were sequenced using standard DNA sequencing techniques.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 3G10 are shown in FIG. 1A and in SEQ ID NO:81 and 1, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 3G10 are shown in FIG. 1B and in SEQ ID NO:91 and 11, respectively.
  • Comparison of the 3G10 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 3G10 heavy chain utilizes a VH segment from human germline VH 1-18, an undetermined D segment, and a JH segment from human germline JH 6b. The alignment of the 3G10 VH sequence to the germline VH 1-18 sequence is shown in FIG. 11. Further analysis of the 3G10 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 1A and 11, and in SEQ ID NOs:21, 31 and 41, respectively.
  • Comparison of the 3G10 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 3G10 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 3G10 VL sequence to the germline VK L6 sequence is shown in FIG. 21. Further analysis of the 3G10 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 1B and 21, and in SEQ ID NOs:51, 61 and 71, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 12A4 are shown in FIG. 2A and in SEQ ID NO:82 and 2, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 12A4 are shown in FIG. 2B and in SEQ ID NO:92 and 12, respectively.
  • Comparison of the 12A4 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 12A4 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 12A4 VH sequence to the germline VH 1-69 sequence is shown in FIG. 12. Further analysis of the 12A4 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 2A and 12, and in SEQ ID NOs:22, 32 and 42, respectively.
  • Comparison of the 12A4 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 12A4 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 12A4 VL sequence to the germline VK L6 sequence is shown in FIG. 22. Further analysis of the 12A4 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 2B and 22, and in SEQ ID NOs:52, 62 and 72, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 10A5 are shown in FIG. 3A and in SEQ ID NO:83 and 3, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 10A5 are shown in FIG. 3B and in SEQ ID NO:93 and 13, respectively.
  • Comparison of the 10A5 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 10A5 heavy chain utilizes a VH segment from human germline VH 1-3, a D segment from human germline 5-5, and a JH segment from human germline JH 4b. The alignment of the 10A5 VH sequence to the germline VH 1-3 sequence is shown in FIG. 13. Further analysis of the 10A5 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 3A and 13, and in SEQ ID NOs:23, 33, and 43, respectively.
  • Comparison of the 10A5 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 10A5 light chain utilizes a VL segment from human germline VK L15 and a JK segment from human germline JK 2. The alignment of the 10A5 VL sequence to the germline VK L15 sequence is shown in FIG. 23. Further analysis of the 10A5 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 3B and 23, and in SEQ ID NOs:53, 63, and 73, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 5F8 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 5F8 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • Comparison of the 5F8 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 5F8 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 6-13, and a JH segment from human germline JH 4b. The alignment of the 5F8 VH sequence to the germline VH 1-69 sequence is shown in FIG. 14. Further analysis of the 5F8 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 4A and 14, and in SEQ ID NOs:24, 34, and 44, respectively.
  • Comparison of the 5F8 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 5F8 light chain utilizes a VL segment from human germline VK A27 and a JK segment from human germline JK 1. The alignment of the 5F8 VL sequence to the germline VK A27 sequence is shown in FIG. 24. Further analysis of the 5F8 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 4B and 24, and in SEQ ID NOs:54, 64, and 74, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 10H10 are shown in FIG. 5A and in SEQ ID NO:85 and 5, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 10H10 are shown in FIG. 5B and in SEQ ID NO:95 and 15, respectively.
  • Comparison of the 10H10 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 10H10 heavy chain utilizes a VH segment from human germline VH 3-9, a D segment from human germline 4-17, and a JH segment from human germline JH 4b. The alignment of the 10H10 VH sequence to the germline VH 3-9 sequence is shown in FIG. 15. Further analysis of the 10H10 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 5A and 15, and in SEQ ID NOs:25, 35, and 45, respectively.
  • Comparison of the 10H10 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 10H10 light chain utilizes a VL segment from human germline VK L15 and a JK segment from human germline JK 2. The alignment of the 10H10 VL sequence to the germline VK L15 sequence is shown in FIG. 25. Further analysis of the 10H10 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 5B and 25, and in SEQ ID NOs:55, 65, and 75, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 1B12 are shown in FIG. 6A and in SEQ ID NO:86 and 6, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 1B12 are shown in FIG. 6B and in SEQ ID NO:96 and 16, respectively.
  • Comparison of the 1B12 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 1B12 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 1B12 VH sequence to the germline VH 1-69 sequence is shown in FIG. 16. Further analysis of the 1B12 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 6A and 16, and in SEQ ID NOs:26, 36, and 46, respectively.
  • Comparison of the 1B12 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 1B12 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 1B12 VL sequence to the germline VK L6 sequence is shown in FIG. 26. Further analysis of the 1B12 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 6B and 26, and in SEQ ID NOs:56, 66, and 76, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 7H1 are shown in FIG. 7A and in SEQ ID NO:87 and 7, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 7H1 are shown in FIG. 7B and in SEQ ID NO:97 and 17, respectively.
  • Comparison of the 7H1 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 7H1 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 7H1 VH sequence to the germline VH 1-69 sequence is shown in FIG. 17. Further analysis of the 7H1 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 7A and 17, and in SEQ ID NOs:27, 37, and 47, respectively.
  • Comparison of the 7H1 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 7H1 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 7H1 VL sequence to the germline VK L6 sequence is shown in FIG. 27. Further analysis of the 7H1 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 7B and 27, and in SEQ ID NOs:57, 67, and 77, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 11E6 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 11E6 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • Comparison of the 11E6 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 11E6 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 6-19, and a JH segment from human germline JH 6c. The alignment of the 11E6 VH sequence to the germline VH 1-69 sequence is shown in FIG. 18. Further analysis of the 11E6 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 8A and 18, and in SEQ ID NOs:28, 38, and 48, respectively.
  • Comparison of the 11E6 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 11E6 light chain utilizes a VL segment from human germline VK A27 and a JK segment from human germline JK 4. The alignment of the 11E6 VL sequence to the germline VK A27 sequence is shown in FIG. 27. Further analysis of the 11E6 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 8B and 28, and in SEQ ID NOs:58, 68, and 78, respectively. In addition, a second related clone included the VK sequence as shown in SEQ ID NO:109. This antibody is denoted herein as 11E6a.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 12B7 are shown in FIG. 9A and in SEQ ID NO:89 and 9, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 12B7 are shown in FIG. 9B and in SEQ ID NO:99 and 19, respectively.
  • Comparison of the 12B7 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 12B7 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 12B7 VH sequence to the germline VH 1-69 sequence is shown in FIG. 19. Further analysis of the 12B7 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 9A and 19, and in SEQ ID NOs:29, 39, and 49, respectively.
  • Comparison of the 12B7 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 12B7 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 5. The alignment of the 12B7 VL sequence to the germline VK L6 sequence is shown in FIG. 29. Further analysis of the 12B7 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 9B and 29, and in SEQ ID NOs:59, 69, and 79, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 13G4 are shown in FIG. 10A and in SEQ ID NO:90 and 10, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 13G4 are shown in FIG. 10B and in SEQ ID NO:100 and 20, respectively.
  • Comparison of the 13G4 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 13G4 heavy chain utilizes a VH segment from human germline VH 3-9, a D segment from human germline 3-9, and a JH segment from human germline JH 4b. The alignment of the 13G4 VH sequence to the germline VH 3-9 sequence is shown in FIG. 20. Further analysis of the 13G4 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 10A and 20, and in SEQ ID NOs:30, 40, and 50, respectively.
  • Comparison of the 13G4 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 13G4 light chain utilizes a VL segment from human germline VK L18 and a JK segment from human germline JK 3. The alignment of the 13G4 VL sequence to the germline VK L18 sequence is shown in FIG. 30. Further analysis of the 13G4 VL sequence using the Kabat, system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 10B and 30, and in SEQ ID NOs:60, 70, and 80, respectively.
    • Example 3: Characterization of Binding Specificity and Binding Kinetics of Anti-PD-L1 Human Monoclonal Antibodies
  • In this example, binding affinity and binding kinetics of anti-PD-L1 antibodies were examined by Biacore analysis. Binding specificity, and cross-competition were examined by flow cytometry.
    • Binding Affinity and Kinetics
  • Anti-PD-L1 antibodies were characterized for affinities and binding kinetics by Biacore analysis (Biacore AB, Uppsala, Sweden). Purified recombinant human PD-L1 fusion protein was covalently linked to a CM5 chip (carboxy methyl dextran coated chip) via primary amines, using standard amine coupling chemistry and kit provided by Biacore, to a density of 562 RUs. Binding was measured by flowing the antibodies in HBS EP buffer (provided by Biacore AB) at a concentration of 133 nM at a flow rate of 50 μl/min. The antigen-antibody association kinetics was followed for 1 minute and the dissociation kinetics was followed for 1 minute. The association and dissociation curves were fit to a 1:1 Langmuir binding model using BIAevaluation software (Biacore AB). To minimize the effects of avidity in the estimation of the binding constants, only the initial segment of data corresponding to association and dissociation phases were used for fitting. The KD, kon and koff values that were determined are shown in Table 2.
  • TABLE 2
    Biacore binding data for PD-L1 human monoclonal antibodies.
    Affinity KD × On rate kon × Off rate koff ×
    Sample # Sample ID 10−9 (M) 105 (1/Ms) 10−4 1/s
    1 3G10 3.39 5.25 17.8
    3 10A5 1.45 2.58 3.72

    Additional binding data obtained by equilibrium binding method and analyzed on GraphPad Prizm is shown in Table 3.
  • TABLE 3
    Biacore equilibrium binding data for
    PD-L1 human monoclonal antibodies.
    KD (nM) KD (nM)
    Clone ID 37 C. 25 C.
    12A4 1.94 0.76
    7H1 2.15 nd
    1B12 1.38 0.61
    12B7 0.83 0.53
    10A5 2.41 0.57
    10H10 5.93 5.48
    13G4 1.87 3.3
    11E6 0.53 2.9
    5F8 2.17 0.75
    • Binding Specificity by Flow Cytometry
  • Chinese hamster ovary (CHO) cell lines that: express recombinant human PD-L1 at the cell surface were developed and used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry. CHO cells were transfected with expression plasmids containing full length cDNA encoding transmembrane forms of PD-L1. Binding of the 3G10, 10A5, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the transfected cells with the anti-PD-L1 human monoclonal antibody. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScan flow cytometry (Becton Dickinson, San Jose, Calif.). The binding was compared to the parent CHO cell line. The results are shown in FIGS. 32A (HuMAb 3G10), 32B (HuMAb 10A5) and 32C (HuMAb 12A4). Binding was also tested using varying concentrations of an anti-PD-L1 antibody. The results are shown in FIG. 33. The anti-PD-L1 human monoclonal antibodies 3G10, 10A5, and 12A4 bound to the CHO cells transfected with PD-L1 in a concentration dependent manner. These data demonstrate that the anti-PD-L1 human monoclonal antibodies specifically bind to cell surface PD-L1.
    • Binding Specificity by ELISA
  • The specificity of the anti-PD-L1 monoclonal antibodies was determined using a standard ELISA assay for binding to a human PD-L1 fusion to an immunoglobulin Fc region.
  • An Fc-fusion protein of human PD-L1 was tested for binding against the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5. Standard ELISA procedures were performed. The anti-PD-L1 human monoclonal antibodies were added at different concentrations. Goat-anti-human IgG (kappa chain-specific) polyclonal antibody conjugated with horseradish peroxidase (HRP) was used as secondary antibody. The results are shown in FIG. 34. Each of the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5 bound with high specificity to PD-L1.
    • Example 4: Characterization of Anti-PD-L1 Antibody Binding to PD-L1 Expressed on the Cell Surface of Human and Monkey T Cells
  • Anti-PD-L1 antibodies were tested by flow cytometry for binding to activated human or cynomolgus monkey T cells expressing PD-L1 on their surface.
  • Human or monkey T cells were activated by anti-CD3 antibody to induce PD-L1 expression prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 1B12, 13G4, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated cells with serial dilutions of the anti-PD-L1 human monoclonal antibodies. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human Ig-kappa light chain Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are shown in FIGS. 35 and 36. The anti-PD-L1 monoclonal antibodies 3G10, 1B12, 13G4, and 12A4 bound to activated human and monkey T cells. These data demonstrate that the anti-PD-L1 human monoclonal antibodies bind to human and cynomolgus monkey cell surface PD-L1.
    • Example 5: Characterization of Anti-PD-L1 Antibody Binding to PD-L1 Expressed on the Cell Surface of Human T Cells
  • Anti-PD-L1 antibodies were tested for binding to activated human T cells expressing PD-L1 on their cell surface by flow cytometry.
  • Human T cells were activated by anti-CD3 antibody to induce PD-L1 expression on T cells prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 10A5 and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated T cells with the anti-PD-L1 human monoclonal antibodies at a concentration of 20 μg/ml. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometry (Becton Dickinson, San Jose, Calif.). The results are shown in FIGS. 37A (HuMAb 3G10), 37B (HuMAb 10A5) and 37C (HuMAb 12A4). The anti-PD-L1 monoclonal antibodies 3G10, 10A5, and 12A4 bound to activated human T cells (bold line), as shown in histogram plots compared to control (light line). These data demonstrate that the anti-PD-L1 human monoclonal antibodies bind to human cell surface PD-L1.
    • Example 6: Binding Specificity by Flow Cytometry
  • The ES-2 human ovarian carcinoma cell line that expresses human PD-L1 at the cell surface was used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry. ES-2 cells were treated overnight with 500 IU/mL of recombinant hIFN-γ to increase PD-L1 expression over the basal level. Binding of the 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 anti-PD-L1 human monoclonal antibodies was assessed by incubating the induced cells with serial dilutions of the anti-PD-L1 human monoclonal antibody. The cells were washed and binding was detected with a PE-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The binding was compared to isotype control antibody. The results are shown in FIG. 38. The anti-PD-L1 human monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 bound to the hIFN-γ-induced ES-2 cells in a concentration dependent manner. These data demonstrate that the anti-PD-L1 human monoclonal antibodies specifically bind to cell surface PD-L1.
    • Example 7: Effect of Human Anti-PD-L1 Antibodies on Cell Proliferation and Cytokine Production in a Mixed Lymphocyte Reaction
  • A mixed lymphocyte reaction was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway to lymphocyte effector cells. T cells in the assay were tested for proliferation, IFN-γ secretion and IL-2 secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ positive selection kit (Dynal Biotech). Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days. Monocytes were prepared using a monocyte negative selection kig (Mitenyi Biotech). Each culture contained 105 purified T-cells and 104 allogeneic dendritic cells in a total volume of 200 μl. Anti-PD-L1 monoclonal antibody 10A5, 12A4, or 3G10 was added to each culture at different antibody concentrations. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. After day 5, 100 μl of medium was taken from each culture for cytokine measurement. The levels of IFN-γ and IL-2 were measured using OptEIA ELISA kits (BD Biosciences). The cells were labeled with 3H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIGS. 39A (T cell proliferation), 39B (IFN-γ secretion using HuMAb 10A5), 39C (IFN-γ secretion using HuMAb 12A4 or 3G10) and 39D (IL-2 secretion). The anti-PD-L1 human monoclonal antibody 10A5 promotes T-cell proliferation, IFN-γ secretion and IL-2 secretion in a concentration dependent manner. The anti-PD-L1 human monoclonal antibodies 12A4 and 3G10 also showed an increase in IFN-γ secretion. In contrast, cultures containing the control antibody did not show an increase in T cell proliferation, IFN-γ or IL-2 secretion.
  • In a separate experiment, an allogeneic mixed lymphocyte reaction (MLR) was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway in lymphocyte effector cells. T cells in the assay were tested for proliferation and IFN-γ secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody or isotype control antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ negative selection kit (Miltenyi). Monocytes were prepared using a monocyte negative selection kit (Mitenyi Biotech). Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days. Each MLR culture contained 105 purified T-cells and 104 allogeneic dendritic cells in a total volume of 200 μl. Anti-PD-L1 monoclonal antibody 12A4, 11E6, 3G10, 13G4, 1B12, 10A5, and 12B7 were added to each culture at different antibody concentrations. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. On day 5, 50 μl of medium was taken from each culture for cytokine measurement and replaced with an equal volume of culture medium containing 1 μCi of 3H-thymidine. The cells were cultured for another 18 hours, harvested, and analyzed for cell proliferation. The levels of IFN-γ in the culture fluid were measured using an OptEIA hIFN-γ ELISA kit (BD Biosciences). The results are shown in FIG. 40. The anti-PD-L1 human monoclonal antibodies promote T-cell proliferation and IFN-γ secretion in a concentration-dependent manner. In contrast, cultures containing the control antibody did not show an increase in T cell proliferation or IFN-γ secretion.
    • Example 8: Effect of Human Anti-PD-L1 Antibody on Function of T Regulatory Cells
  • T regulatory cells (CD4+, CD25+) are lymphocytes that suppress the immune response. The effect of the addition of T regulatory cells on proliferation and IFN-γ secretion in the allogeneic dendritic cell and T cell MLR in the presence or absence of an anti-PD-L1 human monoclonal antibody was tested.
  • T regulatory cells were purified from PBMC using a CD4+CD25+ regulatory T cell isolation kit (Miltenyi Biotec). T regulatory cells were added into a mixed lymphocyte reaction (see above) containing purified CD4+CD25− T cells and allogeneic dendritic cells in a 2:1 ratio of CD4+CD25− to T regulatory cells. Anti-PD-L1 monoclonal antibody 10A5 was added to each culture at a concentration of 10 μg/ml. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. at which time the supernatants were analyzed for IFN-γ secretion using a Beadlyte cytokine detection system (Upstate). The cells were labeled with 3H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIGS. 41A (T cell proliferation) and 41B (IFN-γ secretion). The addition of anti-PD-L1 human monoclonal antibody 10A5 promotes both T cell proliferation and IFN-γ secretion in cell cultures of allogeneic dendritic cells, T cells and T regulatory cells, indicating that anti-PD-L1 antibodies can reverse the effect of T regulatory cells in the allogeneic DC—T cell-MLR
  • In a separate experiment, human anti-PD-L1 antibodies 12A4 and 13G4, and a control antibody 1D12, were tested in the MLR assay with T regulatory cells. The results are shown in FIGS. 42 (T cell proliferation) and 43 (IFN-γ secretion). The addition of anti-PD-L1 human monoclonal antibodies 12A4 or 13G4 partially reverses the suppression of both T cell proliferation and IFN-γ secretion in cell cultures of allogeneic dendritic cells and T cells containing T-regulatory cells, indicating that anti-PD-L1 antibodies may have an effect on T-regulatory cells.
    • Example 9: Effect of Anti-PD-1 Antibodies on Cytokine Secretion by Viral Antigen-Stimulated PBMC Cells from a Positive CMV Responsive Donor
  • CMV antigen-responsive human PBMC (Astarte Biologics, Redmond, Wash.) were cultured at 2e5 cells/well in flat bottom TC-treated 96 well plates, in the presence of 0.5 ug/ml CMV lysate (Astarte Biologics)+/−titrated anti-PD-L1 antibodies. AIM-V medium (Invitrogen) supplemented with heat-inactivated FBS (10% final) was used at a total volume of 200 ul/well. The cells were cultured for 4 days at 37° C., 5% CO2 at which time culture supernatant was harvested for determination of secreted interferon-γ by ELISA (OptEIA hIFN-γ ELISA kit—BD Biosciences). The results are shown in FIG. 44. The anti-PD-L1 human monoclonal antibodies promote IFN-γ secretion by CMV-specific T-cells in a dose-dependent manner. The most robust response was generated by antibodies 13G4, 1B12, and 12A4 compared to isotype control. These results shows that anti-PD-L1 HuMAbs can stimulate IFN-γ release in a memory T cell response from PBMC cells previously stimulated against an antigen.
    • Example 10: Blocking of PD-L1 Ligand Binding to PD-1 by Human Anti-PD-L1 Antibodies
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of the ligand PD-L1 to PD-1 expressed on transfected CHO cells by using a cell cytometry assay.
  • PD-1 expressing CHO cells were suspended in FACS buffer (PBS with 4% fetal calf serum). Various concentrations of the anti-PD-L1 HuMAbs 3G10, 10A5 or 12A4 was added to the cell suspension tubes at 4° C. for 30 minutes, followed by addition FITC-labeled PD-L1 fused to an immunoglobulin Fc-region. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are depicted in FIG. 45. The anti-PD-L1 monoclonal antibodies 3G10, 10A5, and 12A4 blocked binding of PD-L1 to CHO cells transfected with human PD-1, as measured by the mean fluorescent intensity (MFI) of staining. These data demonstrate that the anti-PD-L1 HuMAbs block binding of PD-L1 ligand to cell surface PD-1.
    • Example 11: Inhibition of the Binding of Soluble PD-1 to Cell-Surface PD-L1 Human Anti-PD-L1 Antibodies
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of a soluble dimeric version of the PD-1 receptor (PD-1-hFc) to PD-L1 expressed on hIFN-γ-induced ES-2 human ovarian carcinoma cells using a flow cytometry assay. The blocking was compared to isotype control antibody.
  • ES-2 cells were induced overnight with 500 IU/mL of hIFN-γ to upregulate hPD-L1 cell surface expression. Induced cells were suspended in FACS buffer. Serial dilutions of the anti-PD-L1 HuMAbs 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 were added to the cell suspension tubes at 4° C. for 30 minutes, followed by two washes to remove unbound antibody. Next PD-1-hFc protein was added at a constant 2 ug/mL to all wells at 4° C. for 30 minutes, followed by two washes to remove unbound PD-1-hFc. Next bound PD-1-Fc was detected on the ES-2 cells by addition of biotinylated-non-blocking anti-PD-1 HuMab 26D5, which binds to PD-1 when bound to PD-L1, at 4° C. for 30 minutes, followed by two washes to remove unbound antibody. Finally, bound 26D5 antibody was detected by addition of streptavidin-PE conjugate at 4° C. for 30 minutes, followed by two washes to remove unbound conjugate. Flow cytometric analysis was performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are depicted in FIG. 46. The anti-PD-L1 monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 blocked binding of PD-1 to ES-2 cells that express human PD-L1, as measured by the geometric mean fluorescent intensity (GMFI) of staining. These data demonstrate that the anti-PD-L1 HuMAbs block binding of soluble PD-1 receptor to cell surface PD-L1.
    • Example 12: Treatment of In Vivo Tumor Model Using Anti-PD-L1 Antibodies
  • Mice implanted with a cancerous tumor are treated in viva with anti-PD-L1 antibodies to examine the in vivo effect of the antibodies on tumor growth. For the tumor studies, female AJ mice between 6-8 weeks of age (Harlan Laboratories) are randomized by weight into 6 groups. The mice are implanted subcutaneously in the right flank with 2×106 SA1/N fibrosarcoma cells dissolved in 200 μl of DMEM media on day 0. The mice are treated with PBS vehicle, or anti-PD-L1 antibodies at 10 mg/kg. The animals are dosed by intraperitoneal injection with approximately 200 μl of PBS containing antibody or vehicle on days 1, 4, 3 and 11. Each group contains 10 animals and the groups consist of: (i) a vehicle group, (ii) control mouse IgG, and (iii) an anti-PD-L1 antibody. The mice are monitored twice weekly for tumor growth for approximately 6 weeks. Using an electronic caliper, the tumors are measured three dimensionally (height×width×length) and tumor volume is calculated. Mice are euthanized when the tumors reached tumor end point (1500 mm3) or show greater than 15% weight loss.
    • Example 13: In Vivo Efficacy of Combination Therapy (Anti-CTLA-4 and Anti-PD-L1 Antibodies) on Tumor Establishment and Growth
  • MC38 colorectal cancer cells (available from Dr. N. Restifo, National Cancer Institute, Bethesda, Md.; or Jeffrey Schlom, National Institutes of Health, Bethesda, Md.) were implanted in C57BL/6 mice (2×106 cells/mouse) and selected for treatment when tumors reached a size of 100-200 mm3). On day 0 the first day of treatment), each of four groups of 10 mice each was injected intraperitoneally (IP) with one of the following: (1) 10 mg/kg mouse IgG and 10 mg/kg of rat IgG (control), (2) 10 mg/kg anti-CTLA-4 monoclonal antibody 9D9 (mouse anti-mouse CTLA-4, obtained from J. Allison, Memorial Sloan-Kettering Cancer Center, New York, N.Y.) and 10 mg/kg rat IgG, (3) anti-PD-L1 monoclonal antibody MIH5 (rat anti-mouse PD-L1, eBioscience) and 10 mg/kg mouse IgG, or (4) 10 mg/kg anti-CTLA-4 antibody 9D9 and 10 mg/kg anti-PD-L1 antibody MIH5. Antibody injections were then further administered on days 3 and, 6. Using an electronic caliper, the tumors were measured three dimensionally (height×width×length) and tumor volume was calculated. Mice were euthanized when the tumors reached a designated tumor end-point. The results are shown in FIG. 47.
  • This study indicates that, in the MC38 murine tumor model, anti-PD-L1 antibody treatment alone has a modest effect on tumor growth resulting in a delay of tumor growth while anti-CTLA-4 has little effect in this model. However, the combination treatment of CTLA-4 antibody and PD-L1 antibody has a significantly greater effect on tumor growth and results in tumor free mice.
    • Example 14: Immunohistochemistry Using Anti-PD-L1 Antibodies
  • To assess the tissue binding profiles of HuMab anti-PD-L1, unmodified 12A4, 13G4, 3G10 and 12B7 were examined in a panel of normal (non-neoplastic) human tissues, including spleen, tonsil, cerebrum, cerebellum, heart, liver, lung, kidney, pancreas, pituitary, skin, and small intestine, as well as lung carcinoma tissues (1 sample/each). ES-2 cells were used as positive control. Hu-IgG1 and Hu-IgG4 were used as isotype control antibodies.
  • Snap frozen and OCT embedded normal and tumor tissues were purchased from Cooperative Human Tissue Network (Philadelphia, Pa.) or National Disease Research Institute (Philadelphia, Pa.). Cryostat sections at 5 μm were fixed with acetone for 10 min at room temperature, and stored at −80° C. until use. A Medarex developed immunohistochemistry protocol was performed using unmodified HuMab anti-PD-L1 by pre-complex of the primary antibodies (12A4, 13G4, 3G10 and 12B7) and secondary antibody (FITC conjugated Fab fragment of goat anti-Hu-IgG. Jackson ImmunoResearch Laboratories. West Grove, Pa.) before applying onto the sections. Briefly, 1 μg/ml or 5 μg/ml of the un-conjugated primary antibodies were mixed with 3 fold excess of secondary antibody respectively and incubated for 30 min at room temperature, and then excess human gamma globulin was added for another 30 min to block the unbound secondary antibody. In parallel, isotype control antibodies Hu-IgG1 or Hu-IgG4 were pre-complexed in the same manner. Slides were washed with PBS (Sigma, St. Louis, Mo.) twice, and then incubated with peroxidase block supplied in Dako EnVision+System (Dako. Carpinteria, Calif.) for 10 minutes. After two washes with PBS, slides were incubated with Dako protein block to block the non-specific binding sites. Subsequently, the pre-complex of primary antibodies or isotype controls were applied onto sections and incubated for 1 hr. Following three washes with PBS, slides were incubated with mouse anti-FITC antibody (20 μg/ml. Sigma) for 30 min. After another three washes with PBS, the slides were incubated with the peroxidase-conjugated anti-mouse IgG polymer supplied in the Dako EnVision+System for 30 min. Finally, slides were washed as above and reacted with DAB substrate-chromogen solution supplied in the Dako EnVision+System for 6 min. Slides were then washed with deionized water, counterstained with Mayer's hematoxylin (Dako), dehydrated, cleared and coverslipped with Permount (Fischer Scientific, Fair Lawn, N.J.) following routine histological procedure.
  • Weak to moderate staining was observed in ES-2 cells, as well as in tumor cells of lung carcinoma tissues. In tonsil sections, strong staining was seen in crypt epithelium that is heavily infiltrated by lymphoid cells, but not in the mucous stratified squamous epithelial cells. Moderate staining was seen in some cells in the inter-follicular region, and very weak staining was seen in scattered large cells (dendritic reticulum-like cells) in the germinal center. In lung, weak staining was found in alveoli macrophages. The staining patterns in tonsil and lung tissues were similarly seen in immunohistochemistry sections using commercial anti-PD-L1 mAb (eBiosciences. San Diego, Calif.). There was overall less intense staining by HuMabs, especially for the staining in the germinal centers. In spleen, diffuse weak immunoreactivity in red pulp was slightly above the background staining. In addition, weak to moderate staining was displayed in Kupffer-like cells in liver and scattered cells in Peyer's patch, as well as in scattered macrophage-like cells and fibroblasts mainly in focal region of the muscularis externa of small intestine.
  • In cerebellum, cerebrum, heart, kidney, pancreas, pituitary and skin tissues, no meaningful staining was observed when stained with all four anti-PD-L1 HuMabs. No evident difference in staining was noted among these four antibodies except 12B7 and/or 3G10 displayed slightly stronger staining in liver and ES-2 cells.
  • PD-L1 Antibody Summary
    SEQ ID NO: SEQUENCE
    1 VH a.a. 3G10
    2 VH a.a. 12A4
    3 VH a.a. 10A5
    4 VH a.a. 5F8
    5 VH a.a. 10H10
    6 VH a.a. 1B12
    7 VH a.a. 7H1
    8 VH a.a. 11E6
    9 VH a.a. 12B7
    10 VH a.a. 13G4
    11 VK a.a. 3G10
    12 VK a.a. 12A4
    13 VK a.a. 10A5
    14 VK a.a. 5F8
    15 VK a.a. 10H10
    16 VK a.a. 1B12
    17 VK a.a. 7H1
    18 VK a.a. 11E6
    19 VK a.a. 12B7
    20 VK a.a. 13G4
    21 VH CDR1 a.a. 3G10
    22 VH CDR1 a.a. 12A4
    23 VH CDR1 a.a. 10A5
    24 VH CDR1 a.a. 5F8
    25 VH CDR1 a.a. 10H10
    26 VH CDR1 a.a. 1B12
    27 VH CDR1 a.a. 7H1
    28 VH CDR1 a.a. 11E6
    29 VH CDR1 a.a. 12B7
    30 VH CDR1 a.a. 13G4
    31 VH CDR2 a.a. 3G10
    32 VH CDR2 a.a. 12A4
    33 VH CDR2 a.a. 10A5
    34 VH CDR2 a.a. 5F8
    35 VH CDR2 a.a. 10H10
    36 VH CDR2 a.a. 1B12
    37 VH CDR2 a.a. 7H1
    38 VH CDR2 a.a. 11E6
    39 VH CDR2 a.a. 12B7
    40 VH CDR2 a.a. 13G4
    41 VH CDR3 a.a. 3G10
    42 VH CDR3 a.a. 12A4
    43 VH CDR3 a.a. 10A5
    44 VH CDR3 a.a. 5F8
    45 VH CDR3 a.a. 10H10
    46 VH CDR3 a.a. 1B12
    47 VH CDR3 a.a. 7H1
    48 VH CDR3 a.a. 11E6
    49 VH CDR3 a.a. 12B7
    50 VH CDR3 a.a. 13G4
    51 VK CDR1 a.a. 3G10
    52 VK CDR1 a.a. 12A4
    53 VK CDR1 a.a. 10A5
    54 VK CDR1 a.a. 5F8
    55 VK CDR1 a.a. 10H10
    56 VK CDR1 a.a. 1B12
    57 VK CDR1 a.a. 7H1
    58 VK CDR1 a.a. 11E6
    59 VK CDR1 a.a. 12B7
    60 VK CDR1 a.a. 13G4
    61 VK CDR2 a.a. 3G10
    62 VK CDR2 a.a. 12A4
    63 VK CDR2 a.a. 10A5
    64 VK CDR2 a.a. 5F8
    65 VK CDR2 a.a. 10H10
    66 VK CDR2 a.a. 1B12
    67 VK CDR2 a.a. 7H1
    68 VK CDR2 a.a. 11E6
    69 VK CDR2 a.a. 12B7
    70 VK CDR2 a.a. 13G4
    71 VK CDR3 a.a. 3G10
    72 VK CDR3 a.a. 12A4
    73 VK CDR3 a.a. 10A5
    74 VK CDR3 a.a. 5F8
    75 VK CDR3 a.a. 10H10
    76 VK CDR3 a.a. 1B12
    77 VK CDR3 a.a. 7H1
    78 VK CDR3 a.a. 11E6
    79 VK CDR3 a.a. 12B7
    80 VK CDR3 a.a. 13G4
    81 VH n.t. 3G10
    82 VH n.t. 12A4
    83 VH n.t. 10A5
    84 VH n.t. 5F8
    85 VH n.t. 10H10
    86 VH n.t. 1B12
    87 VH n.t. 7H1
    88 VH n.t. 11E6
    89 VH n.t. 12B7
    90 VH n.t. 13G4
    91 VK n.t. 3G10
    92 VK n.t. 12A4
    93 VK n.t. 10A5
    94 VK n.t. 5F8
    95 VK n.t. 10H10
    96 VK n.t. 1B12
    97 VK n.t. 7H1
    98 VK n.t. 11E6
    99 VK n.t. 12B7
    100 VK n.t. 13G4
    101 VH 1-18 germline a.a.
    102 VH 1-69 germline a.a.
    103 VH 1-3 germline a.a.
    104 VH 3-9 germline a.a.
    105 VK L6 germline a.a.
    106 VK L15 germline a.a.
    107 VK A27 germline a.a.
    108 VK L18 germline a.a.
    109 VK a.a. 11E6a

Claims (23)

1. A monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody, or antigen-binding portion thereof, specifically binds to human PD-L1, and wherein the antibody exhibits at least one of the following properties:
(a) binds to human PD-L1 with a KD of 1×10−7M or less;
(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
(c) increases interferon-γ production in an MLR assay; or
(d) increases interleukin-2 (IL-2) secretion in an MLR assay.
2-22. (canceled)
23. The antibody, or antigen-binding portion thereof, of claim 1, comprising:
(a) a heavy chain variable region CDR1 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;
(b) a heavy chain variable region CDR2 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34 35, 36, 37, 38, 39, and 40;
(c) a heavy chain variable region CDR3 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47 48, 49, and 50;
(d) a light chain variable region CDR1 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;
(e) a light chain variable region CDR2 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70;
(f) a light chain variable region CDR3 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.
24-26. (canceled)
27. The antibody, or antigen binding portion thereof, of claim 1, comprising:
(a) a heavy chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
(b) a light chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
28-42. (canceled)
43. A transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, and wherein the antibody exhibits at least one of the following properties:
(a) binds to human PD-L1 with a KD of 1×10−7M or less;
(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
(c) increases interferon-γ production in an MLR assay; or
(d) increases interleukin-2 (IL-2) secretion in an MLR assay.
44. (canceled)
45. A method of modulating an immune response in a subject comprising administering to the subject an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that the immune response in the subject is modulated, wherein the antibody exhibits at least one of the following properties:
(a) binds to human PD-L1 with a KD of 1×10−7M or less;
(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
(c) increases interferon-γ production in an MLR assay; or
(d) increases interleukin-2 (IL-2) secretion in an MLR assay.
46. A method of inhibiting growth of tumor cells in a subject, comprising administering to the subject an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that growth of tumor cells in the subject is inhibited, wherein the antibody exhibits at least one of the following properties:
(a) binds to human PD-L1 with a KD of 1×10−7M or less;
(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
(c) increases interferon-γ production in an MLR assay; or
(d) increases interleukin-2 (IL-2) secretion in an MLR assay.
47-49. (canceled)
50. The method of claim 46, wherein the tumor cells are of a cancer selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, and lung cancer.
51. The method of claim 46, wherein the tumor cells are of a cancer selected from the list consisting of bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.
52. (canceled)
53. A method of treating an infectious disease in a subject comprising administering to the subject an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that the subject is treated for the infectious disease, wherein the antibody exhibits at least one of the following properties:
(a) binds to human PD-L1 with a KD of 1×10−7M or less;
(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
(c) increases interferon-γ production in an MLR assay; or
(d) increases interleukin-2 (IL-2) secretion in an MLR assay.
54. The method of claim 53, wherein the infectious disease is selected from the list consisting of: HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, the pathogenic infection by the virus Hepatitis (A, B, & C), herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria Chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, diphtheria, Salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria, pathogenic infection by the fungi Candida, Cryptococcus neoformans, Aspergillus, Genus Mucorales, Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, and pathogenic infection by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.
55. A method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) the antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that an immune response to the antigen in the subject is enhanced, wherein the antibody exhibits at least one of the following properties:
(a) binds to human PD-L1 with a KD of 1×10−7M or less;
(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
(c) increases interferon-γ production in an MLR assay; or
(d) increases interleukin-2 (IL-2) secretion in an MLR assay.
56. The method of claim 55, wherein the antigen is a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
57. A method of treating or preventing an inflammatory disease in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 1 such that the subject is treated for the inflammatory disease.
58. (canceled)
59. A method for preparing an anti-PD-L1 antibody comprising:
(a) providing a nucleic acid encoding an antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 domains; and a light chain variable region comprising CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; the heavy chain variable CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; the heavy chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; the light chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60; the light chain variable region CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and the light chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
(b) altering the nucleic acid encoding at least one amino acid residue within at least one variable region to create a nucleic acid encoding an altered antibody sequence or antigen-binding portion thereof comprising at least one amino acid alteration; and
(c) expressing the altered antibody sequence or antigen-binding portion thereof as a protein.
60-67. (canceled)
68. The antibody, or antigen-binding portion thereof, of claim 1, which is a chimeric antibody or antigen-binding portion thereof, a humanized antibody or antigen-binding portion thereof, or a fully human antibody or antigen-binding portion thereof.
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US10988536B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11274152B2 (en) 2013-09-20 2022-03-15 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
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Families Citing this family (1883)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030219B2 (en) 2000-04-28 2006-04-18 Johns Hopkins University B7-DC, Dendritic cell co-stimulatory molecules
ES2350687T3 (en) 2002-07-03 2011-01-26 Ono Pharmaceutical Co., Ltd. IMMUNOPOTENTIAL COMPOSITIONS.
AR045563A1 (en) 2003-09-10 2005-11-02 Warner Lambert Co ANTIBODIES DIRECTED TO M-CSF
DE10347710B4 (en) 2003-10-14 2006-03-30 Johannes-Gutenberg-Universität Mainz Recombinant vaccines and their use
RU2494107C2 (en) 2005-05-09 2013-09-27 Оно Фармасьютикал Ко., Лтд. Human monoclonal antibodies specific for programmed cell death 1 (pd1) protein and methods of treating cancer with using anti-pd1 antibodies either individually, or in combination with other immunotherapeutic agents
CN101355965A (en) 2005-06-08 2009-01-28 达纳－法伯癌症研究院 Methods and compositions for treating persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway
CN104356236B (en) * 2005-07-01 2020-07-03 E.R.施贵宝&圣斯有限责任公司 Human monoclonal antibody against programmed death ligand 1 (PD-L1)
DE102005046490A1 (en) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz New nucleic acid molecule comprising promoter, a transcriptable nucleic acid sequence, a first and second nucleic acid sequence for producing modified RNA with transcriptional stability and translational efficiency
US7700567B2 (en) 2005-09-29 2010-04-20 Supergen, Inc. Oligonucleotide analogues incorporating 5-aza-cytosine therein
US20090304711A1 (en) * 2006-09-20 2009-12-10 Drew Pardoll Combinatorial Therapy of Cancer and Infectious Diseases with Anti-B7-H1 Antibodies
EP2102241A2 (en) 2006-12-15 2009-09-23 Ablynx N.V. Amino acid sequences that modulate the interaction between cells of the immune system
AU2013200388B2 (en) * 2006-12-27 2014-10-23 Dana-Farber Cancer Institute, Inc. Compositions and methods for the treatment of infections and tumors
CN101675075B (en) * 2007-03-01 2014-06-18 西福根有限公司 Recombinant anti-epidermal growth factor receptor antibody compositions
HRP20131167T1 (en) 2007-06-18 2014-01-03 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
US20110014117A1 (en) * 2007-06-28 2011-01-20 Schering Corporation Anti-igf1r
KR101570252B1 (en) 2007-07-17 2015-11-19 메다렉스, 엘.엘.시. Monoclonal Antibodies Against Glypican-3
US8062852B2 (en) 2007-10-01 2011-11-22 The Children's Hospital And Regional Medical Center Detection and treatment of autoimmune disorders
KR101615935B1 (en) 2007-12-14 2016-04-28 노보 노르디스크 에이/에스 Antibodies against human nkg2d and uses thereof
DK3153526T3 (en) 2008-01-31 2020-12-14 Inst Nat Sante Rech Med ANTIBODIES TO HUMAN CD39 AND ITS USE TO INHIBIT THE ACTIVITY OF T-REGULATORY CELLS
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
EP3208612B1 (en) 2008-04-09 2019-09-18 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
US9017660B2 (en) 2009-11-11 2015-04-28 Advaxis, Inc. Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors
US20110129499A1 (en) 2008-05-19 2011-06-02 Paulo Maciag Dual delivery system for heterologous antigens
US9650639B2 (en) 2008-05-19 2017-05-16 Advaxis, Inc. Dual delivery system for heterologous antigens
WO2010098788A2 (en) * 2008-08-25 2010-09-02 Amplimmune, Inc. Pd-i antagonists and methods for treating infectious disease
CN102203132A (en) 2008-08-25 2011-09-28 安普利穆尼股份有限公司 Compositions and methods of use of PD-1 antagonists
AU2013204861B2 (en) * 2008-09-26 2016-05-12 Dana-Farber Cancer Institute, Inc. Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor
KR101814408B1 (en) 2008-09-26 2018-01-04 다나-파버 캔서 인스티튜트 인크. Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses therefor
CA2744449C (en) 2008-11-28 2019-01-29 Emory University Methods for the treatment of infections and tumors
AU2009333580B2 (en) 2008-12-09 2016-07-07 Genentech, Inc. Anti-PD-L1 antibodies and their use to enhance T-cell function
WO2010089411A2 (en) * 2009-02-09 2010-08-12 Universite De La Mediterranee Pd-1 antibodies and pd-l1 antibodies and uses thereof
ES2593027T3 (en) 2009-03-30 2016-12-05 Eisai R&D Management Co., Ltd. Liposomal composition
US8492119B2 (en) * 2009-04-27 2013-07-23 Kyowa Hakko Kirin Co., Ltd Antibody to human IL-3 receptor alpha chain
JP5836940B2 (en) 2009-06-26 2015-12-24 ソリシメド・バイオファーマ・インコーポレーテッド Soricidin derived peptides and methods for detection and drug delivery of TRPV-6 cancer
EP3375791A1 (en) 2009-09-30 2018-09-19 Memorial Sloan Kettering Cancer Center Combination immunotherapy for the treatment of cancer
US10016617B2 (en) 2009-11-11 2018-07-10 The Trustees Of The University Of Pennsylvania Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers
NZ628923A (en) * 2009-11-24 2016-02-26 Medimmune Ltd Targeted binding agents against b7-h1
US20110280877A1 (en) * 2010-05-11 2011-11-17 Koji Tamada Inhibition of B7-H1/CD80 interaction and uses thereof
CN107898791A (en) 2010-06-03 2018-04-13 药品循环有限责任公司 The application of bruton's tyrosine kinase (BTK) inhibitor
US9783578B2 (en) 2010-06-25 2017-10-10 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
US9226958B2 (en) 2010-10-01 2016-01-05 University Of Georgia Research Foundation, Inc. Use of Listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals
US9428567B2 (en) 2010-12-22 2016-08-30 The Board Of Trustees Of The Leland Stanford Junior University Antagonists of interleukin-2 receptor
AU2012229218B2 (en) 2011-03-11 2017-03-02 Advaxis, Inc. Listeria-based adjuvants
US8722044B2 (en) 2011-03-15 2014-05-13 Janssen Biotech, Inc. Human tissue factor antibody and uses thereof
KR101970025B1 (en) 2011-04-20 2019-04-17 메디뮨 엘엘씨 Antibodies and other molecules that bind b7-h1 and pd-1
EP2701699B1 (en) 2011-04-28 2019-10-16 The Broad Institute, Inc. Inhibitors of histone deacetylase
HRP20211595T1 (en) 2011-05-24 2022-01-21 BioNTech SE Individualized vaccines for cancer
CN103732238A (en) 2011-06-08 2014-04-16 奥瑞基尼探索技术有限公司 Therapeutic compounds for immunomodulation
EP2723380B1 (en) 2011-06-24 2019-08-21 Stephen D. Gillies Light chain immunoglobulin fusion proteins and methods of use thereof
EP2734205B1 (en) 2011-07-21 2018-03-21 Tolero Pharmaceuticals, Inc. Heterocyclic protein kinase inhibitors
JP6238459B2 (en) 2011-08-01 2017-11-29 ジェネンテック， インコーポレイテッド Method for treating cancer using PD-1 axis binding antagonist and MEK inhibitor
EP2750768B1 (en) 2011-08-30 2018-10-03 Astex Pharmaceuticals, Inc. Decitabine derivative formulations
WO2013059740A1 (en) 2011-10-21 2013-04-25 Foundation Medicine, Inc. Novel alk and ntrk1 fusion molecules and uses thereof
HRP20201595T1 (en) 2011-11-28 2020-12-11 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
DK2806883T3 (en) * 2012-01-25 2019-07-22 Dnatrix Inc BIOMARKERS AND COMBINATION THERAPIES WITH USING ONCOLYTIC VIRUS AND IMMUNOMODULATION
CN104411327A (en) 2012-03-12 2015-03-11 阿德瓦希斯公司 Suppressor cell function inhibition following listeria vaccine treatment
WO2013143555A1 (en) 2012-03-26 2013-10-03 Biontech Ag Rna formulation for immunotherapy
US9603800B2 (en) 2012-04-12 2017-03-28 Yale University Methods of treating inflammatory and autoimmune diseases and disorders using nanolipogels
CN113967253A (en) 2012-05-15 2022-01-25 百时美施贵宝公司 Immunotherapy by disrupting PD-1/PD-L1 signaling
HK1204557A1 (en) 2012-05-31 2015-11-27 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-l1
WO2013181452A1 (en) * 2012-05-31 2013-12-05 Genentech, Inc. Methods of treating cancer using pd-l1 axis binding antagonists and vegf antagonists
ES2704744T3 (en) 2012-06-13 2019-03-19 Incyte Holdings Corp Substituted tricyclic compounds as FGFR inhibitors
CN112587671A (en) 2012-07-18 2021-04-02 博笛生物科技有限公司 Targeted immunotherapy for cancer
CN104704129A (en) 2012-07-24 2015-06-10 药品循环公司 Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (BTK)
JP6337255B2 (en) 2012-07-27 2018-06-06 ザ ブロード インスティテュート, インコーポレーテッドThe Broad Institute, Inc. Inhibitors of histone deacetylase
JP6403166B2 (en) * 2012-08-03 2018-10-10 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド Single antigen anti-PD-L1 and PD-L2 double-binding antibodies and methods of use thereof
KR101594032B1 (en) * 2012-08-23 2016-02-15 강원대학교산학협력단 Pharmaceutical composition for preventing or treating inflammation or skin aging and cosmetic composition for improving inflammation or skin aging
JP6457940B2 (en) 2012-08-30 2019-01-23 アムジエン・インコーポレーテツド Method for treating melanoma using herpes simplex virus and immune checkpoint inhibitors
PL2904011T3 (en) 2012-10-02 2018-01-31 Bristol Myers Squibb Co Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer
CA2886433C (en) * 2012-10-04 2022-01-04 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-pd-l1 antibodies and methods of use
CA2890346A1 (en) 2012-11-05 2014-05-08 Foundation Medicine, Inc. Novel fusion molecules and uses thereof
AU2013337277B2 (en) 2012-11-05 2018-03-08 Foundation Medicine, Inc. Novel NTRK1 fusion molecules and uses thereof
WO2014082729A1 (en) 2012-11-28 2014-06-05 Biontech Ag Individualized vaccines for cancer
EP2945652B1 (en) 2013-01-18 2021-07-07 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
EP2950814A4 (en) 2013-01-31 2016-06-08 Univ Jefferson Pd-l1 and pd-l2-based fusion proteins and uses thereof
US20150377891A1 (en) 2013-02-07 2015-12-31 (Institute National De La Santé Et De La Rechere Médicale) Methods for Predicting the Survival Time of Patients Suffering from Diffuse Large B-Cell Lymphomas
DK2958943T3 (en) 2013-02-20 2019-12-09 Univ Pennsylvania Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptor
TW201446794A (en) 2013-02-20 2014-12-16 Novartis Ag Effective targeting of primary human leukemia using engineered T cells with anti-CD123 chimeric antigen receptor
EP2958588B1 (en) 2013-02-22 2017-08-23 CureVac AG Combination of vaccination and inhibition of the pd-1 pathway
RU2718988C2 (en) 2013-02-22 2020-04-15 Куревак Аг Combination of anti-cancer rna vaccine and pd-1 pathway inhibitor and its application
SI2961388T1 (en) 2013-03-01 2019-10-30 Astex Pharmaceuticals Inc Drug combinations
CN105209456B (en) 2013-03-06 2018-05-08 阿斯利康(瑞典)有限公司 The quinazoline inhibitor of the activated mutated forms of EGF-R ELISA
ES2812208T3 (en) 2013-03-14 2021-03-16 Bristol Myers Squibb Co Combination of a DR5 agonist and an anti-PD-1 antagonist and methods of use
KR102389677B1 (en) 2013-03-15 2022-04-21 제넨테크, 인크. Biomarkers and methods of treating pd-1 and pd-l1 related conditions
US9308236B2 (en) 2013-03-15 2016-04-12 Bristol-Myers Squibb Company Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions
UY35468A (en) 2013-03-16 2014-10-31 Novartis Ag CANCER TREATMENT USING AN ANTI-CD19 CHEMERIC ANTIGEN RECEIVER
EP2981821B2 (en) 2013-04-02 2021-11-03 Merck Sharp & Dohme Corp. Immunohistochemical assay for detecting expression of programmed death ligand 1 (pd-l1) in tumor tissue
KR20160004299A (en) 2013-04-09 2016-01-12 릭스트 바이오테크놀로지, 인코포레이티드 Formulations of oxabicycloheptanes and oxabicycloheptenes
EP2983790A2 (en) 2013-04-09 2016-02-17 Boston Biomedical, Inc. Methods for treating cancer
EA035095B1 (en) 2013-04-19 2020-04-27 Инсайт Холдингс Корпорейшн Bicyclic heterocycles as fgfr inhibitors
WO2014180490A1 (en) 2013-05-10 2014-11-13 Biontech Ag Predicting immunogenicity of t cell epitopes
WO2014194293A1 (en) 2013-05-30 2014-12-04 Amplimmune, Inc. Improved methods for the selection of patients for pd-1 or b7-h4 targeted therapies, and combination therapies thereof
US9676853B2 (en) * 2013-05-31 2017-06-13 Sorrento Therapeutics, Inc. Antigen binding proteins that bind PD-1
SG11201509742QA (en) 2013-06-03 2015-12-30 Novartis Ag Combinations of an anti-pd-l1 antibody and a mek inhibitor and/or a braf inhibitor
CA2916681A1 (en) 2013-07-16 2015-01-22 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and tigit inhibitors
BR112016002614B8 (en) 2013-08-08 2023-11-07 Hopitaux Paris Assist Publique Immunocytokine and pharmaceutical composition
KR102457731B1 (en) 2013-08-08 2022-10-21 싸이튠 파마 Combined pharmaceutical composition
AR097306A1 (en) 2013-08-20 2016-03-02 Merck Sharp & Dohme MODULATION OF TUMOR IMMUNITY
CA2920113A1 (en) 2013-08-20 2015-02-26 Merck Sharp & Dohme Corp. Treating cancer with a combination of a pd-1 antagonist and dinaciclib
EA034666B1 (en) 2013-09-13 2020-03-04 Бейджин Свитзерланд Гмбх Anti-pd1 antibody and use thereof for treating cancer or viral infection, and antibody fragment
CN105722860A (en) 2013-09-24 2016-06-29 梅迪塞纳医疗股份有限公司 Interleukin-2 fusion proteins and uses thereof
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
WO2015061668A1 (en) * 2013-10-25 2015-04-30 Dana-Farber Cancer Institute, Inc. Anti-pd-l1 monoclonal antibodies and fragments thereof
JP6508785B2 (en) * 2013-10-25 2019-05-08 ファーマサイクリックス エルエルシー Treatment Using Bruton Tyrosine Kinase Inhibitors and Immunotherapy
KR102460800B1 (en) 2013-11-01 2022-10-31 예일 유니버시티 Modular particles for immunotherapy
WO2015066413A1 (en) 2013-11-01 2015-05-07 Novartis Ag Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections
CN105899232A (en) 2013-11-13 2016-08-24 诺华股份有限公司 mTOR Inhibitors for Enhanced Immune Response
WO2015077717A1 (en) 2013-11-25 2015-05-28 The Broad Institute Inc. Compositions and methods for diagnosing, evaluating and treating cancer by means of the dna methylation status
WO2015081158A1 (en) * 2013-11-26 2015-06-04 Bristol-Myers Squibb Company Method of treating hiv by disrupting pd-1/pd-l1 signaling
WO2015085147A1 (en) 2013-12-05 2015-06-11 The Broad Institute Inc. Polymorphic gene typing and somatic change detection using sequencing data
EP3079772B1 (en) 2013-12-10 2020-02-05 Merck Sharp & Dohme Corp. Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue
WO2015095404A2 (en) 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating cancers using pd-1 axis binding antagonists and taxanes
WO2015094992A1 (en) 2013-12-17 2015-06-25 Merck Sharp & Dohme Corp. Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists
MX2016007885A (en) 2013-12-17 2017-01-11 Genentech Inc Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody.
DE202014010499U1 (en) 2013-12-17 2015-10-20 Kymab Limited Targeting of human PCSK9 for cholesterol treatment
UA129760C2 (en) * 2013-12-17 2025-07-30 Дженентек, Інк. ANTI-CD3 ANTIBODY AND METHOD OF USE THEREOF
US9045545B1 (en) * 2014-07-15 2015-06-02 Kymab Limited Precision medicine by targeting PD-L1 variants for treatment of cancer
US9067998B1 (en) * 2014-07-15 2015-06-30 Kymab Limited Targeting PD-1 variants for treatment of cancer
AU2014364606A1 (en) 2013-12-17 2016-07-07 Genentech, Inc. Combination therapy comprising OX40 binding agonists and PD-1 axis binding antagonists
ES2918501T3 (en) 2013-12-19 2022-07-18 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
EP3082853A2 (en) 2013-12-20 2016-10-26 The Broad Institute, Inc. Combination therapy with neoantigen vaccine
ES2857848T3 (en) 2013-12-24 2021-09-29 Bristol Myers Squibb Co Tricyclic compounds as antineoplastic agents
KR20220062143A (en) * 2014-01-06 2022-05-13 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 Pd1 and pdl1 antibodies and vaccine combinations and use of same for immunotherapy
CN105899539B (en) 2014-01-10 2021-11-09 博笛生物科技有限公司 Compounds and compositions for immunotherapy
SI3094351T1 (en) 2014-01-15 2022-05-31 Kadmon Corporation, Llc Immunomodulatory agents
JO3517B1 (en) 2014-01-17 2020-07-05 Novartis Ag N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
TWI681969B (en) 2014-01-23 2020-01-11 美商再生元醫藥公司 Human antibodies to pd-1
TWI680138B (en) * 2014-01-23 2019-12-21 美商再生元醫藥公司 Human antibodies to pd-l1
SG10201900002QA (en) 2014-01-24 2019-02-27 Dana Farber Cancer Institue Inc Antibody molecules to pd-1 and uses thereof
CN111909278B (en) 2014-01-27 2024-04-09 分子模板公司 MHC Class I Epitope Delivery Peptides
EP3099717B1 (en) 2014-01-31 2019-03-27 Novartis AG Antibody molecules to tim-3 and uses thereof
EP3686219A1 (en) 2014-02-04 2020-07-29 Pfizer Inc Combination of a pd-1 antagonist and a 4-1bb agonist for treating cancer
EA201691376A1 (en) 2014-02-04 2017-01-30 Пфайзер Инк. COMBINATION OF ANTAGONIST PD-1 AND VEGFR INHIBITOR FOR CANCER TREATMENT
US20170037125A1 (en) 2014-02-04 2017-02-09 Incyte Corporation Combination of a pd-1 antagonist and an ido1 inhibitor for treating cancer
US9676863B2 (en) 2014-02-10 2017-06-13 Merck Patent Gmbh Targeted TGFβ inhibitors
GB201403775D0 (en) 2014-03-04 2014-04-16 Kymab Ltd Antibodies, uses & methods
EP3114144A1 (en) 2014-03-05 2017-01-11 Bristol-Myers Squibb Company Treatment of renal cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent
US11142584B2 (en) 2014-03-11 2021-10-12 Molecular Templates, Inc. CD20-binding proteins comprising Shiga toxin A subunit effector regions for inducing cellular internalization and methods using same
US10519237B2 (en) 2014-03-12 2019-12-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
WO2015135558A1 (en) 2014-03-12 2015-09-17 Curevac Gmbh Combination of vaccination and ox40 agonists
US10618963B2 (en) 2014-03-12 2020-04-14 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
AU2015228372B2 (en) 2014-03-12 2018-05-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US20150259420A1 (en) 2014-03-14 2015-09-17 Novartis Ag Antibody molecules to lag-3 and uses thereof
EP3593812A3 (en) 2014-03-15 2020-05-27 Novartis AG Treatment of cancer using chimeric antigen receptor
WO2015143400A1 (en) 2014-03-20 2015-09-24 Pharmacyclics, Inc. Phospholipase c gamma 2 and resistance associated mutations
AP2016009374A0 (en) 2014-03-24 2016-08-31 Novartis Ag Monobactam organic compounds for the treatment of bacterial infections
US11230719B2 (en) * 2014-03-26 2022-01-25 Denovo Biopharma Llc Retroviral vector having immune-stimulating activity
RU2016142476A (en) 2014-03-31 2018-05-07 Дженентек, Инк. COMBINED THERAPY, INCLUDING ANTI-ANGIOGENESIS AGENTS AND AGONISTS BINDING OX40
EP3126394B1 (en) 2014-03-31 2019-10-30 F.Hoffmann-La Roche Ag Anti-ox40 antibodies and methods of use
US9987258B2 (en) 2014-04-06 2018-06-05 H. Lee Moffitt Cancer Center And Research Institute, Inc. Histone deacetylase as a modulator of PDL1 expression and activity
AU2015244039B2 (en) 2014-04-07 2021-10-21 Novartis Ag Treatment of cancer using anti-CD19 chimeric antigen receptor
WO2015157636A1 (en) 2014-04-10 2015-10-15 H. Lee Moffitt Cancer Center And Research Institute, Inc. Enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy
WO2015164815A1 (en) 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
PT3142751T (en) * 2014-05-13 2019-10-25 Medimmune Ltd ANTI-B7-H1 AND ANTI-CTLA-4 ANTIBODIES FOR THE TREATMENT OF NON SMALL CELL LUNG CANCER.
JP2017515859A (en) 2014-05-15 2017-06-15 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Treatment of lung cancer using a combination of anti-PD-1 antibodies and other anticancer agents
KR102535283B1 (en) 2014-05-23 2023-05-22 에자이 알앤드디 매니지먼트 가부시키가이샤 Combination therapies for the treatment of cancer
WO2015184061A2 (en) * 2014-05-28 2015-12-03 Dana-Farber Cancer Institute, Inc. Activating jak kinase biomarkers predictive of anti-immune checkpoint inhibitor response
JP2017516779A (en) 2014-05-28 2017-06-22 アイデニクス・ファーマシューティカルズ・エルエルシー Nucleoside derivatives for cancer treatment
CN106535884A (en) 2014-06-06 2017-03-22 弗雷克萨斯生物科学公司 Immunoregulatory agents
PT3151921T (en) 2014-06-06 2019-11-21 Bristol Myers Squibb Co ANTIBODIES AGAINST GLUCOCORTICOID-INDUCED TUMOR NECROSIS FACTOR RECEIVER AND USES OF THE SAME
ES2919749T3 (en) 2014-06-11 2022-07-28 Molecular Templates Inc Molecules targeting cytotoxic cells resistant to cleavage by protease
TWI693232B (en) 2014-06-26 2020-05-11 美商宏觀基因股份有限公司 Covalently bonded diabodies having immunoreactivity with pd-1 and lag-3, and methods of use thereof
TWI726608B (en) 2014-07-03 2021-05-01 英屬開曼群島商百濟神州有限公司 Anti-pd-l1 antibodies and their use as therapeutics and diagnostics
EP3166976B2 (en) 2014-07-09 2026-04-08 Birdie Biopharmaceuticals Inc. Anti-pd-l1 combinations for treating tumors
ES2916923T3 (en) 2014-07-11 2022-07-06 Ventana Med Syst Inc Anti-PD-L1 antibodies and diagnostic uses thereof
US9139648B1 (en) 2014-07-15 2015-09-22 Kymab Limited Precision medicine by targeting human NAV1.9 variants for treatment of pain
SG11201700074YA (en) 2014-07-15 2017-02-27 Genentech Inc Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors
CA2955612C (en) 2014-07-18 2022-05-17 Advaxis, Inc. Combination of a pd-1 antagonist and a listeria-based vaccine for treating prostate cancer
SG10201913765YA (en) 2014-07-21 2020-03-30 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
WO2016014530A1 (en) 2014-07-21 2016-01-28 Novartis Ag Combinations of low, immune enhancing. doses of mtor inhibitors and cars
US11542488B2 (en) 2014-07-21 2023-01-03 Novartis Ag Sortase synthesized chimeric antigen receptors
TWI750110B (en) 2014-07-21 2021-12-21 瑞士商諾華公司 Treatment of cancer using humanized anti- bcma chimeric antigen receptor
KR102524920B1 (en) 2014-07-22 2023-04-25 아폴로믹스 인코포레이티드 Anti-pd-1 antibodies
ES2781175T3 (en) 2014-07-31 2020-08-31 Novartis Ag Optimized subset of T cells containing a chimeric antigen receptor
US10435470B2 (en) * 2014-08-05 2019-10-08 Cb Therapeutics, Inc. Anti-PD-L1 antibodies
WO2016020836A1 (en) 2014-08-06 2016-02-11 Novartis Ag Quinolone derivatives as antibacterials
US9546206B2 (en) * 2014-08-08 2017-01-17 The Board Of Trustees Of The Leland Stanford Junior University High affinity PD-1 agents and methods of use
US10392444B2 (en) * 2014-08-08 2019-08-27 Oncoquest, Inc. Tumor antigen specific antibodies and TLR3 stimulation to enhance the performance of checkpoint interference therapy of cancer
JP6800141B2 (en) 2014-08-12 2020-12-16 マサチューセッツ インスティテュート オブ テクノロジー Synergistic tumor treatment with IL-2 and integrin-binding FC fusion protein
US20170224777A1 (en) 2014-08-12 2017-08-10 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2, a therapeutic antibody, and a cancer vaccine
CA2958200A1 (en) 2014-08-14 2016-02-18 Novartis Ag Treatment of cancer using a gfr alpha-4 chimeric antigen receptor
ES2791248T3 (en) 2014-08-19 2020-11-03 Novartis Ag Anti-CD123 chimeric antigen receptor (CAR) for use in cancer treatment
CA2955676A1 (en) 2014-08-25 2016-03-03 Pfizer Inc. Combination of a pd-1 antagonist and an alk inhibitor for treating cancer
HRP20190881T1 (en) 2014-08-28 2019-07-12 Halozyme, Inc. COMBINATION THERAPY WITH HYALURONAN-DEGRADING ENZYME AND IMMUNOLOGICAL CONTROL POINT INHIBITOR
WO2016030455A1 (en) * 2014-08-28 2016-03-03 Medimmune Limited Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small lung cancer
CN112587672A (en) 2014-09-01 2021-04-02 博笛生物科技有限公司 anti-PD-L1 conjugates for the treatment of tumors
US9535074B2 (en) 2014-09-08 2017-01-03 Merck Sharp & Dohme Corp. Immunoassay for soluble PD-L1
ES2771926T3 (en) 2014-09-13 2020-07-07 Novartis Ag Combination therapies
SMT202000562T1 (en) 2014-09-16 2020-11-10 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
KR20250067191A (en) 2014-09-17 2025-05-14 노파르티스 아게 Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
PT3262071T (en) 2014-09-23 2020-06-16 H Hoffnabb La Roche Ag Method of using anti-cd79b immunoconjugates
WO2016045732A1 (en) 2014-09-25 2016-03-31 Biontech Rna Pharmaceuticals Gmbh Stable formulations of lipids and liposomes
US10550194B2 (en) * 2014-09-30 2020-02-04 Intervet Inc. PD-L1 antibodies binding canine PD-L1
AU2015327868A1 (en) 2014-10-03 2017-04-20 Novartis Ag Combination therapies
KR20170068504A (en) 2014-10-08 2017-06-19 노파르티스 아게 Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
MA41044A (en) 2014-10-08 2017-08-15 Novartis Ag COMPOSITIONS AND METHODS OF USE FOR INCREASED IMMUNE RESPONSE AND CANCER TREATMENT
US9732119B2 (en) 2014-10-10 2017-08-15 Bristol-Myers Squibb Company Immunomodulators
JP6991857B2 (en) 2014-10-10 2022-01-13 イデラ ファーマシューティカルズ インコーポレイテッド Treatment of cancer with TLR9 agonists with checkpoint inhibitors
IL250579B2 (en) 2014-10-10 2023-05-01 Innate Pharma Cd73 blockade
TWI716362B (en) * 2014-10-14 2021-01-21 瑞士商諾華公司 Antibody molecules to pd-l1 and uses thereof
ES2753391T3 (en) 2014-10-14 2020-04-08 Halozyme Inc Adenosine deaminase 2 (ADA2) compositions, variants thereof and methods of use thereof
DK3209778T3 (en) 2014-10-24 2019-05-27 Astrazeneca COMBINATION
JP6882978B2 (en) 2014-10-29 2021-06-02 バイスクルアールディー・リミテッド Bicyclic peptide ligand specific for MT1-MMP
PT3212670T (en) 2014-10-29 2021-02-15 Bristol Myers Squibb Co Combination therapy for cancer
JP7372728B2 (en) 2014-10-31 2023-11-01 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Methods and compositions related to modified T cells
WO2016070051A2 (en) * 2014-10-31 2016-05-06 Oncomed Pharmaceuticals, Inc. Combination therapy for treatment of disease
MX2017005751A (en) 2014-11-03 2018-04-10 Genentech Inc Method and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment.
EP3215850B1 (en) 2014-11-03 2019-07-03 F. Hoffmann-La Roche AG Assays for detecting t cell immune subsets and methods of use thereof
UY36390A (en) 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
UY36391A (en) 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO1), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
MX2017005462A (en) 2014-11-05 2017-07-28 Flexus Biosciences Inc Immunoregulatory agents.
EP3215182B1 (en) 2014-11-05 2023-01-04 The Regents of The University of California Combination immunotherapy
US9856292B2 (en) 2014-11-14 2018-01-02 Bristol-Myers Squibb Company Immunomodulators
WO2016075670A1 (en) 2014-11-14 2016-05-19 Novartis Ag Antibody drug conjugates
MX2017006320A (en) 2014-11-17 2017-08-10 Genentech Inc Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists.
DK3221355T3 (en) 2014-11-20 2020-12-07 Hoffmann La Roche Combination therapy with T cell activating bispecific antigen binding molecules CD3 and folate receptor 1 (FolR1) as well as PD-1 axis binding antagonists
DK3220927T3 (en) 2014-11-20 2022-02-14 Promega Corp Systems and methods for assessing modulators of immune checkpoints
JP6668345B2 (en) 2014-11-21 2020-03-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Antibodies containing modified heavy chain constant regions
MY189836A (en) 2014-11-21 2022-03-11 Bristol Myers Squibb Co Antibodies against cd73 and uses thereof
MX385081B (en) 2014-11-25 2025-03-14 Bristol Myers Squibb Co METHODS AND COMPOSITIONS FOR 18F RADIO-LABELING OF BIOLOGICAL PRODUCTS.
ES2981335T3 (en) 2014-11-25 2024-10-08 Bristol Myers Squibb Co Novel PD-L1 binding polypeptides for imaging
US9763922B2 (en) 2014-11-27 2017-09-19 Genentech, Inc. Therapeutic compounds and uses thereof
US20180334490A1 (en) 2014-12-03 2018-11-22 Qilong H. Wu Methods for b cell preconditioning in car therapy
CN107249632A (en) 2014-12-04 2017-10-13 百时美施贵宝公司 Combination of anti-CS1 and anti-PD‑1 antibodies for the treatment of cancer (myeloma)
WO2016089830A1 (en) 2014-12-05 2016-06-09 Merck Sharp & Dohme Corp. Novel tricyclic compounds as inhibitors of mutant idh enzymes
EP3226690B1 (en) 2014-12-05 2020-05-20 Merck Sharp & Dohme Corp. Novel tricyclic compounds as inhibitors of mutant idh enzymes
US20160158360A1 (en) 2014-12-05 2016-06-09 Genentech, Inc. Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists
US10442819B2 (en) 2014-12-05 2019-10-15 Merck Sharp & Dohme Corp. Tricyclic compounds as inhibitors of mutant IDH enzymes
EP3230498B1 (en) 2014-12-09 2023-01-18 Merck Sharp & Dohme LLC System and methods for deriving gene signature biomarkers of response to pd-1 antagonists
HUE052606T2 (en) * 2014-12-09 2021-05-28 Regeneron Pharma Non-human animals having a humanized cluster of differentiation 274 gene
HRP20192009T1 (en) 2014-12-16 2020-02-07 Novartis Ag ISOXAZOLE HYDROXAMIC ACID COMPOUNDS AS LPXC INHIBITORS
US9861680B2 (en) 2014-12-18 2018-01-09 Bristol-Myers Squibb Company Immunomodulators
ES2948037T3 (en) 2014-12-18 2023-08-30 Amgen Inc Frozen Stable Herpes Simplex Virus Formulation
WO2016100882A1 (en) 2014-12-19 2016-06-23 Novartis Ag Combination therapies
US9944678B2 (en) 2014-12-19 2018-04-17 Bristol-Myers Squibb Company Immunomodulators
US10993997B2 (en) 2014-12-19 2021-05-04 The Broad Institute, Inc. Methods for profiling the t cell repertoire
US10975442B2 (en) 2014-12-19 2021-04-13 Massachusetts Institute Of Technology Molecular biomarkers for cancer immunotherapy
TW201630907A (en) 2014-12-22 2016-09-01 必治妥美雅史谷比公司 TGF[beta]R antagonists
CN107207594B (en) 2014-12-23 2019-05-07 百时美施贵宝公司 Antibodies against TIGIT
DK3240801T3 (en) 2014-12-31 2021-02-08 Checkmate Pharmaceuticals Inc COMBINATION TUMOR IMMUNERAPY
GB201500319D0 (en) 2015-01-09 2015-02-25 Agency Science Tech & Res Anti-PD-L1 antibodies
JP6676058B2 (en) 2015-01-14 2020-04-08 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using
MA41414A (en) 2015-01-28 2017-12-05 Centre Nat Rech Scient ICOS AGONIST BINDING PROTEINS
HK1247861A1 (en) 2015-01-30 2018-10-05 President And Fellows Of Harvard College Peritumoral and intratumoral materials for cancer therapy
US10828353B2 (en) * 2015-01-31 2020-11-10 The Trustees Of The University Of Pennsylvania Compositions and methods for T cell delivery of therapeutic molecules
US11161907B2 (en) 2015-02-02 2021-11-02 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
MA41460A (en) 2015-02-03 2017-12-12 Oncomed Pharm Inc TNFRSF LIAISON AGENTS AND THEIR USES
US20160222060A1 (en) 2015-02-04 2016-08-04 Bristol-Myers Squibb Company Immunomodulators
MX2017010072A (en) * 2015-02-05 2017-11-09 Molecular Templates Inc Multivalent cd20-binding molecules comprising shiga toxin a subunit effector regions and enriched compositions thereof.
US10983128B2 (en) 2015-02-05 2021-04-20 Bristol-Myers Squibb Company CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy
WO2016128060A1 (en) 2015-02-12 2016-08-18 Biontech Ag Predicting t cell epitopes useful for vaccination
MX373169B (en) 2015-02-20 2020-04-24 Incyte Holdings Corp Bicyclic heterocycles as fgfr inhibitors
MA41551A (en) 2015-02-20 2017-12-26 Incyte Corp BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS
NZ733854A (en) * 2015-02-26 2022-07-01 Merck Patent Gmbh Pd-1 / pd-l1 inhibitors for the treatment of cancer
RU2742312C1 (en) * 2015-02-26 2021-02-04 Мерк Патент Гмбх Pd-1/pd-l1 inhibitors for treating cancer
ES2789331T3 (en) 2015-03-02 2020-10-26 Rigel Pharmaceuticals Inc TGF-beta inhibitors
CA2978311A1 (en) 2015-03-04 2016-09-09 Merck Sharp & Dohme Corp. Combination of a pd-1 antagonist and eribulin for treating cancer
KR102662228B1 (en) 2015-03-04 2024-05-02 머크 샤프 앤드 돔 코포레이션 Combination of PD-1 antagonists and VEGFR/FGFR/RET tyrosine kinase inhibitors to treat cancer
HK1249051A1 (en) 2015-03-06 2018-10-26 BeyondSpring Pharmaceuticals Inc. Method of treating a brain tumor
MX383691B (en) 2015-03-06 2025-03-14 Beyondspring Pharmaceuticals Inc TREATMENT METHOD FOR CANCER ASSOCIATED WITH A RAS MUTATION.
US20180044429A1 (en) 2015-03-09 2018-02-15 Celldex Therapeutics, Inc. Cd27 agonists
HK1248603A1 (en) 2015-03-10 2018-10-19 Aduro Biotech, Inc. Compositions and methods for activating "stimulator of interferon gene" -dependent signalling
EP3067062A1 (en) 2015-03-13 2016-09-14 Ipsen Pharma S.A.S. Combination of tasquinimod or a pharmaceutically acceptable salt thereof and a pd1 and/or pdl1 inhibitor, for use as a medicament
CN108112254B (en) 2015-03-13 2022-01-28 西托姆克斯治疗公司 anti-PDL 1 antibodies, activatable anti-PDL 1 antibodies, and methods of use thereof
US9809625B2 (en) 2015-03-18 2017-11-07 Bristol-Myers Squibb Company Immunomodulators
PT3274370T (en) 2015-03-23 2020-01-30 Bayer Pharma AG ANTI-CEACAM6 ANTIBODIES AND USES OF THE SAME
KR20170134980A (en) 2015-04-03 2017-12-07 브리스톨-마이어스 스큅 컴퍼니 Inhibitor of indoleamine-2,3-dioxygenase for the treatment of cancer
US10478494B2 (en) 2015-04-03 2019-11-19 Astex Therapeutics Ltd FGFR/PD-1 combination therapy for the treatment of cancer
EP3770171A1 (en) 2015-04-03 2021-01-27 XOMA Technology Ltd. Treatment of cancer using inhibitors of tgf-beta and pd-1
AU2016246695A1 (en) 2015-04-07 2017-10-26 Genentech, Inc. Antigen binding complex having agonistic activity and methods of use
US20180140602A1 (en) 2015-04-07 2018-05-24 Novartis Ag Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
CN107708733B (en) 2015-04-07 2022-11-15 艾利妥 Anti-sortilin antibodies and methods of use thereof
TW201642897A (en) 2015-04-08 2016-12-16 Ｆ 星生物科技有限公司 HER2 binding agent therapies
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
WO2016168133A1 (en) 2015-04-17 2016-10-20 Merck Sharp & Dohme Corp. Blood-based biomarkers of tumor sensitivity to pd-1 antagonists
SG11201708516YA (en) 2015-04-17 2017-11-29 David Maxwell Barrett Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
TN2017000440A1 (en) 2015-04-17 2019-04-12 Bristol Myers Squibb Co Compositions comprising a combination of an anti-pd-1 antibody and another antibody
EP3286211A1 (en) 2015-04-23 2018-02-28 Novartis AG Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
US20160362489A1 (en) 2015-04-28 2016-12-15 Bristol-Myers Squibb Company Treatment of PD-L1-Positive Melanoma Using an Anti-PD-1 Antibody
EP3288982A1 (en) 2015-04-28 2018-03-07 Bristol-Myers Squibb Company Treatment of pd-l1-negative melanoma using an anti-pd-1 antibody and an anti-ctla-4 antibody
EP3294736B1 (en) 2015-05-11 2020-07-22 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
US9725449B2 (en) 2015-05-12 2017-08-08 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
EP3307740B1 (en) 2015-05-12 2019-12-18 Bristol-Myers Squibb Company 5h-pyrido[3,2-b]indole compounds as anticancer agents
RS61152B2 (en) 2015-05-12 2024-06-28 Hoffmann La Roche Therapeutic and diagnostic methods for cancer
ES2739749T3 (en) 2015-05-18 2020-02-03 Tolero Pharmaceuticals Inc Alvocidib prodrugs that have increased bioavailability
EA201792573A1 (en) 2015-05-21 2018-04-30 Харпун Терапьютикс, Инк. TRISPECIFIC RELATED PROTEINS AND METHODS OF THEIR APPLICATION
HK1252245A1 (en) 2015-05-27 2019-05-24 Idenix Pharmaceuticals Llc Nucleotides for the treatment of cancer
WO2016191751A1 (en) 2015-05-28 2016-12-01 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
EP3763827A1 (en) 2015-05-29 2021-01-13 F. Hoffmann-La Roche AG Pd-l1 promoter methylation in cancer
JP7144935B2 (en) 2015-05-29 2022-09-30 ジェネンテック， インコーポレイテッド Therapeutic and diagnostic methods for cancer
TN2019000101A1 (en) 2015-05-29 2020-07-15 Bristol Myers Squibb Co Antibodies against ox40 and uses thereof.
US11078278B2 (en) 2015-05-29 2021-08-03 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
MA44594B1 (en) 2015-05-29 2020-09-30 Memorial Sloan Kettering Cancer Center Anti-ctla-4 Antibodies and Methods of Use thereof
US10751412B2 (en) 2015-05-29 2020-08-25 Merck Sharp & Dohme Corp. Combination of a PD-1 antagonist and CPG-C type oligonucleotide for treating cancer
AU2016271124C1 (en) 2015-05-30 2020-05-14 Molecular Templates, Inc. De-immunized, Shiga toxin a subunit scaffolds and cell-targeting molecules comprising the same
EP3302467A4 (en) 2015-05-31 2019-01-02 Curegenix Corporation Combination compositions for immunotherapy
MX2017015618A (en) 2015-06-03 2018-08-15 Boston Biomedical Inc Compositions comprising a cancer stemness inhibitor and an immunotherapeutic agent for use in treating cancer.
KR20180011839A (en) 2015-06-08 2018-02-02 제넨테크, 인크. Treatment of Cancer Using Anti-OX40 Antibody
HK1251474A1 (en) 2015-06-08 2019-02-01 豪夫迈‧罗氏有限公司 Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
WO2016197367A1 (en) 2015-06-11 2016-12-15 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
TWI870335B (en) 2015-06-12 2025-01-21 美商宏觀基因股份有限公司 Variant chimeric 4d5 antibodies and uses thereof in combination with anti-pd-1 antibodies for the treatment of cancer
EP3307778A1 (en) 2015-06-12 2018-04-18 Bristol-Myers Squibb Company Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways
PH12017501857B1 (en) 2015-06-16 2024-01-17 Merck Patent Gmbh Pd-l1 antagonist combination treatments
EP3310813A1 (en) 2015-06-17 2018-04-25 Novartis AG Antibody drug conjugates
JP6896650B2 (en) 2015-06-17 2021-06-30 ジェネンテック， インコーポレイテッド Treatment of Locally Advanced or Metastatic Breast Cancer Using PD-1 Axle Antagonists and Taxanes
AU2016285920A1 (en) 2015-06-29 2018-02-01 Bristol-Myers Squibb Company Antibodies to CD40 with enhanced agonist activity
EP3316888A1 (en) 2015-07-02 2018-05-09 Celgene Corporation Combination therapy for treatment of hematological cancers and solid tumors
AU2016287585B2 (en) 2015-07-02 2020-12-17 Otsuka Pharmaceutical Co., Ltd. Lyophilized pharmaceutical compositions
GB201511790D0 (en) 2015-07-06 2015-08-19 Iomet Pharma Ltd Pharmaceutical compound
US10155748B2 (en) 2015-07-13 2018-12-18 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
JP2018522887A (en) 2015-07-14 2018-08-16 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Cancer treatment using immune checkpoint inhibitors
IL274572B2 (en) 2015-07-16 2024-01-01 Biolinerx Ltd Preparations and methods for the treatment of cancer
CN116059219A (en) 2015-07-16 2023-05-05 比奥克斯塞尔医疗股份有限公司 Novel method for treating cancer using immunomodulation
AU2016297014B2 (en) 2015-07-21 2021-06-17 Novartis Ag Methods for improving the efficacy and expansion of immune cells
CN108137597A (en) 2015-07-28 2018-06-08 百时美施贵宝公司 Tgf beta receptor antagonists
US20180222982A1 (en) 2015-07-29 2018-08-09 Novartis Ag Combination therapies comprising antibody molecules to pd-1
JP2018523652A (en) 2015-07-29 2018-08-23 ノバルティス アーゲー Combination of PD-1 antagonist and EGFR inhibitor
DK3317301T3 (en) 2015-07-29 2021-06-28 Immutep Sas COMBINATION THERAPIES INCLUDING ANTIBODY MOLECULES AGAINST LAYER-3
EP3878465A1 (en) 2015-07-29 2021-09-15 Novartis AG Combination therapies comprising antibody molecules to tim-3
WO2017019846A1 (en) 2015-07-30 2017-02-02 Macrogenics, Inc. Pd-1-binding molecules and methods use thereof
CN106397592A (en) * 2015-07-31 2017-02-15 苏州康宁杰瑞生物科技有限公司 Single-domain antibody directed at programmed death ligand (PD-L1) and derived protein thereof
WO2017020291A1 (en) 2015-08-06 2017-02-09 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
EP3331919A1 (en) 2015-08-07 2018-06-13 GlaxoSmithKline Intellectual Property Development Limited Combination therapy comprising anti ctla-4 antibodies
WO2017025498A1 (en) 2015-08-07 2017-02-16 Pieris Pharmaceuticals Gmbh Novel fusion polypeptide specific for lag-3 and pd-1
KR102055396B1 (en) 2015-08-11 2019-12-12 우시 바이올로직스 (케이만) 인코포레이티드 Novel Anti-PD-1 Antibodies
CR20180101A (en) 2015-08-13 2018-04-12 Merck Sharp & Dohme DI-NUCLEOTIC CYCLIC COMPOUNDS AS STING AGONISTS
US11453697B1 (en) 2015-08-13 2022-09-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
AR105654A1 (en) 2015-08-24 2017-10-25 Lilly Co Eli ANTIBODIES PD-L1 (LINKING 1 OF PROGRAMMED CELL DEATH)
WO2017035118A1 (en) 2015-08-25 2017-03-02 Bristol-Myers Squibb Company Tgf beta receptor antagonists
WO2017032867A1 (en) 2015-08-27 2017-03-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from a lung cancer
JP6905163B2 (en) 2015-09-03 2021-07-21 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Biomarkers that predict cytokine release syndrome
MX394957B (en) 2015-09-03 2025-03-24 Ono Pharmaceutical Co AGENT FOR ENHANCING IMMUNITY TO CANCER BY USING Allergin-1 ANTAGONIST
WO2017040990A1 (en) 2015-09-03 2017-03-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
EP4585268A3 (en) 2015-09-14 2025-10-15 Twelve Therapeutics, Inc. Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same
ES2980794T3 (en) 2015-09-15 2024-10-03 Acerta Pharma Bv Therapeutic combinations of a CD19 inhibitor and a BTK inhibitor
WO2017055321A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of fibroblasts in a tissue sample
WO2017055324A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of cells of monocytic origin in a tissue sample
WO2017055326A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of myeloid dendritic cells in a tissue sample
WO2017055322A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of neutrophils in a tissue sample
WO2017055325A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of nk cells in a tissue sample
WO2017055320A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of cytotoxic lymphocytes in a tissue sample
WO2017055327A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of endothelial cells in a tissue sample
WO2017055319A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of b cells in a tissue sample
WO2017055484A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for determining the metabolic status of lymphomas
CA3000386A1 (en) 2015-09-30 2017-04-06 Merck Patent Gmbh Combination of a pd-1 axis binding antagonist and an alk inhibitor for treating alk-negative cancer
EP3355875B1 (en) 2015-10-01 2021-09-29 Gilead Sciences, Inc. Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers
NZ739090A (en) 2015-10-02 2025-06-27 Hoffmann La Roche Bispecific antibodies specific for pd1 and tim3
CR20180151A (en) 2015-10-02 2018-05-25 Hoffmann La Roche ANTI-PD1 ANTIBODIES AND METHODS OF USE
WO2017059902A1 (en) 2015-10-07 2017-04-13 Biontech Rna Pharmaceuticals Gmbh 3' utr sequences for stabilization of rna
CN108136010A (en) 2015-10-08 2018-06-08 宏观基因有限公司 For the conjoint therapy for the treatment of cancer
WO2017060397A1 (en) 2015-10-09 2017-04-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of subjects suffering from melanoma metastases
US11130817B2 (en) 2015-10-12 2021-09-28 Innate Pharma CD73 blocking agents
JP6954648B2 (en) 2015-10-19 2021-10-27 シージー オンコロジー， インコーポレイテッド Treatment of solid tumors or lymphoid tumors with combination therapy
US10149887B2 (en) 2015-10-23 2018-12-11 Canbas Co., Ltd. Peptides and peptidomimetics in combination with t cell activating and/or checkpoint inhibiting agents for cancer treatment
TN2018000112A1 (en) 2015-10-29 2019-10-04 Novartis Ag Antibody conjugates comprising toll-like receptor agonist
EP3370768B9 (en) 2015-11-03 2022-03-16 Janssen Biotech, Inc. Antibodies specifically binding pd-1 and their uses
US11702477B2 (en) 2015-11-06 2023-07-18 Orionis Biosciences BV Bi-functional chimeric proteins and uses thereof
WO2017087280A1 (en) 2015-11-16 2017-05-26 Genentech, Inc. Methods of treating her2-positive cancer
CN109608544B (en) * 2015-11-17 2022-09-16 苏州盛迪亚生物医药有限公司 PD-L1 antibody, antigen binding fragment thereof and medical application thereof
MA43260A (en) 2015-11-18 2018-09-26 Merck Sharp & Dohme BINDERS PD1 AND / OR LAG3
HRP20250902T1 (en) 2015-11-18 2025-09-26 Bristol-Myers Squibb Company TREATMENT OF LUNG CANCER USING A COMBINATION OF ANTI‑PD‑1 ANTIBODIES AND ANTI‑CTLA‑4 ANTIBODIES
CN121154828A (en) 2015-11-19 2025-12-19 豪夫迈·罗氏有限公司 Methods of treating cancer using B-RAF inhibitors and immune checkpoint inhibitors
BR112018010172A2 (en) 2015-11-19 2018-11-21 Bristol Myers Squibb Co antibodies to glucocorticoid-induced tumor necrosis factor receptor (gitr) and their uses
EP4015537A1 (en) 2015-12-01 2022-06-22 GlaxoSmithKline Intellectual Property Development Limited Combination treatments and uses and methods thereof
TWI704154B (en) 2015-12-03 2020-09-11 英商葛蘭素史克智慧財產發展有限公司 Novel compounds
WO2017098421A1 (en) 2015-12-08 2017-06-15 Glaxosmithkline Intellectual Property Development Limited Benzothiadiazine compounds
EP4026848A1 (en) 2015-12-09 2022-07-13 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing the cytokine release syndrome
EP3178848A1 (en) 2015-12-09 2017-06-14 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies
US10954301B2 (en) 2015-12-14 2021-03-23 Macrogenics, Inc. Bispecific molecules having immunoreactivity with PD-1 and CTLA-4, and methods of use thereof
US10538497B2 (en) 2015-12-15 2020-01-21 Merck Sharp & Dohme Corp. Compounds as indoleamine 2,3-dioxygenase inhibitors
FI3389699T3 (en) 2015-12-15 2024-05-28 Oncoc4 Inc CHIMERIC AND HUMANIZED HUMAN MONOCLONAL CTLA4 ANTIBODIES AND USES THEREOF
KR102738306B1 (en) 2015-12-15 2024-12-03 브리스톨-마이어스 스큅 컴퍼니 CXCR4 receptor antagonist
WO2017106656A1 (en) 2015-12-17 2017-06-22 Novartis Ag Antibody molecules to pd-1 and uses thereof
GB201522309D0 (en) 2015-12-17 2016-02-03 Photocure Asa Use
EP3390454B1 (en) 2015-12-17 2026-02-04 University of Maryland, Baltimore County A recombinant bi-specific polypeptide for coordinately activating tumor-reactive t-cells and neutralizing immune suppression
US10392442B2 (en) 2015-12-17 2019-08-27 Bristol-Myers Squibb Company Use of anti-PD-1 antibody in combination with anti-CD27 antibody in cancer treatment
ES2916874T3 (en) 2015-12-17 2022-07-06 Incyte Corp N-phenyl-pyridine-2-carboxamide derivatives and their use as modulators of the PD-1/PD-L1 protein/protein interaction
EP3389711A1 (en) 2015-12-18 2018-10-24 Novartis AG Antibodies targeting cd32b and methods of use thereof
WO2017106630A1 (en) 2015-12-18 2017-06-22 The General Hospital Corporation Polyacetal polymers, conjugates, particles and uses thereof
AU2016377371A1 (en) 2015-12-21 2018-08-09 Bristol-Myers Squibb Company Variant antibodies for site-specific conjugation
JP7126941B2 (en) 2015-12-22 2022-08-29 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Combination of anti-PD-1 antibody and bispecific anti-CD20/anti-CD3 antibody for treating cancer
AU2016379372A1 (en) 2015-12-22 2018-08-02 Incyte Corporation Heterocyclic compounds as immunomodulators
EP3393504B1 (en) 2015-12-22 2025-09-24 Novartis AG Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy
RS63135B1 (en) 2015-12-23 2022-05-31 Modernatx Inc Methods of using ox40 ligand encoding polynucleotides
CN105461808B (en) * 2015-12-24 2019-03-19 长春金赛药业股份有限公司 Monoclonal antibody and its application
WO2017118634A1 (en) 2016-01-04 2017-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma
CN106939047B (en) 2016-01-04 2021-08-31 江苏怀瑜药业有限公司 PD-L1 antibody and preparation method thereof
CN106943596A (en) 2016-01-07 2017-07-14 博笛生物科技（北京）有限公司 Anti-CD20 Combinations for Treating Tumors
CN115350279A (en) 2016-01-07 2022-11-18 博笛生物科技有限公司 anti-HER 2 combinations for the treatment of tumors
CN115252792A (en) 2016-01-07 2022-11-01 博笛生物科技有限公司 anti-EGFR combinations for the treatment of tumors
JP6949030B2 (en) 2016-01-08 2021-10-13 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト Treatment of CEA-Positive Cancer Using PD-1 Axial Binding Antagonists and Anti-CEA / Anti-CD3 Bispecific Antibodies
EP3399981B1 (en) 2016-01-08 2023-08-02 Celgene Corporation Solid forms of 2-(4-chlorophenyl)-n-((2-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses
CN108430473B (en) 2016-01-08 2021-08-31 细胞基因公司 Antiproliferative compounds and pharmaceutical compositions and uses thereof
WO2017120437A1 (en) 2016-01-08 2017-07-13 Celgene Corporation Formulations of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide
HUE052893T2 (en) 2016-01-13 2021-05-28 Acerta Pharma Bv Therapeutic combinations of an antifolate and a btk inhibitor
CA3012055A1 (en) 2016-01-21 2017-07-27 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
WO2017125815A2 (en) * 2016-01-22 2017-07-27 MabQuest SA Immunological reagents
TWI736575B (en) 2016-01-22 2021-08-21 美商默沙東藥廠 Anti-coagulation factor xi antibodies
WO2017129790A1 (en) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of cancer
WO2017129763A1 (en) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer
JP6902040B2 (en) 2016-01-28 2021-07-14 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル How to Increase the Efficacy of Immune Checkpoint Inhibitors
US11001631B2 (en) 2016-02-05 2021-05-11 Orionis Biosciences BV Clec9A binding agents
RU2767329C2 (en) 2016-02-06 2022-03-17 Эпимаб Биотерапьютикс, Инк. Immunoglobulin with tandem fab- fragments and its application options
WO2017139231A1 (en) 2016-02-08 2017-08-17 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
US20200270265A1 (en) 2016-02-19 2020-08-27 Novartis Ag Tetracyclic pyridone compounds as antivirals
KR20190003938A (en) * 2016-02-25 2019-01-10 셀 메디카 스위처란트 아게 Modified cells for immunotherapy
US20230183346A1 (en) 2016-02-26 2023-06-15 Inserm (Institut National De La Sante Et De La Recherche Medicale) Antibodies having specificity for btla and uses thereof
JP6821693B2 (en) 2016-02-29 2021-01-27 ジェネンテック， インコーポレイテッド Treatment and diagnosis for cancer
CA3015913A1 (en) 2016-02-29 2017-09-08 Foundation Medicine, Inc. Methods of treating cancer
AU2017225733A1 (en) 2016-03-04 2018-09-27 Novartis Ag Cells expressing multiple chimeric antigen receptor (CAR) molecules and uses therefore
US10143746B2 (en) 2016-03-04 2018-12-04 Bristol-Myers Squibb Company Immunomodulators
KR20230038311A (en) 2016-03-04 2023-03-17 브리스톨-마이어스 스큅 컴퍼니 Combination therapy with anti-cd73 antibodies
JP6432121B2 (en) 2016-03-04 2018-12-05 シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド PDL-1 antibody, pharmaceutical composition thereof and use thereof
WO2017155981A1 (en) 2016-03-07 2017-09-14 Massachusetts Institute Of Technology Protein-chaperoned t-cell vaccines
WO2017153433A1 (en) 2016-03-08 2017-09-14 Innate Pharma Siglec neutralizing antibodies
PL3426271T3 (en) 2016-03-10 2025-11-24 Cg Oncology, Inc. METHODS OF TREATMENT OF SOLID TUMORS WITH COMBINATION THERAPY
WO2017153952A1 (en) 2016-03-10 2017-09-14 Glaxosmithkline Intellectual Property Development Limited 5-sulfamoyl-2-hydroxybenzamide derivatives
WO2017160599A1 (en) 2016-03-14 2017-09-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of cd300b antagonists to treat sepsis and septic shock
CN116196412A (en) 2016-03-15 2023-06-02 中外制药株式会社 Methods of treating cancer using PD-1 axis binding antagonists and anti-GPC 3 antibodies
CN109310885B (en) 2016-03-15 2022-05-31 梅尔莎纳医疗公司 NaPi2b targeting antibody-drug conjugates and methods of use thereof
US11549099B2 (en) 2016-03-23 2023-01-10 Novartis Ag Cell secreted minibodies and uses thereof
CN108779180B (en) * 2016-03-23 2020-10-16 迈博斯生物医药(苏州)有限公司 Novel anti-PD-L1 antibodies
MA44483A (en) 2016-03-24 2019-01-30 Millennium Pharm Inc METHODS FOR TREATING GASTROINTESTINAL ADVERSE EVENTS OF IMMUNE ORIGIN IN ONCOLOGICAL IMMUNE TREATMENTS
WO2017165742A1 (en) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Methods of treating gastrointestinal immune-related adverse events in anti-ctla4 anti-pd-1 combination treatments
US9988416B2 (en) 2016-03-24 2018-06-05 Novartis Ag Alkynyl nucleoside analogs as inhibitors of human rhinovirus
US11542332B2 (en) 2016-03-26 2023-01-03 Bioatla, Inc. Anti-CTLA4 antibodies, antibody fragments, their immunoconjugates and uses thereof
WO2017172981A2 (en) 2016-03-29 2017-10-05 University Of Southern California Chimeric antigen receptors targeting cancer
WO2017167921A1 (en) 2016-03-30 2017-10-05 Centre Léon-Bérard Lymphocytes expressing cd73 in cancerous patient dictates therapy
WO2017173334A1 (en) 2016-04-01 2017-10-05 Checkmate Pharmaceuticals, Inc. Fc receptor-mediated drug delivery
WO2017176925A1 (en) 2016-04-05 2017-10-12 Bristol-Myers Squibb Company Cytokine profiling analysis for predicting prognosis of a patient in need of an anti-cancer treatment
US10358463B2 (en) 2016-04-05 2019-07-23 Bristol-Myers Squibb Company Immunomodulators
HRP20220936T1 (en) 2016-04-07 2022-10-28 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
JP2019510802A (en) 2016-04-07 2019-04-18 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Heterocyclic amides useful as protein modulators
AU2017248354A1 (en) 2016-04-08 2018-10-04 Gilead Sciences, Inc. Compositions and methods for treating cancer, inflammatory diseases and autoimmune diseases
ES2881801T3 (en) 2016-04-12 2021-11-30 Lilly Co Eli Combination therapy with Notch and CDK4 / 6 inhibitors for use in the treatment of lung cancer
WO2017180385A1 (en) 2016-04-12 2017-10-19 Eli Lilly And Company Combination therapy with notch and pi3k/mtor inhibitors for use in treating cancer
JP7038353B2 (en) 2016-04-13 2022-03-18 ヴィヴィア バイオテック，エス．エル Exvivo BITE-activated T cells
KR102466763B1 (en) 2016-04-13 2022-11-11 오리맵스 리미티드 Anti-PSMA Antibodies and Uses Thereof
RS66062B1 (en) 2016-04-14 2024-11-29 Ose Immunotherapeutics New anti-sirpa antibodies and their therapeutic applications
AU2017248766A1 (en) 2016-04-15 2018-11-01 Genentech, Inc. Methods for monitoring and treating cancer
CN109154613A (en) 2016-04-15 2019-01-04 豪夫迈·罗氏有限公司 For monitoring and the method for the treatment of cancer
US12297266B2 (en) 2016-04-18 2025-05-13 Celldex Therapeutics, Inc. Agonistic antibodies that bind human CD40 and uses thereof
US12029724B2 (en) 2016-04-28 2024-07-09 Eisai R&D Management Co., Ltd. Method for inhibiting tumor growth
EP4014967A1 (en) 2016-04-29 2022-06-22 Icahn School of Medicine at Mount Sinai Targeting the innate immunesystem to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis
WO2017192874A1 (en) 2016-05-04 2017-11-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Albumin-binding immunomodulatory compositions and methods of use thereof
CN109414420A (en) 2016-05-04 2019-03-01 百时美施贵宝公司 The inhibitor and its application method of indole amine 2,3-dioxygenase
US11066383B2 (en) 2016-05-04 2021-07-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
JP2019516682A (en) 2016-05-04 2019-06-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Indoleamine 2,3-dioxygenase inhibitors and methods of use thereof
JP2019516681A (en) 2016-05-04 2019-06-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Indoleamine 2,3-dioxygenase inhibitors and methods of use thereof
US10696648B2 (en) 2016-05-04 2020-06-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CA3023157A1 (en) 2016-05-05 2017-11-09 Glaxosmithkline Intellectual Property (No.2) Limited Enhancer of zeste homolog 2 inhibitors
KR20190005924A (en) 2016-05-10 2019-01-16 브리스톨-마이어스 스큅 컴퍼니 Antibody-drug conjugates of tuburicin analogs with improved stability
WO2017194783A1 (en) 2016-05-13 2017-11-16 Orionis Biosciences Nv Targeted mutant interferon-beta and uses thereof
EP3243832A1 (en) 2016-05-13 2017-11-15 F. Hoffmann-La Roche AG Antigen binding molecules comprising a tnf family ligand trimer and pd1 binding moiety
TWI755395B (en) 2016-05-13 2022-02-21 美商再生元醫藥公司 Combination of anti-pd-1 antibodies and radiation to treat cancer
CN109563141A (en) 2016-05-13 2019-04-02 奥里尼斯生物科学公司 To the therapeutic targeting of cellular structures
EP3458474B1 (en) 2016-05-18 2022-07-06 ModernaTX, Inc. Combinations of mrnas encoding immune modulating polypeptides and uses thereof
WO2017201281A1 (en) 2016-05-18 2017-11-23 Mayo Foundation For Medical Education And Research Targeting pd-l1 on tumor cells
KR102469450B1 (en) 2016-05-18 2022-11-22 모더나티엑스, 인크. Polynucleotides Encoding Interleukin-12 (IL12) and Uses Thereof
CN105968200B (en) * 2016-05-20 2019-03-15 瑞阳(苏州)生物科技有限公司 Anti-human PD-L1 humanized monoclonal antibody and its application
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
MA45025A (en) 2016-05-20 2019-03-27 Lilly Co Eli COMBINATION TREATMENT USING NOTCH AND PD-1 OR PD-L1 INHIBITORS
JP7101621B2 (en) 2016-05-20 2022-07-15 ハープーン セラピューティクス，インク． Single domain serum albumin binding protein
WO2017201502A1 (en) 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of glutamate modulating agents with immunotherapies to treat cancer
MA45122A (en) 2016-05-24 2019-04-10 Constellation Pharmaceuticals Inc CBP / EP300 HETEROCYCLIC INHIBITORS AND THEIR USE IN CANCER TREATMENT
EP3464286B1 (en) 2016-05-24 2021-08-18 Genentech, Inc. Pyrazolopyridine derivatives for the treatment of cancer
EP3463452A1 (en) 2016-05-24 2019-04-10 Institut National de la Sante et de la Recherche Medicale (INSERM) Methods and pharmaceutical compositions for the treatment of non small cell lung cancer (nsclc) that coexists with chronic obstructive pulmonary disease (copd)
CN109689089A (en) 2016-05-25 2019-04-26 国家医疗保健研究所 methods and compositions for treating cancer
TWI781934B (en) 2016-05-27 2022-11-01 美商艾吉納斯公司 Anti-tim-3 antibodies and methods of use thereof
US10994033B2 (en) 2016-06-01 2021-05-04 Bristol-Myers Squibb Company Imaging methods using 18F-radiolabeled biologics
US11344639B2 (en) 2016-06-01 2022-05-31 Bristol-Myers Squibb Company PET imaging with PD-L1 binding polypeptides
WO2017207814A1 (en) 2016-06-02 2017-12-07 Ultimovacs As A vaccine in combination with an immune checkpoint inhibitor for use in treating cancer
EP3252078A1 (en) 2016-06-02 2017-12-06 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
TW201902512A (en) 2016-06-02 2019-01-16 瑞士商赫孚孟拉羅股份公司 treatment method
LT3463457T (en) 2016-06-02 2023-09-11 Bristol-Myers Squibb Company Pd-1 blockade with nivolumab in refractory hodgkin's lymphoma
US11299543B2 (en) * 2016-06-02 2022-04-12 Bristol-Myers Squibb Company Use of an anti-PD-1 antibody in combination with an anti-CD30 antibody in cancer treatment
WO2017210637A1 (en) 2016-06-03 2017-12-07 Bristol-Myers Squibb Company Use of anti-pd-1 antibody in the treatment of patients with colorectal cancer
WO2017210624A1 (en) 2016-06-03 2017-12-07 Bristol-Myers Squibb Company Anti-pd-1 antibody for use in a method of treating a tumor
WO2017210631A1 (en) 2016-06-03 2017-12-07 Bristol-Myers Squibb Company Anti-pd-1 antibody for use in a method of treatment of recurrent small cell lung cancer
RU2760348C2 (en) 2016-06-06 2021-11-24 Бейондспринг Фармасьютикалс, Инк. Method for reducing neutropenia
KR20190015492A (en) 2016-06-08 2019-02-13 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 Chemical compound
US20190298705A1 (en) 2016-06-08 2019-10-03 Glaxosmithkline Intellectual Property Development Limited Chemical Compounds
CN108350082B (en) * 2016-06-13 2021-09-24 天境生物科技(上海)有限公司 PD-L1 antibody and its use
CN107488229B (en) * 2016-06-13 2020-11-17 天境生物科技(上海)有限公司 PD-L1 antibodies and uses thereof
JP7185530B2 (en) 2016-06-13 2022-12-07 トルク セラピューティクス， インコーポレイテッド Methods and compositions for promoting immune cell function
IL263272B2 (en) 2016-06-14 2025-07-01 Merck Sharp & Dohme Anti-coagulation factor xi antibodies
SG11201810656WA (en) 2016-06-14 2018-12-28 Novartis Ag Crystalline form of (r)-4-(5-(cyclopropylethynyl)isoxazol-3-yl)-n-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as an antibacterial agent
WO2017216685A1 (en) 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2017216686A1 (en) 2016-06-16 2017-12-21 Novartis Ag 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals
BR112018076534A2 (en) 2016-06-20 2019-04-02 Incyte Corporation heterocyclic compounds as immunomodulators
WO2018029474A2 (en) 2016-08-09 2018-02-15 Kymab Limited Anti-icos antibodies
KR20190022632A (en) 2016-06-20 2019-03-06 에프-스타 베타 리미티드 LAG-3 binding member
US9567399B1 (en) 2016-06-20 2017-02-14 Kymab Limited Antibodies and immunocytokines
KR102664891B1 (en) * 2016-06-20 2024-05-13 에프-스타 테라퓨틱스 리미티드 Binding molecules binding pd-l1 and lag-3
KR102379464B1 (en) 2016-06-20 2022-03-29 키맵 리미티드 anti-PD-L1 antibody
JP7267014B2 (en) 2016-06-21 2023-05-01 アイオー バイオテック エーピーエス PDL1 peptides for use in cancer vaccines
RU2754507C2 (en) 2016-06-24 2021-09-02 Инфинити Фармасьютикалз, Инк. Combination therapy
FI3478723T3 (en) 2016-06-29 2026-03-17 Checkpoint Therapeutics Inc Pd-l1-specific antibodies and methods of using the same
RU2021127872A (en) 2016-06-30 2021-11-09 Онкорус, Инк. DELIVERY OF THERAPEUTIC POLYPEPTIDES THROUGH PSEUDOTYPED ONCOLYTIC VIRUSES
WO2018009466A1 (en) 2016-07-05 2018-01-11 Aduro Biotech, Inc. Locked nucleic acid cyclic dinucleotide compounds and uses thereof
US10864203B2 (en) 2016-07-05 2020-12-15 Beigene, Ltd. Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer
CN109843921B (en) 2016-07-07 2023-05-26 艾欧凡斯生物治疗公司 Programmed death 1 ligand 1 (PD-L1) binding protein and application method thereof
WO2018011166A2 (en) 2016-07-12 2018-01-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of myeloid dendritic cells in a tissue sample
MY200602A (en) 2016-07-14 2024-01-04 Bristol Myers Squibb Co Antibodies against tim3 and uses thereof
GB201612520D0 (en) 2016-07-19 2016-08-31 F-Star Beta Ltd Binding molecules
EP3487878A4 (en) 2016-07-20 2020-03-25 University of Utah Research Foundation CAR-T CD229 LYMPHOCYTES AND METHODS OF USE
JP2019521166A (en) 2016-07-20 2019-07-25 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Isoquinoline derivatives as PERK inhibitors
WO2018017633A1 (en) 2016-07-21 2018-01-25 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS
US20190269666A1 (en) 2016-07-29 2019-09-05 Eli Lilly And Company Combination therapy with merestinib and anti-pd-l1 or anti-pd-1 inhibitors for use in the treatment of cancer
US20210369746A1 (en) 2016-08-01 2021-12-02 Molecular Templates, Inc. Administration of hypoxia activated prodrugs in combination with immune modulatory agents for treating cancer
KR20190044070A (en) 2016-08-03 2019-04-29 넥스트큐어 인코포레이티드 Composition and method for modulating LAIR signal transduction
US11046776B2 (en) 2016-08-05 2021-06-29 Genentech, Inc. Multivalent and multiepitopic antibodies having agonistic activity and methods of use
WO2018026249A1 (en) * 2016-08-05 2018-02-08 주식회사 와이바이오로직스 Antibody against programmed death-ligand 1 (pd-l1), and use thereof
US10919966B2 (en) 2016-08-05 2021-02-16 Y-Biologics Inc. Antibody to programmed death-ligand 1 (PD-L1) and use thereof
WO2018029124A1 (en) 2016-08-08 2018-02-15 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
KR20260030924A (en) 2016-08-09 2026-03-06 키맵 리미티드 Anti-icos antibodies
MX386014B (en) 2016-08-10 2025-03-18 Univ Ajou Ind Academic Coop Found CYTOKINE FUSED TO HETERODIMERIC FC, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME.
EP3497130B1 (en) 2016-08-12 2021-10-27 Merck Patent GmbH Combination therapy for cancer
WO2018029336A1 (en) 2016-08-12 2018-02-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for determining whether a subject was administered with an activator of the ppar beta/delta pathway.
AU2017311585A1 (en) 2016-08-12 2019-02-28 Genentech, Inc. Combination therapy with a MEK inhibitor, a PD-1 axis inhibitor, and a VEGF inhibitor
JP6960634B2 (en) 2016-08-15 2021-11-05 国立大学法人北海道大学 Anti-PD-L1 antibody
CN109641911B (en) 2016-08-19 2023-02-21 百时美施贵宝公司 seco-cyclopyrroloindole compounds and antibody-drug conjugates thereof and methods of making and using them
PT3500299T (en) 2016-08-19 2024-02-21 Beigene Switzerland Gmbh Use of a combination comprising a btk inhibitor for treating cancers
EP3500294A4 (en) 2016-08-22 2020-07-29 Arbutus Biopharma Corporation ANTI-PD-1 ANTIBODIES OR FRAGMENTS THEREOF FOR TREATING HEPATITIS B
WO2018039518A1 (en) 2016-08-26 2018-03-01 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
EP4342978A3 (en) 2016-09-01 2024-07-03 Chimera Bioengineering Inc. Gold optimized car t-cells
CN106248955A (en) * 2016-09-03 2016-12-21 长春工业大学 A kind of test kit detecting humanization PD L1 antibody
WO2018049014A1 (en) 2016-09-07 2018-03-15 Trustees Of Tufts College Dash inhibitors, and uses related thereto
TW201811788A (en) 2016-09-09 2018-04-01 瑞士商諾華公司 Polycyclic pyridone compounds as antivirals
WO2018048975A1 (en) 2016-09-09 2018-03-15 Bristol-Myers Squibb Company Use of an anti-pd-1 antibody in combination with an anti-mesothelin antibody in cancer treatment
CN110191720A (en) 2016-09-09 2019-08-30 Tg治疗有限公司 For treating the combination of the anti-CD 20 antibodies, 3 kinases-δ inhibitor of PI and anti-PD-1 or anti-PD-L1 antibody of hematologic cancer
WO2018046738A1 (en) 2016-09-12 2018-03-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from cancer
WO2018046736A1 (en) 2016-09-12 2018-03-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from cancer
WO2018052818A1 (en) 2016-09-16 2018-03-22 Henlix, Inc. Anti-pd-1 antibodies
US11090391B2 (en) 2016-09-16 2021-08-17 The Johns Hopkins University Protein nanocages with enhanced mucus penetration for targeted tissue and intracellular delivery
AU2017329780B2 (en) * 2016-09-20 2024-11-14 Merck Patent Gmbh Diagnostic anti-PD-L1 antibody and use thereof
EP4360714A3 (en) 2016-09-21 2024-07-24 Nextcure, Inc. Antibodies for siglec-15 and methods of use thereof
AU2017330346C1 (en) 2016-09-21 2025-03-06 Nextcure, Inc. Antibodies for Siglec-15 and methods of use thereof
CA3037518A1 (en) 2016-09-21 2018-03-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptor (car) that targets chemokine receptor ccr4 and its use
EP3515453A1 (en) 2016-09-22 2019-07-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof
CN109906232B (en) 2016-09-23 2023-11-07 马伦戈治疗公司 Multispecific antibody molecules containing lambda light chains and kappa light chains
EP3516396B1 (en) 2016-09-26 2024-11-13 F. Hoffmann-La Roche AG Predicting response to pd-1 axis inhibitors
MX2019003569A (en) 2016-09-27 2020-07-22 Oncologie Inc Methods for treating cancer with bavituximab based on levels of î²2-glycoprotein 1, and assays therefor.
JOP20190061A1 (en) 2016-09-28 2019-03-26 Novartis Ag Beta-lactamase inhibitors
AU2017335839A1 (en) 2016-09-29 2019-04-18 Genentech, Inc. Combination therapy with a MEK inhibitor, a PD-1 axis inhibitor, and a taxane
US10414747B2 (en) 2016-10-04 2019-09-17 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as sting agonists
KR20190062515A (en) 2016-10-06 2019-06-05 화이자 인코포레이티드 Usage of Abelipab for the Treatment of Cancer
AU2017339517B2 (en) 2016-10-06 2024-03-14 Foundation Medicine, Inc. Therapeutic and diagnostic methods for cancer
EP3523331A1 (en) 2016-10-07 2019-08-14 Novartis AG Chimeric antigen receptors for the treatment of cancer
US12098202B2 (en) 2016-10-10 2024-09-24 The National Institute for Biotechnology in the Negev Ltd. Non-cytotoxic modified cells and use thereof
SG10201912663YA (en) 2016-10-11 2020-03-30 Agenus Inc Anti-lag-3 antibodies and methods of use thereof
US11376259B2 (en) 2016-10-12 2022-07-05 Eli Lilly And Company Targeted treatment of mature T-cell lymphoma
WO2018071576A1 (en) 2016-10-14 2018-04-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Treatment of tumors by inhibition of cd300f
BR112019007145A2 (en) 2016-10-14 2019-07-02 Eisai R&D Man Co Ltd combination of a pd-1 antagonist and eribulin for the treatment of urothelial cancer
WO2018073753A1 (en) 2016-10-18 2018-04-26 Novartis Ag Fused tetracyclic pyridone compounds as antivirals
WO2018075447A1 (en) 2016-10-19 2018-04-26 The Trustees Of Columbia University In The City Of New York Combination of braf inhibitor, talimogene laherparepvec, and immune checkpoint inhibitor for use in the treatment cancer (melanoma)
US10398783B2 (en) 2016-10-20 2019-09-03 Bristol-Myers Squibb Company Antiproliferative compounds and conjugates made therefrom
CA3040802A1 (en) 2016-10-24 2018-05-03 Orionis Biosciences Nv Targeted mutant interferon-gamma and uses thereof
MX2019004707A (en) 2016-10-26 2019-08-12 Iovance Biotherapeutics Inc RE-STIMULATION OF CRYOCONSERVED INFILTRATING TUMOR LYMPHOCYTES.
CN107987153A (en) * 2016-10-27 2018-05-04 广东香雪精准医疗技术有限公司 The soluble PD-1 molecules of high-affinity
CN106478819B (en) * 2016-10-27 2018-12-07 常州费洛斯药业科技有限公司 A kind of monoclonal antibody or antibody fragment for PD-L1
EP4491237A3 (en) 2016-10-28 2025-03-26 Bristol-Myers Squibb Company Methods of treating urothelial carcinoma using an anti-pd-1 antibody
WO2018081531A2 (en) 2016-10-28 2018-05-03 Ariad Pharmaceuticals, Inc. Methods for human t-cell activation
EP3532091A2 (en) 2016-10-29 2019-09-04 H. Hoffnabb-La Roche Ag Anti-mic antibidies and methods of use
CN117088979A (en) 2016-10-30 2023-11-21 上海复宏汉霖生物技术股份有限公司 Anti-PD-L1 antibodies and variants
TWI788307B (en) 2016-10-31 2023-01-01 美商艾歐凡斯生物治療公司 Engineered artificial antigen presenting cells for tumor infiltrating lymphocyte expansion
EP4295918A3 (en) 2016-11-02 2024-03-20 Bristol-Myers Squibb Company Bispecific antibody against bcma and cd3 and an immunological drug for combined use in treating multiple myeloma
EP3534947A1 (en) 2016-11-03 2019-09-11 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses & methods
MX2019004775A (en) 2016-11-03 2019-08-05 Squibb Bristol Myers Co Activatable anti-ctla-4 antibodies and uses thereof.
US10342785B2 (en) 2016-11-04 2019-07-09 Askat Inc. Use of EP4 receptor antagonists for the treatment of NASH-associated liver cancer
KR102526034B1 (en) 2016-11-07 2023-04-25 브리스톨-마이어스 스큅 컴퍼니 immunomodulator
WO2018087391A1 (en) 2016-11-14 2018-05-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation
WO2018093821A1 (en) 2016-11-15 2018-05-24 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
US11401507B2 (en) 2016-11-17 2022-08-02 Iovance Biotherapeutics, Inc. Remnant tumor infiltrating lymphocytes and methods of preparing and using the same
US10660909B2 (en) 2016-11-17 2020-05-26 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists
CN106496327B (en) * 2016-11-18 2019-01-15 昆山百尔泰生物科技有限公司 Human antibody or antibody fragment and purposes, nucleotide sequence and carrier for PD-L1 extracellular fragment
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
EP3541825B1 (en) 2016-11-21 2026-04-01 Idenix Pharmaceuticals LLC Cyclic phosphate substituted nucleoside derivatives for the treatment of liver diseases
WO2018098352A2 (en) 2016-11-22 2018-05-31 Jun Oishi Targeting kras induced immune checkpoint expression
US11135307B2 (en) 2016-11-23 2021-10-05 Mersana Therapeutics, Inc. Peptide-containing linkers for antibody-drug conjugates
JP7106563B2 (en) 2016-11-29 2022-07-26 スミトモ ファーマ オンコロジー， インコーポレイテッド Naphthofuran derivatives, their preparation and methods of use
CN110662552A (en) 2016-11-30 2020-01-07 昂科梅德制药有限公司 Cancer Treatment Methods Containing TIGIT Binders
EP3548515B1 (en) 2016-12-01 2026-01-21 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-pd-l1 antibodies for immuno-pet imaging
JP2020500878A (en) 2016-12-01 2020-01-16 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Combination therapy
WO2018100535A1 (en) 2016-12-01 2018-06-07 Glaxosmithkline Intellectual Property Development Limited Combination therapy
AU2017368332A1 (en) 2016-12-03 2019-06-13 Juno Therapeutics, Inc. Methods for modulation of CAR-T cells
WO2018106738A1 (en) 2016-12-05 2018-06-14 Massachusetts Institute Of Technology Brush-arm star polymers, conjugates and particles, and uses thereof
WO2018106895A1 (en) 2016-12-07 2018-06-14 Molecular Templates, Inc. Shiga toxin a subunit effector polypeptides, shiga toxin effector scaffolds, and cell-targeting molecules for site-specific conjugation
WO2018106862A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
JP7106538B2 (en) 2016-12-07 2022-07-26 アジェナス インコーポレイテッド Antibodies and methods of their use
EP4324477A3 (en) 2016-12-08 2024-05-22 Lixte Biotechnology, Inc. Oxabicycloheptanes for modulation of immune response
AU2017375946A1 (en) 2016-12-12 2019-06-20 Genentech, Inc. Methods of treating cancer using anti-PD-l1 antibodies and antiandrogens
WO2018111976A1 (en) 2016-12-14 2018-06-21 Janssen Biotech, Inc. Pd-l1 binding fibronectin type iii domains
WO2018112266A1 (en) 2016-12-14 2018-06-21 The Board Of Trustees Of The Leland Stanford Junior University Il-13 superkine: immune cell targeting constructs and methods of use thereof
US10611823B2 (en) 2016-12-14 2020-04-07 Hanssen Biotech, Inc CD137 binding fibronectin type III domains
NZ754187A (en) 2016-12-14 2026-02-27 Janssen Biotech Inc Cd8a-binding fibronectin type iii domains
WO2018112360A1 (en) 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Combination therapies for treating cancer
WO2018112364A1 (en) 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Combination therapies for treating melanoma
CN110526973A (en) * 2016-12-21 2019-12-03 南京金斯瑞生物科技有限公司 High-affinity, high specific, more antigen recognizing epitopes the anti-human CTLA4 antibody with higher function
WO2018119286A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Bicyclic heteroaromatic compounds as immunomodulators
AU2017382870B2 (en) 2016-12-22 2022-03-24 Incyte Corporation Benzooxazole derivatives as immunomodulators
WO2018115262A1 (en) 2016-12-23 2018-06-28 Innate Pharma Heterodimeric antigen binding proteins
JP2020501589A (en) 2016-12-23 2020-01-23 ウイルツ・バイオロジクス・リミテッド Cancer treatment
CN110337448B (en) * 2016-12-23 2023-08-08 瑞美德生物医药科技有限公司 Immunotherapy using antibodies that bind to programmed death-ligand 1 (PD-L1)
WO2018122245A1 (en) 2016-12-28 2018-07-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting the survival time of patients suffering from cms3 colorectal cancer
WO2018122249A1 (en) 2016-12-28 2018-07-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from a microsatellite stable colorectal cancer
WO2018127570A1 (en) 2017-01-05 2018-07-12 Netris Pharma Combined treatment with netrin-1 interfering drug and immune checkpoint inhibitors drugs
US10961239B2 (en) 2017-01-05 2021-03-30 Bristol-Myers Squibb Company TGF beta receptor antagonists
JP2020503363A (en) 2017-01-06 2020-01-30 ビヨンドスプリング ファーマシューティカルズ，インコーポレイテッド Tubulin binding compounds and their therapeutic use
CA3049165A1 (en) 2017-01-06 2018-07-12 Iovance Biotherapeutics, Inc. Expansion of tumor infiltrating lymphocytes with potassium channel agonists and therapeutic uses thereof
WO2018129533A1 (en) 2017-01-09 2018-07-12 Shuttle Pharmaceuticals, Llc Selective histone deacetylase inhibitors for the treatment of human disease
US11584733B2 (en) 2017-01-09 2023-02-21 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
EP3565560B1 (en) 2017-01-09 2024-05-29 OnkosXcel Therapeutics, LLC Predictive and diagnostic methods for prostate cancer
US12473343B2 (en) 2017-01-10 2025-11-18 The General Hospital Corporation Targeted t cells with cytotoxicity toward immunosuppressive cells
CN110198954A (en) 2017-01-13 2019-09-03 艾吉纳斯公司 T cell receptor and its application method in conjunction with NY-ESO-1
WO2018134279A1 (en) 2017-01-18 2018-07-26 Pieris Pharmaceuticals Gmbh Novel fusion polypeptides specific for lag-3 and pd-1
CN110214012B (en) 2017-01-20 2023-05-09 艾库斯生物科学有限公司 Azolopyrimidines for the treatment of cancer related disorders
EP3573989A4 (en) 2017-01-25 2020-11-18 Beigene, Ltd. CRYSTALLINE FORMS OF (S) -7- (1- (BUT-2-YNOYL) -PIPERIDINE-4-YL) -2- (4-PHENOXYPHENYL) -4,5,6,7-TETRAHYDROPYRAZOLO [1,5-A ] PYRIMIDINE-3-CARBOXAMIDE, MANUFACTURING AND USES THEREOF
EP3573648B1 (en) 2017-01-25 2023-11-22 Molecular Templates, Inc. Cell-targeting molecules comprising de-immunized, shiga toxin a subunit effectors and cd8+ t-cell epitopes
US10434095B2 (en) 2017-01-27 2019-10-08 Celgene Corporation 3-(1-oxo-4-((4-((3-oxomorpholino)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione and isotopologues thereof
US11492367B2 (en) 2017-01-27 2022-11-08 Janssen Biotech, Inc. Cyclic dinucleotides as sting agonists
US11021511B2 (en) 2017-01-27 2021-06-01 Janssen Biotech, Inc. Cyclic dinucleotides as sting agonists
BR112019015974A2 (en) 2017-02-01 2020-03-31 Beyondspring Pharmaceuticals, Inc. METHOD TO REDUCE NEUTROPENY
JOP20190187A1 (en) 2017-02-03 2019-08-01 Novartis Ag Anti-ccr7 antibody drug conjugates
US20200023071A1 (en) 2017-02-06 2020-01-23 Innate Pharma Immunomodulatory antibody drug conjugates binding to a human mica polypeptide
EP3577133A1 (en) 2017-02-06 2019-12-11 Orionis Biosciences NV Targeted chimeric proteins and uses thereof
CN110573172A (en) 2017-02-06 2019-12-13 奥里尼斯生物科学有限公司 Targeted engineered interferon and uses thereof
WO2018146148A1 (en) 2017-02-07 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) A method for predicting the response to checkpoint blockade cancer immunotherapy
WO2018146128A1 (en) 2017-02-07 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Detection of kit polymorphism for predicting the response to checkpoint blockade cancer immunotherapy
US10899844B2 (en) 2017-02-08 2021-01-26 Novartis Ag FGF21 mimetic antibodies and uses thereof
DK3579874T3 (en) 2017-02-10 2021-10-11 Novartis Ag 1- (4-AMINO-5-BROMO-6- (1H-PYRAZOL-1-YL) PYRIMIDIN-2-YL) -1H-PYRAZOL-4-OL AND ITS USE FOR CANCER TREATMENT
WO2018151820A1 (en) 2017-02-16 2018-08-23 Elstar Therapeutics, Inc. Multifunctional molecules comprising a trimeric ligand and uses thereof
WO2018150224A1 (en) 2017-02-16 2018-08-23 Shenzhen Runshin Bioscience Anti-programmed death-ligand 1 (pd-l1) antibodies and therapeutic uses thereof
TWI674261B (en) 2017-02-17 2019-10-11 美商英能腫瘤免疫股份有限公司 Nlrp3 modulators
IL268349B2 (en) 2017-02-17 2024-08-01 Hutchinson Fred Cancer Res Combination therapies for the treatment of BCMA-associated cancer and autoimmune disorders
CN108456251A (en) * 2017-02-21 2018-08-28 上海君实生物医药科技股份有限公司 Anti- PD-L1 antibody and its application
KR20240011262A (en) 2017-02-21 2024-01-25 리제너론 파아마슈티컬스, 인크. Anti-pd-1 antibodies for treatment of lung cancer
IL268836B2 (en) 2017-02-24 2024-04-01 Macrogenics Inc Bispecific molecules that bind CD137 and cancer antigens and their uses
EP3585782A1 (en) 2017-02-27 2020-01-01 GlaxoSmithKline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
AU2018223349A1 (en) 2017-02-27 2019-08-29 Bristol-Myers Squibb Dosing schedule for a combination of ceritinib and an anti-PD-1 antibody molecule
EP3366703B1 (en) 2017-02-28 2019-04-03 Ralf Kleef Immune checkpoint therapy with hyperthermia
TW201834697A (en) 2017-02-28 2018-10-01 美商梅爾莎納醫療公司 Combination therapies of her2-targeted antibody-drug conjugates
CN110546277B (en) 2017-03-01 2024-06-11 豪夫迈·罗氏有限公司 For diagnosis and treatment of cancer
EP3372615A1 (en) * 2017-03-06 2018-09-12 Merck Patent GmbH Composition comprising avelumab
BR112019018533A2 (en) 2017-03-09 2020-04-14 Genmab A/S antibody, nucleic acid construction, expression vector, host cell, pharmaceutical composition, method for treating a disease, and, use of an antibody
JP2020510050A (en) 2017-03-15 2020-04-02 アムジエン・インコーポレーテツド Use of an oncolytic virus alone or in combination with a checkpoint inhibitor to treat cancer
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
ES2894731T3 (en) 2017-03-15 2022-02-15 Silverback Therapeutics Inc Benzazepine compounds, conjugates and uses thereof
CN110382544B (en) 2017-03-16 2023-12-22 先天制药公司 Compositions and methods for treating cancer
US20200102618A1 (en) * 2017-03-17 2020-04-02 Nantomics, Llc LIQUID BIOPSY FOR cfRNA
US20210186982A1 (en) 2017-03-24 2021-06-24 Universite Nice Sophia Antipolis Methods and compositions for treating melanoma
CN108623686A (en) 2017-03-25 2018-10-09 信达生物制药(苏州)有限公司 Anti- OX40 antibody and application thereof
US11254913B1 (en) 2017-03-29 2022-02-22 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
JOP20190224A1 (en) 2017-03-29 2019-09-26 Iovance Biotherapeutics Inc Operations for the production of tumor-infiltrating lymphocytes and their use in immunotherapy
MX2019011511A (en) 2017-03-30 2019-11-18 Hoffmann La Roche Naphthyridines as inhibitors of hpk1.
SG10202110707UA (en) 2017-03-30 2021-11-29 Merck Patent Gmbh Combination of an anti-pd-l1 antibody and a dna-pk inhibitor for the treatment of cancer
RU2019133646A (en) 2017-03-30 2021-04-30 Ф. Хоффманн-Ля Рош Аг Isoquinolines as HPK1 Inhibitors
KR102775647B1 (en) 2017-03-31 2025-03-06 브리스톨-마이어스 스큅 컴퍼니 How to treat tumors
JP2020515637A (en) 2017-04-03 2020-05-28 オンコロジー、インコーポレイテッド Method for treating cancer using PS targeting antibody with immunotumor agent
RU2761377C2 (en) 2017-04-03 2021-12-07 Ф. Хоффманн-Ля Рош Аг Immunoconjugates of antibody to pd-1 with il-2 or il-15 mutant
TWI690538B (en) 2017-04-05 2020-04-11 瑞士商赫孚孟拉羅股份公司 Bispecific antibodies specifically binding to pd1 and lag3
BR112019020909A2 (en) * 2017-04-05 2020-05-12 Korea Research Institute Of Bioscience And Biotechnology NK CELL ACTIVATING FUSION PROTEIN, NK CELL AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME
US11603407B2 (en) 2017-04-06 2023-03-14 Regeneron Pharmaceuticals, Inc. Stable antibody formulation
TWI788340B (en) 2017-04-07 2023-01-01 美商必治妥美雅史谷比公司 Anti-icos agonist antibodies and uses thereof
KR20190136076A (en) 2017-04-13 2019-12-09 에프. 호프만-라 로슈 아게 Interleukin-2 immunoconjugates, CD40 agonists and optional PD-1 axis binding antagonists for use in cancer treatment methods
JP7297672B2 (en) 2017-04-13 2023-06-26 アジェナス インコーポレイテッド ANTI-CD137 ANTIBODY AND METHODS OF USE THEREOF
KR20200005540A (en) 2017-04-14 2020-01-15 제넨테크, 인크. How to diagnose and treat cancer
RU2665790C1 (en) * 2017-04-17 2018-09-04 Закрытое Акционерное Общество "Биокад" Monoclonal pd-l1 antibody
CN108728444A (en) 2017-04-18 2018-11-02 长春华普生物技术股份有限公司 Immunoregulation polynucleotide and its application
AU2018255300B2 (en) 2017-04-18 2021-10-28 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
US12460208B2 (en) 2017-04-18 2025-11-04 Parr Biotechnology Co., Ltd. Immunomodulatory polynucleotides and uses thereof
US12134654B2 (en) 2017-04-19 2024-11-05 Marengo Therapeutics, Inc. Multispecific molecules and uses thereof
ES2977788T3 (en) 2017-04-20 2024-08-30 Adc Therapeutics Sa Combination therapy with an anti-AXL antibody-drug conjugate
AU2018253950A1 (en) 2017-04-20 2019-09-19 Adc Therapeutics Sa Combination therapy with an anti-CD25 antibody-drug conjugate
BR102018007822A2 (en) 2017-04-20 2018-11-06 Gilead Sciences, Inc. compound, methods for inhibiting pd-1, pd-11 and / or interaction of pd-1 / pd-11 and for cancer treatment, pharmaceutical composition, and kit for treating or preventing cancer or a disease or condition
CN106939049B (en) 2017-04-20 2019-10-01 苏州思坦维生物技术股份有限公司 The monoclonal antibody and the preparation method and application thereof of antagonism inhibition people PD-1 antigen and its ligand binding
WO2018195397A2 (en) 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
EP3615070A1 (en) 2017-04-26 2020-03-04 Bristol-Myers Squibb Company Methods of antibody production that minimize disulfide bond reduction
CN118515666A (en) 2017-04-27 2024-08-20 博笛生物科技有限公司 2-Amino-quinoline derivatives
AR111419A1 (en) 2017-04-27 2019-07-10 Novartis Ag INDAZOL PIRIDONA FUSIONED COMPOUNDS AS ANTIVIRALS
CA3059769A1 (en) 2017-04-28 2018-11-01 Elstar Therapeutics, Inc. Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof
EP3615068A1 (en) 2017-04-28 2020-03-04 Novartis AG Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor
US12310999B2 (en) 2017-04-28 2025-05-27 Merck Sharp & Dohme Corp. Biomarkers for cancer therapeutics
WO2018201056A1 (en) 2017-04-28 2018-11-01 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
UY37695A (en) 2017-04-28 2018-11-30 Novartis Ag BIS 2’-5’-RR- (3’F-A) (3’F-A) CYCLE DINUCLEOTIDE COMPOUND AND USES OF THE SAME
AR111651A1 (en) 2017-04-28 2019-08-07 Novartis Ag CONJUGATES OF ANTIBODIES THAT INCLUDE TOLL TYPE RECEIVER AGONISTS AND COMBINATION THERAPIES
RS64576B1 (en) 2017-05-01 2023-10-31 Agenus Inc Anti-tigit antibodies and methods of use thereof
AR111658A1 (en) 2017-05-05 2019-08-07 Novartis Ag 2-TRICYCLINAL CHINOLINONES AS ANTIBACTERIAL AGENTS
AU2018264321B2 (en) 2017-05-08 2025-03-06 Shanghai Jmt-Bio Technology Co., Ltd. Bispecific recombinant protein and use thereof
AU2018265856B2 (en) 2017-05-12 2023-04-27 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US11466047B2 (en) 2017-05-12 2022-10-11 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US11066392B2 (en) 2017-05-12 2021-07-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN110198739B (en) * 2017-05-16 2023-04-04 江苏恒瑞医药股份有限公司 PD-L1 antibody pharmaceutical composition and application thereof
WO2018213316A1 (en) * 2017-05-16 2018-11-22 Alector Llc Anti-siglec-5 antibodies and methods of use thereof
CN110869392A (en) 2017-05-16 2020-03-06 百时美施贵宝公司 Treatment of cancer with anti-GITR agonistic antibodies
CA3062656A1 (en) 2017-05-17 2018-11-22 Boston Biomedical, Inc. Methods for treating cancer
US11220492B2 (en) 2017-05-17 2022-01-11 Arcus Biosciences, Inc. Quinazoline-pyrazole derivatives for the treatment of cancer-related disorders
JP7285220B2 (en) 2017-05-18 2023-06-01 モデルナティエックス インコーポレイテッド Lipid nanoparticles comprising linked interleukin-12 (IL12) polypeptide-encoding polynucleotides
BR112019024556A2 (en) 2017-05-24 2020-06-23 Novartis Ag GRAFT PROTEINS WITH ANTIBODY CYTOKIN AND METHODS FOR USE IN CANCER TREATMENT
IL270596B2 (en) 2017-05-25 2026-01-01 Bristol Myers Squibb Co Antibodies comprising modified heavy constant region for use in treating cancer
AR111960A1 (en) 2017-05-26 2019-09-04 Incyte Corp CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION
US20210340250A1 (en) 2017-05-30 2021-11-04 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
JP2020522254A (en) 2017-05-31 2020-07-30 エルスター セラピューティクス， インコーポレイテッド Multispecific molecules that bind myeloproliferative leukemia (MPL) proteins and uses thereof
US12215151B2 (en) 2017-05-31 2025-02-04 Stcube & Co., Inc. Methods of treating cancer using antibodies and molecules that immunospecifically bind to BTN1A1
AU2018277241B2 (en) 2017-05-31 2021-03-04 Novartis Ag Crystalline forms of 5-bromo-2,6-di(1H-pyrazol-1- yl)pyrimidin-4-amine and new salts
US11566073B2 (en) 2017-06-01 2023-01-31 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-PD-1 antibody
WO2018223004A1 (en) 2017-06-01 2018-12-06 Xencor, Inc. Bispecific antibodies that bind cd20 and cd3
JP2020522486A (en) 2017-06-01 2020-07-30 サイトメックス セラピューティクス インコーポレイテッド Activatable anti-PDL1 antibody and method of using the same
KR20200041834A (en) 2017-06-01 2020-04-22 젠코어 인코포레이티드 Bispecific antibodies that bind CD123 and CD3
AU2018275894B2 (en) 2017-06-02 2025-04-24 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
EP3635097A1 (en) 2017-06-05 2020-04-15 Iovance Biotherapeutics, Inc. Methods of using tumor infiltrating lymphocytes in double-refractory melanoma
CN110997724A (en) 2017-06-06 2020-04-10 斯特库伯株式会社 Methods of treating cancer using antibodies and molecules that bind BTN1A1 or BTN1A1-ligands
WO2018225093A1 (en) 2017-06-07 2018-12-13 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as atf4 pathway inhibitors
WO2018224166A1 (en) 2017-06-09 2018-12-13 Biontech Rna Pharmaceuticals Gmbh Methods for predicting the usefulness of disease specific amino acid modifications for immunotherapy
KR20200015717A (en) 2017-06-09 2020-02-12 프로비던스 헬스 앤드 서비시즈 - 오레곤 Utilization of CD39 and CD103 for Identification of Human Tumor Reactive T Cells for Cancer Treatment
EP3634483A1 (en) 2017-06-09 2020-04-15 GlaxoSmithKline Intellectual Property Development Limited Combination therapy
MX2019015042A (en) 2017-06-14 2020-08-06 Adc Therapeutics Sa DOSAGE REGIME.
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
AU2018287317B2 (en) 2017-06-19 2024-06-20 Medicenna Therapeutics Inc. Uses and methods for IL-2 superagonists, agonists, and fusions thereof
WO2018234367A1 (en) 2017-06-20 2018-12-27 Institut Curie Inhibitor of suv39h1 histone methyltransferase for use in cancer combination therapy
GB201709808D0 (en) 2017-06-20 2017-08-02 Kymab Ltd Antibodies
JP2020524694A (en) 2017-06-22 2020-08-20 ノバルティス アーゲー IL-1β binding antibodies for use in the treatment of cancer
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER
CN118307674A (en) 2017-06-22 2024-07-09 诺华股份有限公司 Antibody molecules targeting CD73 and uses thereof
EP3641772B1 (en) 2017-06-22 2023-08-02 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis b virus infection
WO2018237173A1 (en) 2017-06-22 2018-12-27 Novartis Ag ANTIBODY MOLECULES DIRECTED AGAINST CD73 AND CORRESPONDING USES
IL312120B2 (en) 2017-06-23 2025-06-01 Birdie Biopharmaceuticals Inc Medical preparation
CN110997698B (en) 2017-06-23 2023-12-26 百时美施贵宝公司 Immunomodulators that act as PD-1 antagonists
TW202515616A (en) 2017-06-26 2025-04-16 英屬開曼群島商百濟神州有限公司 Use of anti-pd-1 antibody or antigen-binding fragment thereof in preparation of medicine for treatment of hepatocellular carcinoma (hcc)
JP7301757B2 (en) 2017-06-26 2023-07-03 バイスクルアールディー・リミテッド Bicyclic peptide ligands with detectable moieties and uses thereof
JP7012384B2 (en) 2017-06-27 2022-02-14 ニューラクル サイエンス カンパニー リミテッド Uses of anti-FAM19A5 antibody for cancer treatment
AU2018292618A1 (en) 2017-06-27 2019-12-19 Novartis Ag Dosage regimens for anti-TIM-3 antibodies and uses thereof
EP3644721A1 (en) 2017-06-29 2020-05-06 Juno Therapeutics, Inc. Mouse model for assessing toxicities associated with immunotherapies
EP4201399A3 (en) 2017-06-30 2023-08-09 Celgene Corporation Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide
US11236049B2 (en) 2017-06-30 2022-02-01 Bristol-Myers Squibb Company Amorphous and crystalline forms of IDO inhibitors
EP3649108A1 (en) 2017-07-03 2020-05-13 GlaxoSmithKline Intellectual Property Development Limited 2-(4-chlorophenoxy)-n-((1 -(2-(4-chlorophenoxy)ethynazetidin-3-yl)methyl)acetamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases
BR112020000122A2 (en) 2017-07-03 2020-07-07 Glaxosmithkline Intellectual Property Development Limited derivatives of n- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) -2-cyclobutane-1-carboxamide and related compounds as inhibitors of atf4 for treatment against cancer and other diseases
GB201710973D0 (en) 2017-07-07 2017-08-23 Avacta Life Sciences Ltd Scaffold proteins
TWI791552B (en) 2017-07-10 2023-02-11 美商西建公司 Antiproliferative compounds and methods of use thereof
AU2018298676A1 (en) 2017-07-10 2019-12-19 Innate Pharma Siglec-9-neutralizing antibodies
CN107266572A (en) * 2017-07-13 2017-10-20 无锡傲锐东源生物科技有限公司 Anti- PD L1 protein monoclonal antibodies and application thereof
MY201080A (en) 2017-07-14 2024-02-03 Innate Tumor Immunity Inc Nlrp3 modulators
WO2019016174A1 (en) 2017-07-18 2019-01-24 Institut Gustave Roussy Method for assessing the response to pd-1/pdl-1 targeting drugs
CN111163798A (en) 2017-07-20 2020-05-15 诺华股份有限公司 Dosing regimens for anti-LAG-3 antibodies and uses thereof
KR102922386B1 (en) 2017-07-21 2026-02-04 제넨테크, 인크. Therapeutic and diagnostic methods for cancer
US11926664B2 (en) 2017-07-25 2024-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for modulating monocytopoiesis
WO2019021208A1 (en) 2017-07-27 2019-01-31 Glaxosmithkline Intellectual Property Development Limited Indazole derivatives useful as perk inhibitors
US11899017B2 (en) 2017-07-28 2024-02-13 Bristol-Myers Squibb Company Predictive peripheral blood biomarker for checkpoint inhibitors
KR20200035438A (en) 2017-08-03 2020-04-03 오쓰까 세이야꾸 가부시키가이샤 Drug compound and purification method thereof
CN111183147B (en) 2017-08-04 2024-07-05 拜斯科技术开发有限公司 CD137-specific bicyclic peptide ligand
US11312772B2 (en) 2017-08-04 2022-04-26 Merck Sharp & Dohme Corp. Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment
SG11202000198QA (en) 2017-08-04 2020-02-27 Genmab As Binding agents binding to pd-l1 and cd137 and use thereof
US11285131B2 (en) 2017-08-04 2022-03-29 Merck Sharp & Dohme Corp. Benzo[b]thiophene STING agonists for cancer treatment
CA3071599A1 (en) 2017-08-07 2019-02-14 Amgen Inc. Treatment of triple negative breast cancer or colorectal cancer with liver metastases with an anti pd-l1 antibody and an oncolytic virus
WO2019035938A1 (en) 2017-08-16 2019-02-21 Elstar Therapeutics, Inc. Multispecific molecules that bind to bcma and uses thereof
US10457681B2 (en) 2017-08-16 2019-10-29 Bristol_Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor
US10472361B2 (en) 2017-08-16 2019-11-12 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor
US10487084B2 (en) 2017-08-16 2019-11-26 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a heterobiaryl moiety, conjugates thereof, and methods and uses therefor
US10494370B2 (en) 2017-08-16 2019-12-03 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a pyridine or pyrazine moiety, conjugates thereof, and methods and uses therefor
US10508115B2 (en) 2017-08-16 2019-12-17 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having heteroatom-linked aromatic moieties, conjugates thereof, and methods and uses therefor
WO2019036657A1 (en) 2017-08-17 2019-02-21 Kyn Therapeutics Ahr inhibitors and uses thereof
EP3672990A1 (en) 2017-08-25 2020-07-01 Five Prime Therapeutics, Inc. B7-h4 antibodies and methods of use thereof
EP3676616A1 (en) 2017-08-28 2020-07-08 Bristol-Myers Squibb Company Tim-3 antagonists for the treatment and diagnosis of cancers
KR20200052327A (en) 2017-09-04 2020-05-14 아게누스 인코포레이티드 T cell receptor binding to mixed lineage leukemia (MLL) -specific phosphopeptides and methods of use thereof
CN118909118A (en) 2017-09-07 2024-11-08 奥古斯塔大学研究所公司 Programming cell death protein 1 antibodies
UY37866A (en) 2017-09-07 2019-03-29 Glaxosmithkline Ip Dev Ltd NEW SUBSTITUTED BENZOIMIDAZOL COMPOUNDS THAT REDUCE MYC PROTEIN (C-MYC) IN THE CELLS AND INHIBIT THE HISTONE ACETYLTRANSPHERASE OF P300 / CBP.
WO2019053617A1 (en) 2017-09-12 2019-03-21 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
WO2019055579A1 (en) 2017-09-12 2019-03-21 Tolero Pharmaceuticals, Inc. Treatment regimen for cancers that are insensitive to bcl-2 inhibitors using the mcl-1 inhibitor alvocidib
WO2019057744A1 (en) 2017-09-19 2019-03-28 Institut Curie Agonist of aryl hydrocarbon receptor for use in cancer combination therapy
WO2019059411A1 (en) 2017-09-20 2019-03-28 Chugai Seiyaku Kabushiki Kaisha Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent
MX2020003190A (en) 2017-09-22 2020-11-11 Kymera Therapeutics Inc Protein degraders and uses thereof.
WO2019060693A1 (en) 2017-09-22 2019-03-28 Kymera Therapeutics, Inc. Crbn ligands and uses thereof
EA039662B1 (en) 2017-10-03 2022-02-24 Закрытое Акционерное Общество "Биокад" Antibodies specific to cd47 and pd-l1
US11492375B2 (en) 2017-10-03 2022-11-08 Bristol-Myers Squibb Company Cyclic peptide immunomodulators
CA3077337A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting)
US20210238172A1 (en) 2017-10-05 2021-08-05 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators and methods of using the same
WO2019068907A1 (en) 2017-10-06 2019-04-11 Innate Pharma Restoration of t cell activity via the cd39/cd73 axis
US11649212B2 (en) 2017-10-09 2023-05-16 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11203592B2 (en) 2017-10-09 2021-12-21 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN111194323B (en) 2017-10-10 2024-07-09 努玛治疗有限公司 Multispecific antibodies
EP3470426A1 (en) 2017-10-10 2019-04-17 Numab Therapeutics AG Multispecific antibody
CN111183159B (en) 2017-10-10 2024-09-03 努玛治疗有限公司 Antibodies targeting CD137 and methods of use thereof
WO2019075097A1 (en) * 2017-10-11 2019-04-18 Board Of Regents, The University Of Texas System Human pd-l1 antibodies and methods of use therefor
IL315737A (en) 2017-10-13 2024-11-01 Harpoon Therapeutics Inc B cell maturation antigen binding proteins
JP7395471B2 (en) 2017-10-13 2023-12-11 オーセ イミュノセラピューティクス Modified anti-SIRPa antibody and its use
HRP20241268T1 (en) 2017-10-13 2024-12-06 Harpoon Therapeutics, Inc. TRISPECIFIC PROTEINS AND APPLICATION PROCEDURES
US20200239577A1 (en) 2017-10-15 2020-07-30 Bristol-Myers Squibb Company Methods of treating tumor
SMT202600062T1 (en) 2017-10-18 2026-03-09 Alpine Immune Sciences Inc Variant icos ligand immunomodulatory proteins and related compositions and methods
US20210189336A1 (en) 2017-10-18 2021-06-24 Vivia Biotech, S.L. Bite-activated car-t cells
KR20200072507A (en) 2017-10-19 2020-06-22 데비오팜 인터네셔날 에스 에이 Combination products for cancer treatment
EP3700933A1 (en) 2017-10-25 2020-09-02 Novartis AG Antibodies targeting cd32b and methods of use thereof
WO2019089753A2 (en) 2017-10-31 2019-05-09 Compass Therapeutics Llc Cd137 antibodies and pd-1 antagonists and uses thereof
JP7447006B2 (en) 2017-11-01 2024-03-11 ジュノー セラピューティクス インコーポレイテッド Chimeric antigen receptor specific for B cell maturation antigen (BCMA)
CN111542544A (en) 2017-11-01 2020-08-14 百时美施贵宝公司 Immunostimulatory antibodies for the treatment of cancer
AU2018358067A1 (en) 2017-11-01 2020-05-07 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
WO2019089858A2 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
EP3703692B1 (en) 2017-11-01 2025-07-23 Merck Sharp & Dohme LLC Novel substituted tetrahydroquinolin compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
JP7167146B2 (en) 2017-11-06 2022-11-08 ブリストル－マイヤーズ スクイブ カンパニー ISOFURANONE COMPOUNDS USEFUL AS HPK1 INHIBITORS
SG11202003427XA (en) 2017-11-06 2020-05-28 Juno Therapeutics Inc Combination of a cell therapy and a gamma secretase inhibitor
ES2984919T3 (en) 2017-11-06 2024-10-31 Hoffmann La Roche Diagnostic and therapeutic procedures for cancer
EP3706778A1 (en) 2017-11-06 2020-09-16 Bristol-Myers Squibb Company Methods of treating a tumor
CA3079844A1 (en) 2017-11-10 2019-05-16 Armo Biosciences, Inc. Compositions and methods of use of interleukin-10 in combination with immune checkpoint pathway inhibitors
CN111344287B (en) 2017-11-14 2023-12-19 默沙东有限责任公司 Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
KR20200088386A (en) 2017-11-14 2020-07-22 화이자 인코포레이티드 EZH2 inhibitor combination therapy
EP3709986B1 (en) 2017-11-14 2023-11-01 Merck Sharp & Dohme LLC Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
EP4501408A3 (en) 2017-11-17 2025-04-09 Iovance Biotherapeutics, Inc. Til expansion from fine needle aspirates and small biopsies
JP7194481B2 (en) 2017-11-17 2022-12-22 メルク・シャープ・アンド・ドーム・エルエルシー Antibodies specific for immunoglobulin-like transcript 3 (ILT3) and uses thereof
EP3710455A1 (en) 2017-11-17 2020-09-23 Novartis AG Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b
KR20250008153A (en) 2017-11-24 2025-01-14 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) Methods and compositions for treating cancers
EP3717021A1 (en) 2017-11-27 2020-10-07 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
CN111801334B (en) 2017-11-29 2023-06-09 百济神州瑞士有限责任公司 Treatment of Indolent or Aggressive B-Cell Lymphoma Using Combinations Containing BTK Inhibitors
BR112020010579A2 (en) 2017-11-30 2020-11-10 Novartis Ag bcma targeting chimeric antigen receptor and uses thereof
CN111356702B (en) * 2017-12-06 2022-07-26 正大天晴药业集团南京顺欣制药有限公司 anti-PD-L1 antibodies and antigen binding fragments thereof
JP7348899B2 (en) 2017-12-08 2023-09-21 マレンゴ・セラピューティクス，インコーポレーテッド Multispecific molecules and their uses
US11946094B2 (en) 2017-12-10 2024-04-02 Augusta University Research Institute, Inc. Combination therapies and methods of use thereof
WO2019118839A1 (en) 2017-12-15 2019-06-20 Janssen Biotech, Inc. Cyclic dinucleotides as sting agonists
WO2019118937A1 (en) 2017-12-15 2019-06-20 Juno Therapeutics, Inc. Anti-cct5 binding molecules and methods of use thereof
JP7774283B2 (en) 2017-12-19 2025-11-21 ザ ロックフェラー ユニバーシティー Human IgG Fc region variants with improved effector functions
WO2019121906A1 (en) 2017-12-19 2019-06-27 F-Star Beta Limited Specific pd-l1 binding sequences inserted in a ch3 domain
EP3728314A1 (en) 2017-12-19 2020-10-28 Kymab Limited Bispecific antibody for icos and pd-l1
GB201721338D0 (en) 2017-12-19 2018-01-31 Kymab Ltd Anti-icos Antibodies
JP2021507906A (en) 2017-12-20 2021-02-25 ノバルティス アーゲー Fusion tricyclic pyrazolo-dihydropyrazinyl-pyridone compound as an antiviral agent
EP3727401A4 (en) 2017-12-20 2022-04-06 Merck Sharp & Dohme Corp. CYCLIC DINUCLEOTIDE COMPOUNDS USED AS STING AGONISTS
EP3727463A1 (en) 2017-12-21 2020-10-28 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
IL315310A (en) 2017-12-26 2024-10-01 Kymera Therapeutics Inc IRAK joints and used in them
CN111788227B (en) 2017-12-27 2025-02-25 百时美施贵宝公司 Anti-CD40 antibodies and uses thereof
CN115925943A (en) * 2017-12-27 2023-04-07 信达生物制药(苏州)有限公司 Anti-PD-L1 antibodies and uses thereof
WO2019129137A1 (en) 2017-12-27 2019-07-04 信达生物制药(苏州)有限公司 Anti-lag-3 antibody and uses thereof
CN109970856B (en) 2017-12-27 2022-08-23 信达生物制药(苏州)有限公司 anti-LAG-3 antibodies and uses thereof
WO2019129054A1 (en) 2017-12-27 2019-07-04 信达生物制药(苏州)有限公司 Triabody, preparation method and use thereof
MX2020006808A (en) 2017-12-28 2020-12-11 Massachusetts Gen Hospital Targeting the cbm signalosome complex induces regulatory t cells to inflame the tumor microenvironment.
US11865081B2 (en) 2017-12-29 2024-01-09 Virogin Biotech Canada Ltd. Oncolytic viral delivery of therapeutic polypeptides
CN118047873A (en) * 2017-12-29 2024-05-17 圆祥生技股份有限公司 Monospecific proteins that modulate immune checkpoints as cancer therapy
EP3735590A1 (en) 2018-01-04 2020-11-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma resistant
US11447449B2 (en) 2018-01-05 2022-09-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11324774B2 (en) 2018-01-05 2022-05-10 Augusta University Research Institute, Inc. Compositions of oral alkaline salts and metabolic acid inducers and uses thereof
TW201930591A (en) 2018-01-08 2019-08-01 瑞士商諾華公司 Immune-enhancing RNAs for combination with chimeric antigen receptor therapy
SG11202006541UA (en) 2018-01-08 2020-08-28 Iovance Biotherapeutics Inc Processes for generating til products enriched for tumor antigen-specific t-cells
US11713446B2 (en) 2018-01-08 2023-08-01 Iovance Biotherapeutics, Inc. Processes for generating TIL products enriched for tumor antigen-specific T-cells
WO2019136459A1 (en) 2018-01-08 2019-07-11 Iovance Biotherapeutics, Inc. Processes for generating til products enriched for tumor antigen-specific t-cells
US11407723B2 (en) 2018-01-09 2022-08-09 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
EP3737692A4 (en) 2018-01-09 2021-09-29 Elstar Therapeutics, Inc. CALRETICULIN-BINDING CONSTRUCTS AND GENERALLY MODIFIED T-CELLS FOR THE TREATMENT OF DISEASES
EP3741777A4 (en) * 2018-01-10 2021-10-13 Jiangsu Hengrui Medicine Co., Ltd. PD-L1 ANTIBODIES, ANTIGEN BINDING FRAGMENT AND ASSOCIATED PHARMACEUTICAL USE
CA3125731A1 (en) 2018-01-12 2019-07-18 KDAc Therapeutics, Inc. Combination of a selective histone deacetylase 3 (hdac3) inhibitor and an immunotherapy agent for the treatment of cancer
WO2019140150A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2019140380A1 (en) 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Protein degraders and uses thereof
WO2019140387A1 (en) 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Crbn ligands and uses thereof
KR20250078626A (en) 2018-01-12 2025-06-02 브리스톨-마이어스 스큅 컴퍼니 Antibodies against tim3 and uses thereof
US20210363242A1 (en) 2018-01-16 2021-11-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2019143884A1 (en) * 2018-01-19 2019-07-25 Vanderbilt University Conserved hiv antibody clonotypes and methods of use
JP2021511344A (en) 2018-01-22 2021-05-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Compositions and Methods for Treating Cancer
US12398209B2 (en) 2018-01-22 2025-08-26 Janssen Biotech, Inc. Methods of treating cancers with antagonistic anti-PD-1 antibodies
CA3096287A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
CN112566934B (en) 2018-01-23 2024-09-17 奈斯科尔公司 B7-H4 antibodies and methods of use thereof
KR20200112881A (en) 2018-01-24 2020-10-05 비욘드스프링 파마수티컬스, 인코포레이티드. Composition and method for reducing thrombocytopenia through administration of plinabulin
US20200354424A1 (en) 2018-01-26 2020-11-12 Orionis Biosciences, Inc. Xcr1 binding agents and uses thereof
EP3746071A4 (en) 2018-01-29 2021-09-01 Merck Patent GmbH GCN2 INHIBITORS AND USES THEREOF
KR20200116481A (en) 2018-01-29 2020-10-12 메르크 파텐트 게엠베하 GCN2 inhibitors and uses thereof
US20200354457A1 (en) 2018-01-31 2020-11-12 Hoffmann-La Roche Inc. Bispecific antibodies comprising an antigen-binding site binding to lag3
JP7383620B2 (en) 2018-01-31 2023-11-20 セルジーン コーポレイション Combination therapy using adoptive cell therapy and checkpoint inhibitors
EP3746116A1 (en) 2018-01-31 2020-12-09 Novartis AG Combination therapy using a chimeric antigen receptor
JP2021513361A (en) 2018-02-05 2021-05-27 オリオニス バイオサイエンシーズ，インコーポレイテッド Fibroblast binding substances and their use
US20200352906A1 (en) 2018-02-05 2020-11-12 Shenzhen Ionova Life Science Co., Ltd. Heterobicyclic Carboxylic Acids for Treating Cancer or Inflammatory Diseases
US20200405806A1 (en) 2018-02-08 2020-12-31 Bristol-Myers Squibb Company Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors
NL2020422B1 (en) 2018-02-12 2019-08-19 Stichting Het Nederlands Kanker Inst Antoni Van Leeuwenhoek Ziekenhuis Methods for Predicting Treatment Outcome and/or for Selecting a Subject Suitable for Immune Checkpoint Therapy.
TWI707849B (en) 2018-02-13 2020-10-21 美商基利科學股份有限公司 Pd-1/pd-l1 inhibitors
WO2019160956A1 (en) 2018-02-13 2019-08-22 Novartis Ag Chimeric antigen receptor therapy in combination with il-15r and il15
US12246031B2 (en) 2018-02-13 2025-03-11 Checkmate Pharmaceuticals, Inc. Compositions and methods for tumor immunotherapy
CA3090922A1 (en) 2018-02-16 2019-08-22 Arcus Biosciences, Inc. Dosing with an azolopyrimidine compound
US20210080467A1 (en) 2018-02-21 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors
JP2021514379A (en) 2018-02-21 2021-06-10 ファイブ プライム セラピューティクス， インコーポレイテッド B7-H4 antibody preparation
WO2019165315A1 (en) 2018-02-23 2019-08-29 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists alone or in combination
JP2021514953A (en) 2018-02-23 2021-06-17 バイスクルテクス・リミテッド Multicyclic bicyclic peptide ligand
CN111836831A (en) 2018-02-26 2020-10-27 豪夫迈·罗氏有限公司 Administration for Anti-TIGIT Antagonist Antibody and Anti-PD-L1 Antagonist Antibody Therapy
BR122023024273A2 (en) 2018-02-27 2024-02-20 Incyte Corporation IMIDAZOPIRIMIDINE AND TRIAZOLOPYRIMIDIINE COMPOUNDS, THEIR USES, METHOD FOR INHIBITING AN ADENOSINE RECEPTOR ACTIVITY AND PHARMACEUTICAL COMPOSITION THEREOF
CN111801331A (en) 2018-02-28 2020-10-20 诺华股份有限公司 Indole-2-carbonyl compounds and their use for the treatment of hepatitis b
US20210002373A1 (en) 2018-03-01 2021-01-07 Nextcure, Inc. KLRG1 Binding Compositions and Methods of Use Thereof
AU2019228128A1 (en) 2018-03-02 2020-09-03 Cdr-Life Ag Trispecific antigen binding proteins
MA52416A (en) 2018-03-02 2021-04-21 Five Prime Therapeutics Inc B7-H4 ANTIBODIES AND PROCESSES FOR USE
CN111818928A (en) 2018-03-05 2020-10-23 艾库斯生物科学有限公司 Arginase inhibitor
CA3090620A1 (en) 2018-03-06 2019-09-12 Institut Curie Inhibitor of setdb1 histone methyltransferase for use in cancer combination therapy
JP2021517589A (en) 2018-03-12 2021-07-26 アンセルム（アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル） Use of calorie restriction mimics to enhance chemoimmunotherapy for the treatment of cancer
EP3765006A4 (en) 2018-03-13 2022-02-23 Merck Sharp & Dohme Corp. ARGINASE INHIBITORS AND METHODS OF USE
AU2019233577A1 (en) 2018-03-13 2020-09-03 Ose Immunotherapeutics Use of anti-human SIRPa v1 antibodies and method for producing anti-SIRPa v1 antibodies
US12152073B2 (en) 2018-03-14 2024-11-26 Marengo Therapeutics, Inc. Multifunctional molecules that bind to calreticulin and uses thereof
MX394121B (en) 2018-03-14 2025-03-24 Surface Oncology Inc ANTIBODIES THAT BIND TO CD39 AND THEIR USES
AU2019233596A1 (en) 2018-03-14 2020-10-08 Merck Patent Gmbh Compounds and uses thereof to treat tumors in a subject
WO2019178364A2 (en) 2018-03-14 2019-09-19 Elstar Therapeutics, Inc. Multifunctional molecules and uses thereof
WO2019183093A1 (en) * 2018-03-19 2019-09-26 Abeome Corporation High affinity neutralizing monoclonal antibodies to programmed death ligand 1 (pd-l1) and uses thereof
US11458171B2 (en) * 2018-03-21 2022-10-04 China Medical University Engineering stem cells for cancer therapy
BR112020019083A2 (en) 2018-03-21 2020-12-29 Five Prime Therapeutics, Inc. ANTIBODIES, NUCLEIC ACID, COMPOSITIONS, CELL AND METHODS FOR PREPARING AN ANTIBODY, FOR TREATING CANCER, FOR TREATING AN INFECTIOUS DISEASE, FOR TREATING INFLAMMATION, FOR THE IDENTIFICATION OF AN ANTIBODY, TO IMPROVE THE ANTICORUS OF ANTICORUS AND ANTICORUS OF AN ANTIBODY, TO SELECT AN ANTIBODY, TO IMPROVE ANTIBODY EFFICIENCY, TO ISOLATE ANTIBODIES, TO DETECT VIEW IN A SAMPLE AND TO TREAT CANCER
CN120463807A (en) 2018-03-22 2025-08-12 表面肿瘤学有限责任公司 Anti-IL-27 antibodies and their uses
CN119101158A (en) 2018-03-23 2024-12-10 得克萨斯州大学系统董事会 Human PD-L2 antibodies and methods of use thereof
WO2019182867A1 (en) 2018-03-23 2019-09-26 Board Of Regents, The University Of Texas System Dual specificity antibodies to human pd-l1 and pd-l2 and methods of use therefor
EP3768726B1 (en) 2018-03-23 2024-10-30 Board of Regents, The University of Texas System Dual specificity antibodies to pd-l1 and pd-l2 and methods of use therefor
PE20210665A1 (en) 2018-03-23 2021-03-31 Bristol Myers Squibb Co ANTIBODIES AGAINST MICA AND / OR MICB AND ITS USES
CN111971305A (en) * 2018-03-27 2020-11-20 美国控股实验室公司 Sandwich enzyme-linked immunosorbent assay for identifying subjects who may benefit from treatment with a therapeutic agent
WO2019184909A1 (en) 2018-03-27 2019-10-03 信达生物制药(苏州)有限公司 Novel antibody molecule, and preparation method and use thereof
CN110305210B (en) 2018-03-27 2023-02-28 信达生物制药(苏州)有限公司 Novel antibody molecule, its preparation method and its use
MA52667B1 (en) 2018-03-29 2024-07-31 Iovance Biotherapeutics, Inc. METHODS FOR PRODUCING TUMOR-INFILTRATING LYMPHOCYTES AND THEIR USES IN IMMUNOTHERAPY
WO2019185035A1 (en) * 2018-03-29 2019-10-03 Adagene Inc. Anti-pd-l1 antibodies and use thereof
WO2019185792A1 (en) 2018-03-29 2019-10-03 Philogen S.P.A Cancer treatment using immunoconjugates and immune check-point inhibitors
EP3774911A1 (en) 2018-03-30 2021-02-17 Bristol-Myers Squibb Company Methods of treating tumor
CR20200520A (en) 2018-03-30 2021-03-09 Incyte Corp Heterocyclic compounds as immunomodulators
US11702430B2 (en) 2018-04-03 2023-07-18 Merck Sharp & Dohme Llc Aza-benzothiophene compounds as STING agonists
US10793557B2 (en) 2018-04-03 2020-10-06 Merck Sharp & Dohme Corp. Sting agonist compounds
JP7680208B2 (en) 2018-04-04 2025-05-20 ブリストル－マイヤーズ スクイブ カンパニー Anti-CD27 Antibodies and Uses Thereof
US11874276B2 (en) 2018-04-05 2024-01-16 Dana-Farber Cancer Institute, Inc. STING levels as a biomarker for cancer immunotherapy
CA3096222A1 (en) 2018-04-06 2019-10-10 Atyr Pharma, Inc. Compositions and methods comprising anti-nrp2 antibodies
WO2019193540A1 (en) 2018-04-06 2019-10-10 Glaxosmithkline Intellectual Property Development Limited Heteroaryl derivatives of formula (i) as atf4 inhibitors
WO2019193541A1 (en) 2018-04-06 2019-10-10 Glaxosmithkline Intellectual Property Development Limited Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors
KR102890791B1 (en) 2018-04-09 2025-11-24 체크메이트 파마슈티칼스, 인크. Packaging of oligonucleotides into virus-like particles
AU2018418224B2 (en) 2018-04-09 2025-04-17 Oricell Therapeutics Co., Ltd. Anti-PD-L1 antibody and use thereof
US20210147570A1 (en) 2018-04-12 2021-05-20 Bristol-Myers Squibb Company Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody
US20210147547A1 (en) 2018-04-13 2021-05-20 Novartis Ag Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof
CN117568287A (en) * 2018-04-15 2024-02-20 深圳市亦诺微医药科技有限公司 Antibodies that bind PD-1 and their uses
CN111989095A (en) 2018-04-16 2020-11-24 上海岸阔医药科技有限公司 Methods of preventing or treating side effects of tumor therapy
US10973834B2 (en) 2018-04-16 2021-04-13 Arrys Therapeutics, Inc. EP4 inhibitors and use thereof
IL277963B2 (en) 2018-04-17 2024-09-01 Tempest Therapeutics Inc Bicyclic carboxamides and methods of using them
US11459393B2 (en) 2018-04-17 2022-10-04 Celldex Therapeutics, Inc. Anti-CD27 and anti-PD-L1 antibodies and bispecific constructs
AU2019257343A1 (en) 2018-04-17 2020-09-10 Molecular Templates, Inc. HER2-targeting molecules comprising de-immunized, Shiga toxin A Subunit scaffolds
SG11202010163QA (en) 2018-04-18 2020-11-27 Xencor Inc Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof
CA3097625A1 (en) 2018-04-18 2019-10-24 Xencor, Inc. Il-15/il-15ra heterodimeric fc fusion proteins and uses thereof
KR102591947B1 (en) 2018-04-19 2023-10-25 길리애드 사이언시즈, 인코포레이티드 PD-1/PD-L1 inhibitors
WO2019204743A1 (en) 2018-04-19 2019-10-24 Checkmate Pharmaceuticals, Inc. Synthetic rig-i-like receptor agonists
EP3781687A4 (en) 2018-04-20 2022-02-09 Merck Sharp & Dohme Corp. NEW SUBSTITUTE RIG-I AGONISTS: COMPOSITIONS AND ASSOCIATED METHODS
WO2019209811A1 (en) 2018-04-24 2019-10-31 Bristol-Myers Squibb Company Macrocyclic toll-like receptor 7 (tlr7) agonists
PE20210160A1 (en) 2018-04-25 2021-01-26 Innate Tumor Immunity Inc NLRP3 MODULATORS
WO2019207030A1 (en) 2018-04-26 2019-10-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting a response with an immune checkpoint inhibitor in a patient suffering from a lung cancer
MA52363A (en) 2018-04-26 2021-03-03 Agenus Inc THERMAL SHOCK PROTEIN (HSP) PEPTIDIC COMPOSITIONS AND THEIR METHODS OF USE
US20210130779A1 (en) 2018-04-27 2021-05-06 Iovance Biotherapeutics, Inc. Closed process for expansion and gene editing of tumor infiltrating lymphocytes and uses of same in immunotherapy
EP3784351A1 (en) 2018-04-27 2021-03-03 Novartis AG Car t cell therapies with enhanced efficacy
US20210396739A1 (en) 2018-05-01 2021-12-23 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
US12048745B2 (en) 2018-05-01 2024-07-30 Augusta University Research Institute, Inc. Methods for detecting and reversing immune therapy resistance
US12037323B2 (en) 2018-05-03 2024-07-16 Bristol-Myers Squibb Company Uracil derivatives as Mer-AXL inhibitors
MX2020011588A (en) 2018-05-03 2020-12-07 Shanghai Epimab Biotherapeutics Co Ltd HIGH AFFINITY ANTIBODIES TO PD-1 AND LAG-3 AND BISECIFIC BINDING PROTEINS PREPARED FROM THEM.
MA52493A (en) 2018-05-04 2021-03-10 Incyte Corp FGFR INHIBITOR SALTS
CN112512576A (en) 2018-05-04 2021-03-16 默克专利有限公司 Combined inhibition of PD-1/PD-L1, TGF beta and DNA-PK for the treatment of cancer
AU2019264232A1 (en) 2018-05-04 2020-11-12 Tollys TLR3 ligands that activate both epithelial and myeloid cells
CR20200590A (en) 2018-05-04 2021-04-26 Incyte Corp Solid forms of an fgfr inhibitor and processes for preparing the same
WO2019217753A1 (en) 2018-05-10 2019-11-14 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
WO2019217821A1 (en) 2018-05-11 2019-11-14 Incyte Corporation Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators
EP3793565B1 (en) 2018-05-14 2022-01-05 Gilead Sciences, Inc. Mcl-1 inhibitors
EP3793607A1 (en) 2018-05-15 2021-03-24 MedImmune Limited Treatment of cancer
GB201807924D0 (en) 2018-05-16 2018-06-27 Ctxt Pty Ltd Compounds
CN112236455B (en) * 2018-05-17 2023-05-16 南京维立志博生物科技有限公司 Antibodies binding to PD-1 and uses thereof
WO2019222677A1 (en) 2018-05-18 2019-11-21 Incyte Corporation Fused pyrimidine derivatives as a2a / a2b inhibitors
BR112020023756A2 (en) 2018-05-23 2021-02-09 Celgene Corporation treatment of multiple myeloma and use of biomarkers for 4- (4- (4 - (((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzyl) piperazin- 1-yl) -3-fluorobenzonitrile
EA202092830A1 (en) 2018-05-23 2021-04-08 Селджин Корпорейшн ANTIPROLIFERATIVE COMPOUNDS AND SPECIFIC ANTIBODIES TO BCMA AND CD3 FOR COMBINED USE
CA3098103A1 (en) 2018-05-23 2019-11-28 Adc Therapeutics Sa Molecular adjuvant
CN112188902A (en) 2018-05-29 2021-01-05 百时美施贵宝公司 Modified self-immolative moieties for prodrugs and conjugates and methods of use and manufacture
AR126019A1 (en) 2018-05-30 2023-09-06 Novartis Ag ANTIBODIES AGAINST ENTPD2, COMBINATION THERAPIES AND METHODS OF USE OF ANTIBODIES AND COMBINATION THERAPIES
US11932681B2 (en) 2018-05-31 2024-03-19 Novartis Ag Hepatitis B antibodies
TW202015732A (en) 2018-05-31 2020-05-01 日商小野藥品工業股份有限公司 Biomarkers for the determination of the effectiveness of immune checkpoint blocking drugs
EP3810116B1 (en) 2018-05-31 2023-11-15 Merck Sharp & Dohme LLC Novel substituted [1.1.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors
US20210214459A1 (en) 2018-05-31 2021-07-15 Novartis Ag Antibody molecules to cd73 and uses thereof
EP3810109B1 (en) 2018-05-31 2024-08-07 Peloton Therapeutics, Inc. Compounds and compositions for inhibiting cd73
EP3801617A1 (en) 2018-06-01 2021-04-14 Novartis Ag Dosing of a bispecific antibody that bind cd123 and cd3
KR20210056288A (en) * 2018-06-01 2021-05-18 타유 후아시아 바이오테크 메디컬 그룹 컴퍼니 리미티드 Compositions for treating diseases or conditions and uses thereof
UY38251A (en) 2018-06-01 2019-12-31 Novartis Ag BINDING MOLECULES AGAINST BCMA AND USES OF THEM
WO2019232523A1 (en) 2018-06-01 2019-12-05 The Board Of Trustees Of The Leland Stanford Junior University Il-13/il-4 superkines: immune cell targeting constructs and methods of use thereof
WO2019227490A1 (en) 2018-06-01 2019-12-05 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and methods for imaging
EP3802599B1 (en) 2018-06-03 2023-12-20 LamKap Bio beta AG Bispecific antibodies against ceacam5 and cd47
CN110563842B (en) 2018-06-06 2022-07-29 浙江博锐生物制药有限公司 Antibodies to programmed death ligand (PD-L1) and uses thereof
CA3100724A1 (en) 2018-06-13 2019-12-19 Novartis Ag B-cell maturation antigen protein (bcma) chimeric antigen receptors and uses thereof
CN112638375A (en) 2018-06-15 2021-04-09 旗舰创业创新五公司 Increasing immune activity through modulation of post-cellular signaling factors
MX2020012107A (en) 2018-06-18 2021-01-29 Innate Pharma Compositions and methods for treating cancer.
CN112533629A (en) 2018-06-19 2021-03-19 阿尔莫生物科技股份有限公司 Compositions and methods for combined use of IL-10 agents with chimeric antigen receptor cell therapy
CN120714024A (en) 2018-06-20 2025-09-30 因赛特公司 Anti-PD-1 antibodies and their uses
EP3810615B1 (en) 2018-06-20 2026-01-28 Merck Sharp & Dohme LLC Arginase inhibitors and methods of use
IL279489B2 (en) 2018-06-22 2025-10-01 Bicycletx Ltd Bicyclic peptide ligands specific for nectin-4, a drug conjugate comprising the peptide ligand and a pharmaceutical composition comprising the drug conjugate
CN112585166A (en) 2018-06-23 2021-03-30 豪夫迈·罗氏有限公司 Methods of treating lung cancer with PD-1 axis binding antagonists, platinating agents, and topoisomerase II inhibitors
PT3814347T (en) 2018-06-27 2023-07-18 Bristol Myers Squibb Co Naphthyridinone compounds useful as t cell activators
CN112654621B (en) 2018-06-27 2024-05-14 百时美施贵宝公司 Substituted naphthyridinone compounds as T cell activators
EP3818083A2 (en) 2018-07-03 2021-05-12 Elstar Therapeutics, Inc. Anti-tcr antibody molecules and uses thereof
GEP20237548B (en) 2018-07-05 2023-10-10 Incyte Corp Fused pyrazine derivatives as a2a /a2b inhibitors
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
WO2020010227A1 (en) 2018-07-06 2020-01-09 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US20220017617A1 (en) * 2018-07-09 2022-01-20 Shanghai Epimab Biotherapeutics Co., Ltd. Efficiently expressed egfr and pd-l1 bispecific binding proteins
WO2020012339A1 (en) 2018-07-09 2020-01-16 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
TW202428604A (en) 2018-07-09 2024-07-16 美商戊瑞治療有限公司 Antibodies binding to ilt4
DK3820573T3 (en) 2018-07-10 2023-10-23 Novartis Ag 3-(5-HYDROXY-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES AND THEIR USE IN THE TREATMENT OF IKAROS FAMILY ZINC FINGER 2 (IKZF2)-DEPENDENT DISEASES
AR116109A1 (en) 2018-07-10 2021-03-31 Novartis Ag DERIVATIVES OF 3- (5-AMINO-1-OXOISOINDOLIN-2-IL) PIPERIDINE-2,6-DIONA AND USES OF THE SAME
WO2020014543A2 (en) 2018-07-11 2020-01-16 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof
BR112021000303A2 (en) 2018-07-11 2021-04-13 Five Prime Therapeutics, Inc. ANTIBODIES THAT BIND THE SIGHT IN ACID PH
GB201811403D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd Antibody molecules
BR112021000282A2 (en) 2018-07-12 2021-04-06 F-Star Beta Limited ANTIBODY MOLECULES THAT CONNECT TO CD137 AND OX40
GB201811404D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd Anti-CD137 Antibodies
GB201811408D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd CD137 Binding Molecules
PL3820569T3 (en) 2018-07-12 2025-07-14 Invox Pharma Limited Antibody molecules that bind pd-l1 and cd137
GB201811410D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd OX40 Binding molecules
GB201811415D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd Anti-Mesothelin Anti bodies
GB201811450D0 (en) 2018-07-12 2018-08-29 F Star Delta Ltd Mesothelin and CD137 binding molecules
EP3820572B1 (en) 2018-07-13 2023-08-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
TWI809147B (en) 2018-07-13 2023-07-21 美商阿列克特有限責任公司 Anti-sortilin antibodies and methods of use thereof
WO2020014583A1 (en) 2018-07-13 2020-01-16 Bristol-Myers Squibb Company Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a mehtod of treating a cancer or a solid tumor
EP3823614A4 (en) 2018-07-18 2022-03-30 Arcus Biosciences, Inc. SOLID FORMS OF AN AZOLOPYRIMIDINE COMPOUND
BR112021000673A2 (en) 2018-07-18 2021-04-20 Genentech, Inc. methods for treating an individual with lung cancer, kits, anti-pd-l1 antibody and compositions
BR112021000727A2 (en) 2018-07-20 2021-04-13 Surface Oncology, Inc. ANTI-CD112R COMPOSITIONS AND METHODS
US12059420B2 (en) 2018-07-23 2024-08-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020023356A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN112601584A (en) 2018-07-24 2021-04-02 豪夫迈·罗氏有限公司 Isoquinoline compounds and uses thereof
US20210301020A1 (en) 2018-07-24 2021-09-30 Amgen Inc. Combination of lilrb1/2 pathway inhibitors and pd-1 pathway inhibitors
TW202012405A (en) 2018-07-24 2020-04-01 瑞士商赫孚孟拉羅股份公司 Naphthyridine compounds and uses thereof
WO2020020307A1 (en) 2018-07-25 2020-01-30 I-Mab Biopharma Co., Ltd. Anti-cd73 anti-pd-l1 bispecific antibodies
US12459980B2 (en) 2018-07-25 2025-11-04 AskGene Pharma, Inc. IL-21 prodrugs and methods of use thereof
CA3106563A1 (en) 2018-07-26 2020-01-30 Atyr Pharma, Inc. Compositions and methods for treating nrp2-associated diseases
MX2021000726A (en) 2018-07-26 2021-03-25 Bristol Myers Squibb Co Lag-3 combination therapy for the treatment of cancer.
WO2020021061A1 (en) 2018-07-26 2020-01-30 Pieris Pharmaceuticals Gmbh Humanized anti-pd-1 antibodies and uses thereof
US11554120B2 (en) 2018-08-03 2023-01-17 Bristol-Myers Squibb Company 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor
WO2020030634A1 (en) 2018-08-06 2020-02-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers
WO2020031107A1 (en) 2018-08-08 2020-02-13 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
EP3833762A4 (en) 2018-08-09 2022-09-28 Verseau Therapeutics, Inc. OLIGONUCLEOTIDE COMPOSITIONS FOR TARGETING CCR2 AND CSF1R AND THEIR USES
CN113307872B (en) * 2018-08-11 2022-12-06 广东天科雅生物医药科技有限公司 Engineered nucleic acid, T cell, application and production method thereof
JP7433291B2 (en) 2018-08-16 2024-02-19 イネイト・テューマー・イミュニティ・インコーポレイテッド NLRP3 modulators of imidazo[4,5-c]quinoline derivatives
KR102768379B1 (en) 2018-08-16 2025-02-13 인네이트 튜머 이뮤니티, 인코포레이티드 Imidaz[4,5-c]quinoline-derived NLRP3-modulator
CN112888677A (en) 2018-08-16 2021-06-01 先天肿瘤免疫公司 Substituted 4-amino-1H-imidazo [4,5-c ] quinoline compounds and improved process for their preparation
US12391758B2 (en) 2018-08-20 2025-08-19 1Globe Biomedical Co., Ltd. Anti-PD-L1 cancer immunotherapy antibodies
CN112955221A (en) 2018-08-27 2021-06-11 皮里斯制药有限公司 Combination therapy comprising a CD137/HER2 bispecific agent and a PD-1 axis inhibitor and uses thereof
US10959986B2 (en) 2018-08-29 2021-03-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11253525B2 (en) 2018-08-29 2022-02-22 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020044206A1 (en) 2018-08-29 2020-03-05 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors for use in the treatment cancer
TW202031273A (en) 2018-08-31 2020-09-01 美商艾歐凡斯生物治療公司 Treatment of nsclc patients refractory for anti-pd-1 antibody
WO2020047345A1 (en) 2018-08-31 2020-03-05 Yale University Compositions and methods of using cell-penetrating antibodies in combination with immune checkpoint modulators
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020048942A1 (en) 2018-09-04 2020-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses
US11359024B2 (en) 2018-09-07 2022-06-14 Pfizer Inc. Anti-AVB8 antibodies and compositions and uses thereof
US12030875B2 (en) 2018-09-07 2024-07-09 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
WO2020053742A2 (en) 2018-09-10 2020-03-19 Novartis Ag Anti-hla-hbv peptide antibodies
SG11202102343QA (en) 2018-09-11 2021-04-29 Curis Inc Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US20200113912A1 (en) 2018-09-12 2020-04-16 Silverback Therapeutics, Inc. Methods and Compositions for the Treatment of Disease with Immune Stimulatory Conjugates
JP2022500413A (en) 2018-09-12 2022-01-04 シルバーバック セラピューティックス インコーポレイテッド Antibody conjugates of Toll-like receptor agonists
WO2020056194A1 (en) 2018-09-12 2020-03-19 Silverback Therapeutics, Inc. Benzazepine compounds, conjugates, and uses thereof
AU2019339777B2 (en) 2018-09-12 2022-09-01 Novartis Ag Antiviral pyridopyrazinedione compounds
AU2019337654A1 (en) 2018-09-12 2021-04-08 Silverback Therapeutics, Inc. Substituted benzazepine compounds, conjugates, and uses thereof
AU2019337547A1 (en) 2018-09-13 2021-03-18 Merck Sharp & Dohme Llc Combination of PD-1 antagonist and LAG3 antagonist for treating non-microsatellite instablity-high/proficient mismatch repair colorectal cancer
CN109053891B (en) * 2018-09-17 2021-12-21 苏州泓迅生物科技股份有限公司 anti-PD-L1 antibody, and preparation method and application thereof
AU2019345151B2 (en) 2018-09-19 2025-04-17 Alpine Immune Sciences, Inc. Methods and uses of variant CD80 fusion proteins and related constructs
JP2022501332A (en) 2018-09-19 2022-01-06 ジェネンテック， インコーポレイテッド How to treat and diagnose bladder cancer
EP3853251A1 (en) 2018-09-19 2021-07-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy
WO2020061377A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
CA3112599A1 (en) 2018-09-20 2020-03-26 Iovance Biotherapeutics, Inc. Expansion of tils from cryopreserved tumor samples
KR102739487B1 (en) 2018-09-21 2024-12-10 제넨테크, 인크. Diagnostic methods for triple-negative breast cancer
WO2020061482A1 (en) 2018-09-21 2020-03-26 Harpoon Therapeutics, Inc. Egfr binding proteins and methods of use
SG11202103022WA (en) 2018-09-25 2021-04-29 Harpoon Therapeutics Inc Dll3 binding proteins and methods of use
WO2020064971A1 (en) 2018-09-26 2020-04-02 Merck Patent Gmbh Combination of a pd-1 antagonist, an atr inhibitor and a platinating agent for the treatment of cancer
JP7465272B2 (en) 2018-09-27 2024-04-10 マレンゴ・セラピューティクス，インコーポレーテッド CSF1R/CCR2 multispecific antibodies
EP3856763A1 (en) 2018-09-28 2021-08-04 Massachusetts Institute of Technology Collagen-localized immunomodulatory molecules and methods thereof
WO2020069409A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd19 chimeric antigen receptor (car) and cd22 car combination therapies
EP3856779A1 (en) 2018-09-28 2021-08-04 Novartis AG Cd22 chimeric antigen receptor (car) therapies
JP2022502385A (en) 2018-09-29 2022-01-11 ノバルティス アーゲー Method for producing a compound for inhibiting the activity of SHP2
CN113454070A (en) 2018-09-30 2021-09-28 豪夫迈·罗氏有限公司 Cinnoline compounds and their use for the treatment of HPK 1-dependent disorders such as cancer
US20220040183A1 (en) 2018-10-01 2022-02-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of stress granule formation for targeting the regulation of immune responses
TW202024053A (en) 2018-10-02 2020-07-01 美商建南德克公司 Isoquinoline compounds and uses thereof
EP3861016A2 (en) 2018-10-03 2021-08-11 Xencor, Inc. Il-12 heterodimeric fc-fusion proteins
CN113166062A (en) 2018-10-03 2021-07-23 豪夫迈·罗氏有限公司 8-aminoisoquinoline compounds and uses thereof
WO2020076799A1 (en) 2018-10-09 2020-04-16 Bristol-Myers Squibb Company Anti-mertk antibodies for treating cancer
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
TWI855000B (en) 2018-10-11 2024-09-11 日商小野藥品工業股份有限公司 Sting agonist compound
JP2022502531A (en) 2018-10-12 2022-01-11 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイションUniversity of Pittsburgh − Of the Commonwealth System of Higher Education Small polymer carrier for delivering the drug
AU2019359475A1 (en) 2018-10-12 2021-05-20 Xencor, Inc. PD-1 targeted IL-15/IL-15Ralpha Fc fusion proteins and uses in combination therapies thereof
US20210348238A1 (en) 2018-10-16 2021-11-11 Novartis Ag Tumor mutation burden alone or in combination with immune markers as biomarkers for predicting response to targeted therapy
WO2020081493A1 (en) * 2018-10-16 2020-04-23 Molecular Templates, Inc. Pd-l1 binding proteins
US12152019B2 (en) 2018-10-17 2024-11-26 Merck Sharp & Dohme Llc Arylalkyl pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
US20210340240A1 (en) 2018-10-18 2021-11-04 INSERM (Institut National de la Santé et de la Recherche Médicale Combination of a big-h3 antagonist and an immune checkpoint inhibitor for the treatment of solid tumor
MX2021004348A (en) 2018-10-18 2021-05-28 Genentech Inc DIAGNOSTIC AND THERAPEUTIC PROCEDURES FOR SARCOMATOID KIDNEY CANCER.
JP2022512750A (en) 2018-10-19 2022-02-07 ブリストル－マイヤーズ スクイブ カンパニー Combination therapy for melanoma
JP2022513374A (en) 2018-10-22 2022-02-07 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド dosage
AU2019366956B2 (en) 2018-10-23 2025-10-30 Dragonfly Therapeutics, Inc. Heterodimeric Fc-fused proteins
JP2022505647A (en) 2018-10-23 2022-01-14 ブリストル－マイヤーズ スクイブ カンパニー How to treat a tumor
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
AU2019369340A1 (en) 2018-10-29 2021-05-20 Mersana Therapeutics, Inc. Cysteine engineered antibody-drug conjugates with peptide-containing linkers
US11564995B2 (en) 2018-10-29 2023-01-31 Wisconsin Alumni Research Foundation Peptide-nanoparticle conjugates
US20210393799A1 (en) 2018-10-29 2021-12-23 Wisconsin Alumni Research Foundation Dendritic polymers complexed with immune checkpoint inhibitors for enhanced cancer immunotherapy
EP3873532A1 (en) 2018-10-31 2021-09-08 Novartis AG Dc-sign antibody drug conjugates
MA54079A (en) 2018-11-01 2021-09-08 Juno Therapeutics Inc GPRC5D SPECIFIC CHIMERIC ANTIGEN RECEPTORS (G PROTEIN COUPLED RECEPTOR CLASS C GROUP 5 D ELEMENT)
KR20210113169A (en) 2018-11-01 2021-09-15 주노 쎄러퓨티크스 인코퍼레이티드 Treatment method using chimeric antigen receptor specific for Β cell maturation antigen
WO2020092183A1 (en) 2018-11-01 2020-05-07 Merck Sharp & Dohme Corp. Novel substituted pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
US20230039976A1 (en) 2018-11-05 2023-02-09 Iovance Biotherapeutics, Inc. Selection of improved tumor reactive t-cells
TW202039830A (en) 2018-11-05 2020-11-01 美商艾歐凡斯生物治療公司 Processes for production of tumor infiltrating lymphocytes and uses of the same in immunotherapy
US20210369842A1 (en) 2018-11-06 2021-12-02 Genmab A/S Antibody formulation
EP3877366B1 (en) 2018-11-06 2026-01-28 Merck Sharp & Dohme LLC Novel substituted tricyclic compounds as indoleamine 2,3-dioxygenase inhibitors
WO2020097409A2 (en) 2018-11-08 2020-05-14 Modernatx, Inc. Use of mrna encoding ox40l to treat cancer in human patients
US12410225B2 (en) 2018-11-08 2025-09-09 Orionis Biosciences, Inc Modulation of dendritic cell lineages
WO2020097495A1 (en) 2018-11-09 2020-05-14 Pierian Biosciences, LLC Methods and compositions for determining the composition of a tumor microenvironment
US11046769B2 (en) 2018-11-13 2021-06-29 Compass Therapeutics Llc Multispecific binding constructs against checkpoint molecules and uses thereof
TW202028222A (en) 2018-11-14 2020-08-01 美商Ionis製藥公司 Modulators of foxp3 expression
BR112021007448A2 (en) 2018-11-14 2021-10-26 Bayer Aktiengesellschaft PHARMACEUTICAL COMBINATION OF ANTI-CEACAM6 AND ANTI-PD-1 OR ANTI-PD-L1 ANTIBODIES FOR THE TREATMENT OF CANCER
HUE067601T2 (en) 2018-11-14 2024-10-28 Regeneron Pharma Intralesional administration of pd-1 inhibitors for treating skin cancer
KR20210104713A (en) 2018-11-16 2021-08-25 주노 쎄러퓨티크스 인코퍼레이티드 Engineered T-cell dosing methods for treatment of B-cell malignancies
US11274150B2 (en) 2018-11-16 2022-03-15 Bristol-Myers Squibb Company Anti-human natural killer cell inhibitory receptor group 2A protein (NKG2A) antibodies
EP3880202A2 (en) 2018-11-16 2021-09-22 ArQule, Inc. Pharmaceutical combination for treatment of cancer
ES3034676T3 (en) 2018-11-16 2025-08-21 Arcus Biosciences Inc Inhibitors of arg1 and/or arg2
EP3880231A1 (en) 2018-11-16 2021-09-22 NeoImmuneTech, Inc. Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor
KR20210093964A (en) 2018-11-20 2021-07-28 머크 샤프 앤드 돔 코포레이션 Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and uses thereof
WO2020104479A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies
US20230183379A1 (en) 2018-11-20 2023-06-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Bispecific antibody targeting transferrin receptor 1 and soluble antigen
WO2020106560A1 (en) 2018-11-20 2020-05-28 Merck Sharp & Dohme Corp. Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use
CN113453678A (en) 2018-11-26 2021-09-28 德彪药业国际股份公司 Combination therapy for HIV infection
JP7491220B2 (en) 2018-11-27 2024-05-28 小野薬品工業株式会社 Cancer treatment in combination with immune checkpoint inhibitors and FOLFIRINOX therapy
US20220018828A1 (en) 2018-11-28 2022-01-20 Inserm (Institut National De La Santé Et La Recherche Médicale Methods and kit for assaying lytic potential of immune effector cells
EP3887397A1 (en) 2018-11-28 2021-10-06 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
EP3886845B1 (en) 2018-11-28 2024-09-04 Merck Sharp & Dohme LLC Novel substituted piperazine amide compounds as indoleamine 2, 3-dioxygenase (ido) inhibitors
JP7623943B2 (en) 2018-11-30 2025-01-29 カイメラ セラピューティクス， インコーポレイテッド IRAK degraders and their uses
AR117206A1 (en) 2018-11-30 2021-07-21 Glaxosmithkline Ip Dev Ltd OCTAHYDROPIRROLO [2,1-B] [1,3] THIAZEPIN-7-CARBOXAMIDE DERIVATIVES USEFUL IN HIV THERAPY AND FOR THE TREATMENT OF CANCER
TW202039496A (en) 2018-11-30 2020-11-01 美商默沙東藥廠 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use
PL3886875T3 (en) 2018-11-30 2024-09-09 Juno Therapeutics, Inc. Methods for treatment using adoptive cell therapy
ES2943474T3 (en) 2018-11-30 2023-06-13 Bristol Myers Squibb Co Antibody comprising a carboxy-terminal extension of a glutamine-containing light chain, conjugates thereof, and methods and uses
IL283522B2 (en) 2018-12-03 2025-03-01 Agensys Inc Pharmaceutical compositions comprising anti-191p4d12 antibody drug conjugates and methods of use thereof
JP7584418B2 (en) 2018-12-04 2024-11-15 ブリストル－マイヤーズ スクイブ カンパニー Analysis method using in-sample calibration curves by multiple reaction isotope molecular species reaction monitoring
US11034710B2 (en) 2018-12-04 2021-06-15 Sumitomo Dainippon Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
WO2020117952A2 (en) 2018-12-05 2020-06-11 Genentech, Inc. Diagnostic methods and compositions for cancer immunotherapy
US20220018835A1 (en) 2018-12-07 2022-01-20 INSERM (Institut National de la Santé et de la Recherche Médicale Use of cd26 and cd39 as new phenotypic markers for assessing maturation of foxp3+ t cells and uses thereof for diagnostic purposes
WO2020115261A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
SG11202104331YA (en) 2018-12-11 2021-05-28 Theravance Biopharma R&D Ip Llc Naphthyridine and quinoline derivatives useful as alk5 inhibitors
WO2020120592A1 (en) 2018-12-12 2020-06-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating melanoma
KR20210102334A (en) 2018-12-12 2021-08-19 브리스톨-마이어스 스큅 컴퍼니 Antibodies modified for transglutaminase conjugation, conjugates thereof, and methods and uses
GB201820325D0 (en) 2018-12-13 2019-01-30 Bicyclerd Ltd Bicyclic peptide ligands specific for psma
BR112021011393A2 (en) 2018-12-13 2021-08-31 Surface Oncology, Inc. ANTI-IL-27 ANTIBODIES AND USES THEREOF
GB201820288D0 (en) 2018-12-13 2019-01-30 Bicycle Tx Ltd Bicycle peptide ligaands specific for MT1-MMP
GB201820295D0 (en) 2018-12-13 2019-01-30 Bicyclerd Ltd Bicyclic peptide ligands specific for MT1-MMP
EP3897624A1 (en) 2018-12-17 2021-10-27 Institut National de la Santé et de la Recherche Médicale (INSERM) Use of sulconazole as a furin inhibitor
US12240867B2 (en) 2018-12-18 2025-03-04 Merck Sharp & Dohme Llc Arginase inhibitors and methods of use
WO2020127411A1 (en) 2018-12-19 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d
JP7521163B2 (en) 2018-12-19 2024-07-24 ドイチェス クレープスフォルシュングスツェントルム シュティフトゥング デス エッフェントリッヒェン レヒツ Pharmaceutical combination of anti-CEACAM6 and TIM3 antibodies
KR20210106437A (en) 2018-12-20 2021-08-30 노파르티스 아게 Dosage regimens and pharmaceutical combinations comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
CN113438961A (en) 2018-12-20 2021-09-24 Xencor股份有限公司 Targeting heterodimeric Fc fusion proteins containing IL-15/IL-15R α and NKG2D antigen binding domains
EP3670659A1 (en) 2018-12-20 2020-06-24 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
JP2022514618A (en) 2018-12-21 2022-02-14 バイスクルテクス・リミテッド Bicyclic peptide ligand specific for PD-L1
WO2020127885A1 (en) 2018-12-21 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions for treating cancers and resistant cancers
EP3897613A1 (en) 2018-12-21 2021-10-27 Novartis AG Use of il-1beta binding antibodies
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
JP7607564B2 (en) 2018-12-21 2024-12-27 ノバルティス アーゲー Antibodies to PMEL17 and conjugates thereof
WO2020128893A1 (en) 2018-12-21 2020-06-25 Pfizer Inc. Combination treatments of cancer comprising a tlr agonist
BR112021011351A2 (en) 2018-12-21 2021-11-16 Novartis Ag Use of IL-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome
US12551567B2 (en) 2018-12-21 2026-02-17 Bicyclerd Limited Bicyclic peptide ligands specific for PD-L1
WO2020127965A1 (en) 2018-12-21 2020-06-25 Onxeo New conjugated nucleic acid molecules and their uses
CN113227138A (en) 2018-12-21 2021-08-06 诺华股份有限公司 Use of IL-1 beta binding antibodies
CA3124690A1 (en) 2018-12-27 2020-07-02 Amgen Inc. Lyophilized virus formulations
SG11202106768RA (en) * 2018-12-27 2021-07-29 Gigagen Inc Anti-pd-l1 binding proteins and methods of use thereof
EP3906415B1 (en) 2019-01-03 2026-04-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer
WO2020146440A1 (en) 2019-01-09 2020-07-16 Celgene Corporation Antiproliferative compounds and second active agents for use in treating multiple myeloma
AU2020206692B2 (en) 2019-01-09 2025-03-27 Celgene Corporation Pharmaceutical compositions comprising (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same
RS67646B1 (en) 2019-01-09 2026-02-27 Celgene Corp Solid forms comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and salts thereof, and compositions comprising and methods of using the same
WO2020150116A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Nlrp3 modulators
ES2930151T3 (en) 2019-01-14 2022-12-07 Innate Tumor Immunity Inc NLRP3 heterocyclic modulators, for use in cancer treatment
EP3911641A1 (en) 2019-01-14 2021-11-24 Innate Tumor Immunity, Inc. Nlrp3 modulators
CN113301963A (en) 2019-01-14 2021-08-24 先天肿瘤免疫公司 Substituted quinazolines as NLRP3 modulators for the treatment of cancer
TW202515617A (en) 2019-01-14 2025-04-16 美商建南德克公司 Rna molecules for use in cancer therapies
EP3911670B1 (en) 2019-01-15 2024-12-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy
JP7636330B2 (en) 2019-01-17 2025-02-26 ジョージア テック リサーチ コーポレイション Drug delivery system containing oxidized cholesterol - Patents.com
WO2020154032A1 (en) 2019-01-23 2020-07-30 Massachusetts Institute Of Technology Combination immunotherapy dosing regimen for immune checkpoint blockade
WO2020151572A1 (en) 2019-01-23 2020-07-30 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-pd-l1 diabodies and the use thereof
CA3123303A1 (en) 2019-01-29 2020-08-06 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1)
TWI829857B (en) 2019-01-29 2024-01-21 美商英塞特公司 Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors
WO2020157131A1 (en) 2019-01-30 2020-08-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor
MX2021009189A (en) 2019-02-01 2021-11-12 Glaxosmithkline Ip Dev Ltd Belantamab mafodotin in combination with pembrolizumab for treating cancer.
US20220117911A1 (en) 2019-02-04 2022-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating blood-brain barrier
EP3921443A1 (en) 2019-02-08 2021-12-15 F. Hoffmann-La Roche AG Diagnostic and therapeutic methods for cancer
NZ778055A (en) 2019-02-12 2025-11-28 Sumitomo Pharma America Inc Formulations comprising heterocyclic protein kinase inhibitors
WO2020165370A1 (en) 2019-02-13 2020-08-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for selecting a cancer treatment in a subject suffering from cancer
CN113490528B (en) 2019-02-15 2024-12-03 诺华股份有限公司 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020168244A1 (en) 2019-02-15 2020-08-20 Incelldx, Inc. Assaying bladder-associated samples, identifying and treating bladder-associated neoplasia, and kits for use therein
WO2020168197A1 (en) 2019-02-15 2020-08-20 Incyte Corporation Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors
EP3924055B1 (en) 2019-02-15 2024-04-03 Novartis AG Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US20200316064A1 (en) 2019-02-15 2020-10-08 Incyte Corporation Cyclin-dependent kinase 2 biomarkers and uses thereof
WO2020169472A2 (en) 2019-02-18 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of inducing phenotypic changes in macrophages
AU2020224681A1 (en) 2019-02-21 2021-09-16 Marengo Therapeutics, Inc. Antibody molecules that bind to NKp30 and uses thereof
WO2020169062A1 (en) * 2019-02-21 2020-08-27 祐和医药科技(北京)有限公司 Anti-pd-l1 antibody and use thereof
JP7710373B2 (en) 2019-02-21 2025-07-18 マレンゴ・セラピューティクス，インコーポレーテッド Multifunctional molecules that bind to T-cell-associated cancer cells and uses thereof
TW202540426A (en) 2019-02-27 2025-10-16 美商Ionis製藥公司 Modulators of malat1 expression
MA55084A (en) 2019-02-28 2022-01-05 Regeneron Pharma ADMINISTRATION OF PD-1 INHIBITORS FOR THE TREATMENT OF SKIN CANCER
AU2020232264B2 (en) 2019-03-05 2026-02-19 Amgen Inc. Use of oncolytic viruses for the treatment of cancer
WO2020180959A1 (en) 2019-03-05 2020-09-10 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
MA55204A (en) 2019-03-06 2022-01-12 Regeneron Pharma IL-4/IL-13 PATHWAY INHIBITORS FOR IMPROVED EFFECTIVENESS IN THE TREATMENT OF CANCER
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
WO2020185859A1 (en) 2019-03-12 2020-09-17 Arcus Biosciences, Inc. Treatment of oncogene-driven cancers
TW202100556A (en) 2019-03-14 2021-01-01 美商建南德克公司 Treatment with her2 t cell-dependent bispecific antibodies
CN120131907A (en) 2019-03-19 2025-06-13 瓦尔希伯伦私人肿瘤研究基金会 Combination therapy using Omomyc and antibodies binding to PD-1 or CTLA-4 for the treatment of cancer
US11793802B2 (en) 2019-03-20 2023-10-24 Sumitomo Pharma Oncology, Inc. Treatment of acute myeloid leukemia (AML) with venetoclax failure
CA3133460A1 (en) 2019-03-22 2020-10-01 Sumitomo Dainippon Pharma Oncology, Inc. Compositions comprising pkm2 modulators and methods of treatment using the same
KR20210146348A (en) 2019-03-28 2021-12-03 브리스톨-마이어스 스큅 컴퍼니 how to treat a tumor
CN113891748A (en) 2019-03-28 2022-01-04 百时美施贵宝公司 Method for treating tumors
CA3133648A1 (en) 2019-03-28 2020-10-01 Orionis Biosciences, Inc. Fibroblast activation protein binding agents and use thereof
CN113631910A (en) 2019-03-29 2021-11-09 豪夫迈·罗氏有限公司 Modulators of cell surface protein interactions and related methods and compositions
TW202102543A (en) 2019-03-29 2021-01-16 美商安進公司 Use of oncolytic viruses in the neoadjuvant therapy of cancer
US12310965B2 (en) 2019-03-29 2025-05-27 Arcus Biosciences, Inc. Treatment of cancer utilizing an identified adenosine fingerprint
WO2020205560A1 (en) 2019-03-29 2020-10-08 Incyte Corporation Sulfonylamide compounds as cdk2 inhibitors
CN109929037B (en) * 2019-04-01 2023-03-17 华博生物医药技术（上海）有限公司 Conjugates to programmed death ligands and uses thereof
JP2022527972A (en) 2019-04-02 2022-06-07 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル How to predict and prevent cancer in patients with premalignant lesions
US20220184222A1 (en) 2019-04-02 2022-06-16 Bicycletx Limited Bicycle toxin conjugates and uses thereof
US12281109B2 (en) 2019-04-04 2025-04-22 Merck Sharp & Dohme Llc Inhibitors of histone deacetylase-3 useful for the treatment of cancer, inflammation, neurodegeneration diseases and diabetes
TWI875749B (en) 2019-04-05 2025-03-11 美商凱麥拉醫療公司 Stat degraders and uses thereof
US20220160692A1 (en) 2019-04-09 2022-05-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk2 inhibitors in combination with immune checkpoint blockade therapy for the treatment of cancer
SG11202109441UA (en) 2019-04-12 2021-09-29 Vascular Biogenics Ltd Methods of anti-tumor therapy
US20220220480A1 (en) 2019-04-17 2022-07-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treatment of nlrp3 inflammasome mediated il-1beta dependent disorders
WO2020215020A1 (en) * 2019-04-18 2020-10-22 Qlsf Biotherapeutics Inc. Humanized anti-pd-l1 antibodies
EP3725370A1 (en) 2019-04-19 2020-10-21 ImmunoBrain Checkpoint, Inc. Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease
BR112021020867A2 (en) 2019-04-19 2022-01-04 Genentech Inc Antibodies, nucleic acid, vector, host cell, method of producing an antibody, immunoconjugate, pharmaceutical formulation, uses of the antibody, method of treating an individual with cancer, and method of reducing clearance
SG11202111106WA (en) 2019-04-23 2021-11-29 Innate Pharma Cd73 blocking antibodies
WO2020221796A1 (en) 2019-04-30 2020-11-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2020223639A1 (en) 2019-05-01 2020-11-05 Sensei Biotherapeutics, Inc. Combination therapies for cancer
WO2020223558A1 (en) 2019-05-01 2020-11-05 Incyte Corporation Tricyclic amine compounds as cdk2 inhibitors
CN114269376A (en) 2019-05-03 2022-04-01 豪夫迈·罗氏有限公司 Methods of treating cancer with anti-PD-L1 antibodies
WO2020227159A2 (en) 2019-05-03 2020-11-12 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity
US20220211847A1 (en) 2019-05-06 2022-07-07 Medimmune Limited Combination of monalizumab, durvalumab, chemotherapy and bevacizumab or cetuximab for the treatment of colorectal cancer
IL287801A (en) 2019-05-07 2022-07-01 Immunicom Inc Augmentation of responses to checkpoint inhibitors using in vitro apheresis
JP2022533194A (en) 2019-05-16 2022-07-21 スティングセラ インコーポレイテッド Benzo [B] [1,8] Diazanaphthalene Acetic Acid Derivatives and Usage
US20220227761A1 (en) 2019-05-16 2022-07-21 Stingthera, Inc. Oxoacridinyl acetic acid derivatives and methods of use
AU2020278465B2 (en) 2019-05-20 2026-04-23 Dana-Farber Cancer Institute, Inc. Boronic ester prodrugs and uses thereof
AU2020281535A1 (en) 2019-05-24 2022-01-27 Merck Patent Gmbh Combination therapies using CDK inhibitors
JP2022534967A (en) 2019-05-30 2022-08-04 ブリストル－マイヤーズ スクイブ カンパニー Multiple tumor gene signatures and their uses
EP3977132A1 (en) 2019-05-30 2022-04-06 Bristol-Myers Squibb Company Cell localization signature and combination therapy
KR20220016155A (en) 2019-05-30 2022-02-08 브리스톨-마이어스 스큅 컴퍼니 Methods of Identifying Suitable Subjects for Immuno-Oncology (I-O) Therapy
WO2020243423A1 (en) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2020251972A1 (en) 2019-06-10 2020-12-17 Kymera Therapeutics, Inc. Smarca degraders and uses thereof
CA3135988C (en) 2019-06-10 2024-11-19 Shandong Boan Biotechnology Co., Ltd. Bifunctional fusion protein against pdl1 and tgf.beta. and use thereof
US11246906B2 (en) 2019-06-11 2022-02-15 Alkermes Pharma Ireland Limited Compositions and methods for subcutaneous administration of cancer immunotherapy
WO2020248156A1 (en) * 2019-06-12 2020-12-17 苏州工业园区唯可达生物科技有限公司 Pd-l1-targeting binding agent and use thereof
KR20220020879A (en) 2019-06-12 2022-02-21 에스크진 파마, 아이엔씨. New IL-15 prodrugs and how to use them
MA56533A (en) 2019-06-18 2022-04-27 Janssen Sciences Ireland Unlimited Co COMBINATION OF HEPATITIS B VIRUS (HBV) VACCINES AND ANTI-PD-1 ANTIBODIES
JP2022536850A (en) 2019-06-18 2022-08-19 ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー Combination of hepatitis B virus (HBV) vaccine and anti-PD-1 or anti-PD-L1 antibody
TWI761869B (en) 2019-06-25 2022-04-21 大陸商信達生物製藥（蘇州）有限公司 Formulation containing anti-cd47 / pd-l1 bispecific antibody and preparation and use thereof
JP2022538974A (en) 2019-06-26 2022-09-07 マサチューセッツ インスチテュート オブ テクノロジー Immunomodulatory fusion protein-metal hydroxide complexes and methods thereof
KR20220026585A (en) 2019-06-26 2022-03-04 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 IL1RAP binding protein
WO2020260547A1 (en) 2019-06-27 2020-12-30 Rigontec Gmbh Design method for optimized rig-i ligands
BR112021026517A2 (en) 2019-06-28 2022-05-10 Kymera Therapeutics Inc Irak degraders and uses thereof
JP2022539248A (en) 2019-07-02 2022-09-07 フレッド ハッチンソン キャンサー リサーチ センター Recombinant AD35 vectors and related gene therapy improvements
JP2022539208A (en) 2019-07-03 2022-09-07 スミトモ ファーマ オンコロジー， インコーポレイテッド Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
WO2021007269A1 (en) 2019-07-09 2021-01-14 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US20220356255A1 (en) * 2019-07-15 2022-11-10 Capella Bioscience Ltd Anti-pd-l1 antibodies
WO2021011868A1 (en) 2019-07-17 2021-01-21 Kymera Therapeutics, Inc. Irak degraders and uses thereof
GB201910305D0 (en) 2019-07-18 2019-09-04 Ctxt Pty Ltd Compounds
GB201910304D0 (en) 2019-07-18 2019-09-04 Ctxt Pty Ltd Compounds
US12036204B2 (en) 2019-07-26 2024-07-16 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
US11083705B2 (en) 2019-07-26 2021-08-10 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
TWI860386B (en) 2019-07-30 2024-11-01 英商拜西可泰克斯有限公司 Heterotandem bicyclic peptide complex
WO2021023698A1 (en) 2019-08-02 2021-02-11 Lanthiopep B.V Angiotensin type 2 (at2) receptor agonists for use in the treatment of cancer
PH12022550244A1 (en) 2019-08-05 2022-12-12 Nat Cancer Ct Biomarkers for determining the efficacy of immune checkpoint inhibitors
WO2021024020A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
KR20220061977A (en) 2019-08-12 2022-05-13 퓨리노미아 바이오테크, 아이엔씨. Methods and compositions for promoting and enhancing T cell mediated immune response through ADCC targeting of CD39 expressing cells
TW202115024A (en) 2019-08-14 2021-04-16 美商英塞特公司 Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2021030665A1 (en) 2019-08-15 2021-02-18 Silverback Therapeutics, Inc. Formulations of benzazepine conjugates and uses thereof
GB201912107D0 (en) 2019-08-22 2019-10-09 Amazentis Sa Combination
EP4017882A4 (en) * 2019-08-23 2023-09-27 Wuxi Biologics Ireland Limited HUMANIZED ANTIBODIES AGAINST PD-L1
US20220305048A1 (en) 2019-08-26 2022-09-29 Dana-Farber Cancer Institute, Inc. Use of heparin to promote type 1 interferon signaling
AR119821A1 (en) 2019-08-28 2022-01-12 Bristol Myers Squibb Co SUBSTITUTED PYRIDOPYRIMIDINOL COMPOUNDS USEFUL AS T-CELL ACTIVATORS
WO2021037007A1 (en) * 2019-08-29 2021-03-04 荣昌生物制药(烟台)股份有限公司 Anti pd-l1 antibody and use thereof
WO2021042066A1 (en) 2019-08-30 2021-03-04 Foundation Medicine, Inc. Kmt2a-maml2 fusion molecules and uses thereof
TW202122420A (en) 2019-08-30 2021-06-16 美商艾吉納斯公司 Anti-cd96 antibodies and methods of use thereof
WO2021043961A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy
WO2021048292A1 (en) 2019-09-11 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
CN114945366B (en) 2019-09-13 2025-01-07 林伯士萨顿公司 HPK1 antagonists and uses thereof
US20220372160A1 (en) 2019-09-16 2022-11-24 Surface Oncology, Inc. Anti-CD39 Antibody Compositions and Methods
WO2021055306A1 (en) 2019-09-16 2021-03-25 Bristol-Myers Squibb Company Dual capture method for analysis of antibody-drug conjugates
JP2022548747A (en) 2019-09-17 2022-11-21 バイアル－アールアンドディー インベストメンツ ソシエダッド アノニマ Substituted N-heterocyclic carboxamides as acid ceramidase inhibitors and their use as pharmaceuticals
KR20220100860A (en) 2019-09-17 2022-07-18 비알 - 알&디 인베스트먼츠, 에스.에이. Substituted, saturated and unsaturated N-heterocyclic carboxamides and related compounds for use in the treatment of diseases
KR20220100858A (en) 2019-09-17 2022-07-18 비알 - 알&디 인베스트먼츠, 에스.에이. Substituted imidazole carboxamides and their use in the treatment of diseases
WO2021055816A1 (en) 2019-09-18 2021-03-25 Molecular Templates, Inc. Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds
CN114423793A (en) 2019-09-18 2022-04-29 分子模板公司 PD-L1 Binding Molecules Containing Shigella Toxin A Subunit Scaffolds
TW202124446A (en) 2019-09-18 2021-07-01 瑞士商諾華公司 Combination therapies with entpd2 antibodies
MX2022003192A (en) 2019-09-18 2022-04-11 Novartis Ag NKG2D FUSION PROTEINS AND THEIR USES.
CN114786776B (en) 2019-09-18 2026-03-24 拉姆卡普生物阿尔法股份公司 Bispecific antibodies against CEACAM5 and CD3
US20220348651A1 (en) 2019-09-18 2022-11-03 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
EP4031575A1 (en) 2019-09-19 2022-07-27 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
JP7732977B2 (en) 2019-09-20 2025-09-02 トランスジーン Combination of poxvirus encoding HPV polypeptides and IL-2 with anti-PD-L1 antibodies
CA3153777A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
MX2022003719A (en) 2019-09-25 2022-04-26 Surface Oncology Inc ANTI-IL-27 ANTIBODIES AND THEIR USES.
US20220339249A1 (en) 2019-09-25 2022-10-27 Bristol-Myers Squibb Company Composite biomarker for cancer therapy
AU2020353055B2 (en) 2019-09-26 2024-03-07 Gilead Sciences, Inc. Antiviral pyrazolopyridinone compounds
AU2020353660A1 (en) * 2019-09-26 2022-04-14 Orionis Biosciences, Inc. PD-L1 targeted chimeric proteins and uses thereof
JP7280387B2 (en) 2019-09-27 2023-05-23 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド antigen binding protein
EP4048693A1 (en) 2019-09-27 2022-08-31 F. Hoffmann-La Roche AG Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
US20220356221A1 (en) 2019-09-28 2022-11-10 AskGene Pharma, Inc. Cytokine prodrugs and dual-prodrugs
CN114514037B (en) 2019-09-30 2024-12-27 阿斯利康(瑞典)有限公司 Combination therapy for cancer
WO2021067217A1 (en) 2019-09-30 2021-04-08 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
WO2021067374A1 (en) 2019-10-01 2021-04-08 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
EP3800201A1 (en) 2019-10-01 2021-04-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Cd28h stimulation enhances nk cell killing activities
CA3151322A1 (en) 2019-10-01 2021-04-08 Silverback Therapeutics, Inc. Combination therapy with immune stimulatory conjugates
CN115916233A (en) 2019-10-03 2023-04-04 Xencor股份有限公司 Targeting IL-12 heterodimeric Fc fusion protein
WO2021064180A1 (en) 2019-10-03 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating macrophages polarization
WO2021064184A1 (en) 2019-10-04 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer
AU2020358859A1 (en) * 2019-10-04 2022-05-12 Seagen Inc. Anti-PD-L1 antibodies and antibody-drug conjugates
TW202128757A (en) 2019-10-11 2021-08-01 美商建南德克公司 Pd-1 targeted il-15/il-15ralpha fc fusion proteins with improved properties
AU2020364007A1 (en) 2019-10-11 2022-04-28 Incyte Corporation Bicyclic amines as CDK2 inhibitors
WO2021076574A2 (en) 2019-10-14 2021-04-22 Aro Biotherapeutics Company Fn3 domain-sirna conjugates and uses thereof
TWI891666B (en) 2019-10-14 2025-08-01 美商英塞特公司 Bicyclic heterocycles as fgfr inhibitors
CN114786682B (en) 2019-10-14 2024-07-16 Aro生物疗法公司 Fibronectin type III domain that binds CD71
WO2021076543A1 (en) 2019-10-14 2021-04-22 Aro Biotherapeutics Company Epcam binding fibronectin type iii domains
WO2021074683A1 (en) 2019-10-16 2021-04-22 Avacta Life Sciences Limited Bispecific anti-pd-l1 and anti-fcrn polypeptides
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US20240301497A1 (en) 2019-10-17 2024-09-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing nasal intestinal type adenocarcinomas
TW202128191A (en) 2019-10-21 2021-08-01 瑞士商諾華公司 Tim-3 inhibitors and uses thereof
CN114786679A (en) 2019-10-21 2022-07-22 诺华股份有限公司 Combination therapy with Vernetork and TIM-3 inhibitors
EP4048795A1 (en) 2019-10-23 2022-08-31 Checkmate Pharmaceuticals, Inc. Synthetic rig-i-like receptor agonists
US11459389B2 (en) 2019-10-24 2022-10-04 Massachusetts Institute Of Technology Monoclonal antibodies that bind human CD161
JP2022553389A (en) 2019-10-25 2022-12-22 アイオバンス バイオセラピューティクス，インコーポレイテッド Gene editing of tumor-infiltrating lymphocytes and its use in immunotherapy
CN112724127B (en) 2019-10-28 2023-02-17 中国科学院上海药物研究所 Five-membered heteroepoxy carboxylic acid compound and its medical application
MX2022005056A (en) 2019-10-29 2022-05-18 Eisai R&D Man Co Ltd COMBINATION OF A PD-1 ANTAGONIST, A VEGFR/FGFR/RET TYROSINE KINASE INHIBITOR AND A CBP/BETA-CATENIN INHIBITOR FOR THE TREATMENT OF CANCER.
EP4051286A1 (en) 2019-10-29 2022-09-07 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods and compositions for treating uveal melanoma
US11987612B2 (en) 2019-11-04 2024-05-21 Alector Llc Siglec-9 ECD fusion molecules
EP4054591A1 (en) 2019-11-04 2022-09-14 Astrazeneca AB Combination therapy for treating cancer
JP2022554346A (en) 2019-11-05 2022-12-28 セルジーン コーポレーション Combination with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide therapy
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
AU2020378330A1 (en) 2019-11-06 2022-05-12 F. Hoffmann-La Roche Ag Diagnostic and therapeutic methods for treatment of hematologic cancers
CA3151629A1 (en) 2019-11-07 2021-05-14 Laura E. BENJAMIN Classification of tumor microenvironments
BR112022008191A2 (en) 2019-11-08 2022-07-12 Bristol Myers Squibb Co LAG-3 ANTAGONIST THERAPY FOR MELANOMA
BR112022009031A2 (en) 2019-11-11 2022-10-11 Incyte Corp SALTS AND CRYSTALLINE FORMS OF A PD-1/PD-L1 INHIBITOR
EP4058593A4 (en) 2019-11-12 2023-11-15 Foundation Medicine, Inc. METHOD FOR DETECTING A FUSION GENE CODING A NEOANTIGEN
CN114728905B (en) 2019-11-13 2025-08-01 基因泰克公司 Therapeutic compounds and methods of use
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
AU2020387392B2 (en) 2019-11-19 2025-09-11 Bristol-Myers Squibb Company Compounds useful as inhibitors of Helios protein
CN114728941A (en) 2019-11-22 2022-07-08 施万生物制药研发Ip有限责任公司 Substituted 1,5-naphthyridines or quinolines as ALK5 inhibitors
WO2021102343A1 (en) 2019-11-22 2021-05-27 Sumitomo Dainippon Pharma Oncology, Inc. Solid dose pharmaceutical composition
US20210154281A1 (en) 2019-11-26 2021-05-27 Massachusetts Institute Of Technology Cell-based cancer vaccines and cancer therapies
IL292924A (en) 2019-11-26 2022-07-01 Novartis Ag Cd19 and cd22 chimeric antigen receptors and uses thereof
PT4065582T (en) 2019-11-26 2025-05-22 Ikena Oncology Inc Polymorphic carbazole derivatives and uses thereof
WO2021108288A1 (en) 2019-11-26 2021-06-03 Bristol-Myers Squibb Company Salts/cocrystals of (r)-n-(4-chlorophenyl)-2-((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide
GB201917254D0 (en) 2019-11-27 2020-01-08 Adc Therapeutics Sa Combination therapy
EP3831849A1 (en) 2019-12-02 2021-06-09 LamKap Bio beta AG Bispecific antibodies against ceacam5 and cd47
EP4069696A1 (en) 2019-12-04 2022-10-12 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
BR112022010664A2 (en) 2019-12-04 2022-08-16 Incyte Corp DERIVATIVES OF A FGFR INHIBITOR
WO2021113679A1 (en) 2019-12-06 2021-06-10 Mersana Therapeutics, Inc. Dimeric compounds as sting agonists
US11897950B2 (en) 2019-12-06 2024-02-13 Augusta University Research Institute, Inc. Osteopontin monoclonal antibodies
US12551564B2 (en) 2019-12-10 2026-02-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12516291B2 (en) 2019-12-11 2026-01-06 Iovance Biotherapeutics, Inc. Processes for the production of tumor infiltrating lymphocytes (TILs) and methods of using the same
JP7807076B2 (en) 2019-12-13 2026-01-27 キュージーン インコーポレイテッド Novel interleukin-15 (IL-15) fusion proteins and uses thereof
JP2023509359A (en) 2019-12-17 2023-03-08 フラグシップ パイオニアリング イノベーションズ ブイ，インコーポレーテッド Combination anticancer therapy with inducers of iron-dependent cell degradation
WO2021126725A1 (en) 2019-12-17 2021-06-24 Merck Sharp & Dohme Corp. Novel substituted 1,3,8-triazaspiro[4,5]decane-2,4-dione compounds as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (tdo) inhibitors
WO2021127283A2 (en) 2019-12-17 2021-06-24 Kymera Therapeutics, Inc. Irak degraders and uses thereof
WO2021127190A1 (en) 2019-12-17 2021-06-24 Kymera Therapeutics, Inc. Irak degraders and uses thereof
CN114981265B (en) 2019-12-18 2025-01-03 Ctxt私人有限公司 Compound
BR112022009631A2 (en) 2019-12-19 2022-08-09 Bristol Myers Squibb Co COMBINATIONS OF DGK INHIBITORS AND CHECKPOINT ANTAGONISTS
EP4076508A1 (en) 2019-12-19 2022-10-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and vaccine compositions to treat cancers
MX2022007759A (en) 2019-12-20 2022-07-19 Novartis Ag Combination of anti tim-3 antibody mbg453 and anti tgf-beta antibody nis793, with or without decitabine or the anti pd-1 antibody spartalizumab, for treating myelofibrosis and myelodysplastic syndrome.
CN114846007B (en) 2019-12-23 2024-11-22 百时美施贵宝公司 Substituted quinazoline compounds useful as T cell activators
BR112022012410A2 (en) 2019-12-23 2022-08-30 Kymera Therapeutics Inc SMARCA DEGRADATORS AND USE THEREOF
KR20220119456A (en) 2019-12-23 2022-08-29 브리스톨-마이어스 스큅 컴퍼니 Substituted Quinolinonyl Piperazine Compounds Useful as T Cell Activators
EP4081522A1 (en) 2019-12-23 2022-11-02 Bristol-Myers Squibb Company Substituted piperazine derivatives useful as t cell activators
WO2021133917A1 (en) 2019-12-23 2021-07-01 Kymera Therapeutics, Inc. Smarca inhibitors and uses thereof
IL294273A (en) 2019-12-23 2022-08-01 Bristol Myers Squibb Co Substituted heteroaryl compounds useful as t cell activators
AR120823A1 (en) 2019-12-23 2022-03-23 Bristol Myers Squibb Co SUBSTITUTED BICYCLIC COMPOUNDS USEFUL AS T-CELL ACTIVATORS
CN113045655A (en) 2019-12-27 2021-06-29 高诚生物医药(香港)有限公司 anti-OX 40 antibodies and uses thereof
MX2022008208A (en) 2020-01-03 2022-10-21 Incyte Corp COMBINATION THERAPY COMPRISING A2A/A2B INHIBITORS AND PROGRAMMED DEATH PROTEIN 1/PROGRAMMED DEATH LIGAND 1 (PD-1/PDL1).
CN116234829A (en) 2020-01-03 2023-06-06 马伦戈治疗公司 Anti-TCR antibody molecules and uses thereof
WO2021138407A2 (en) 2020-01-03 2021-07-08 Marengo Therapeutics, Inc. Multifunctional molecules that bind to cd33 and uses thereof
BR112022013424A2 (en) 2020-01-06 2022-12-13 Hifibio Hk Ltd ANTI-TNFR2 ANTIBODY AND ITS USES
EP4087857B1 (en) 2020-01-06 2023-11-01 Bristol-Myers Squibb Company Immunomodulators
KR20220123105A (en) 2020-01-07 2022-09-05 하이파이바이오 (에이치케이) 리미티드 Anti-galectin-9 antibodies and uses thereof
EP4087583B1 (en) 2020-01-07 2026-04-22 Merck Sharp & Dohme LLC Arginase inhibitors and methods of use
CN115244052A (en) 2020-01-10 2022-10-25 先天肿瘤免疫公司 NLRP3 modulators
WO2021142471A1 (en) 2020-01-11 2021-07-15 AskGene Pharma, Inc. Novel masked cytokines and methods of use thereof
EP4090674A4 (en) 2020-01-14 2024-01-24 Synthekine, Inc. METHODS AND COMPOSITIONS OF BIASED IL2 MUTEINS
EP4090663A1 (en) 2020-01-15 2022-11-23 Blueprint Medicines Corporation Map4k1 inhibitors
WO2021146424A1 (en) 2020-01-15 2021-07-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
JP2023510393A (en) 2020-01-17 2023-03-13 ノバルティス アーゲー A combination comprising a TIM-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia
EP4090770A1 (en) 2020-01-17 2022-11-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2022050954A1 (en) 2020-09-04 2022-03-10 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
EP4096718A1 (en) 2020-01-28 2022-12-07 GlaxoSmithKline Intellectual Property Development Limited Combination treatments and uses and methods thereof
KR20220132598A (en) 2020-01-28 2022-09-30 제넨테크, 인크. IL15/IL15R alpha heterodimer Fc-fusion protein for cancer treatment
WO2021152548A1 (en) 2020-01-30 2021-08-05 Benitah Salvador Aznar Combination therapy for treatment of cancer and cancer metastasis
WO2021152400A1 (en) 2020-01-30 2021-08-05 Gnubiotics Sciences Sa Compositions comprising pig stomach mucins and uses thereof
MX2022009391A (en) 2020-01-31 2022-09-26 Genentech Inc Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine.
US20230072528A1 (en) 2020-02-05 2023-03-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki)
KR20220139915A (en) 2020-02-06 2022-10-17 브리스톨-마이어스 스큅 컴퍼니 IL-10 and its uses
EP4100016A1 (en) 2020-02-07 2022-12-14 AI Therapeutics, Inc. Anti-viral compositions and methods of use
JP2023513834A (en) 2020-02-18 2023-04-03 アレクトル エルエルシー PILRA antibody and method of use thereof
JP7735291B2 (en) 2020-02-21 2025-09-08 エーアールエス ファーマシューティカルズ、インコーポレイテッド Nectin-4 antibody conjugates and uses thereof
IL295896A (en) 2020-02-26 2022-10-01 Biograph 55 Inc C19 c38 bispecific antibodies
US20230113705A1 (en) 2020-02-28 2023-04-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing, prognosing and managing treatment of breast cancer
JP2023515633A (en) 2020-02-28 2023-04-13 ブリストル－マイヤーズ スクイブ カンパニー Radiolabeled fibronectin-based scaffolds and antibodies and their theranostic uses
TW202146452A (en) 2020-02-28 2021-12-16 瑞士商諾華公司 Dosing of a bispecific antibody that binds cd123 and cd3
AU2021230289A1 (en) 2020-03-03 2022-09-29 PIC Therapeutics, Inc. eIF4E inhibitors and uses thereof
IL296103A (en) 2020-03-05 2022-11-01 Neotx Therapeutics Ltd Methods and preparations for treating cancer with immune cells
US20230114276A1 (en) 2020-03-06 2023-04-13 Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Modulating anti-tumor immunity
EP4114401A1 (en) 2020-03-06 2023-01-11 Incyte Corporation Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors
EP4114398A1 (en) 2020-03-06 2023-01-11 Celgene Quanticel Research, Inc. Combination of an lsd-1 inhibitor and nivolumab for use in treating sclc or sqnsclc
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
US20230235073A1 (en) 2020-03-06 2023-07-27 Ona Therapeutics, S.L. Anti-cd36 antibodies and their use to treat cancer
US20230093147A1 (en) 2020-03-09 2023-03-23 President And Fellows Of Harvard College Methods and compositions relating to improved combination therapies
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
US12528785B2 (en) 2020-03-19 2026-01-20 Kymera Therapeutics, Inc. MDM2 degraders and uses thereof
CN115298165B (en) 2020-03-19 2024-09-17 艾库斯生物科学有限公司 Tetralin and tetrahydroquinoline compounds as HIF-2α inhibitors
TW202140441A (en) 2020-03-23 2021-11-01 美商必治妥美雅史谷比公司 Substituted oxoisoindoline compounds
US20230119066A1 (en) 2020-03-23 2023-04-20 Bristol-Myers Squibb Company Anti-ccr8 antibodies for treating cancer
CN115362166A (en) 2020-03-30 2022-11-18 百时美施贵宝公司 Immunomodulator
TW202204339A (en) 2020-03-31 2022-02-01 美商施萬生物製藥研發 Ip有限責任公司 Substituted pyrimidines and methods of use
EP4127724A1 (en) 2020-04-03 2023-02-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2021206158A1 (en) 2020-04-10 2021-10-14 小野薬品工業株式会社 Method of cancer therapy
KR20230009386A (en) 2020-04-10 2023-01-17 주노 쎄러퓨티크스 인코퍼레이티드 Methods and uses for cell therapy engineered with chimeric antigen receptors targeting B-cell maturation antigens
EP4134134A4 (en) 2020-04-10 2023-12-27 ONO Pharmaceutical Co., Ltd. STING AGONIST COMPOUND
AU2021256925A1 (en) 2020-04-14 2022-11-03 Ares Trading S.A. Combination treatment for cancer based upon an ICOS antibody and a PD-L1 antibody TGF-beta-receptor fusion protein
CA3179692A1 (en) 2020-04-16 2021-10-21 Incyte Corporation Fused tricyclic kras inhibitors
WO2021216572A1 (en) 2020-04-20 2021-10-28 Massachusetts Institute Of Technology Lipid compositions for delivery of sting agonist compounds and uses thereof
EP4139341A1 (en) 2020-04-21 2023-03-01 Regeneron Pharmaceuticals, Inc. Il-2 variants with reduced binding to il-2 receptor alpha and uses thereof
US12159700B2 (en) 2020-04-22 2024-12-03 Iovance Biotherapeutics, Inc. Systems and methods for coordinating manufacturing of cells for patient-specific immunotherapy
US20230272041A1 (en) 2020-04-22 2023-08-31 Dragonfly Therapeutics, Inc. Formulation, Dosage Regimen, and Manufacturing Process for Heterodimeric FC-Fused Proteins
TW202206100A (en) 2020-04-27 2022-02-16 美商西健公司 Treatment for cancer
EP4143345A1 (en) 2020-04-28 2023-03-08 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
US20230181756A1 (en) 2020-04-30 2023-06-15 Novartis Ag Ccr7 antibody drug conjugates for treating cancer
BR112022022335A2 (en) 2020-05-05 2023-01-10 Teon Therapeutics Inc TYPE 2 CANNABINOID RECEPTOR MODULATORS AND USES THEREOF
JP2023524257A (en) 2020-05-05 2023-06-09 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Prediction of response to PD-1 axis inhibitors
CN115836054B (en) 2020-05-06 2024-12-10 默沙东有限责任公司 IL4I1 inhibitors and methods of use
JP7748393B2 (en) 2020-05-08 2025-10-02 アルパイン イミューン サイエンシズ インコーポレイテッド APRIL and BAFF-inhibitory immunomodulatory proteins and methods of use thereof
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
WO2021231773A1 (en) 2020-05-13 2021-11-18 Good Therapeutics, Inc. Compositions of protein complexes and methods of use thereof
JP7776145B2 (en) 2020-05-13 2025-11-26 マサチューセッツ インスティテュート オブ テクノロジー Compositions of polymeric microdevices and their use in cancer immunotherapy
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
WO2021239838A2 (en) 2020-05-26 2021-12-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes
MX2022014734A (en) 2020-05-26 2023-03-15 Regeneron Pharma Methods of treating cervical cancer by administering the pd-1 inhibitor antibody cemiplimab.
EP4157319A1 (en) 2020-05-28 2023-04-05 Modernatx, Inc. Use of mrnas encoding ox40l, il-23 and il-36gamma for treating cancer
EP4157923A2 (en) 2020-05-29 2023-04-05 President And Fellows Of Harvard College Living cells engineered with polyphenol-functionalized biologically active nanocomplexes
BR112022024221A2 (en) 2020-06-02 2022-12-20 Arcus Biosciences Inc ANTIBODIES TO TIGIT
TW202210483A (en) 2020-06-03 2022-03-16 美商凱麥拉醫療公司 Crystalline forms of irak degraders
WO2021247897A1 (en) 2020-06-03 2021-12-09 Kymera Therapeutics, Inc. Deuterated irak degraders and uses thereof
US11767353B2 (en) 2020-06-05 2023-09-26 Theraly Fibrosis, Inc. Trail compositions with reduced immunogenicity
CN116323607A (en) 2020-06-10 2023-06-23 施万生物制药研发Ip有限责任公司 Naphthyridine derivatives useful as ALK5 inhibitors
WO2021249969A1 (en) 2020-06-10 2021-12-16 Merck Patent Gmbh Combination product for the treatment of cancer diseases
WO2021252977A1 (en) 2020-06-12 2021-12-16 Genentech, Inc. Methods and compositions for cancer immunotherapy
MX2022015877A (en) 2020-06-16 2023-01-24 Genentech Inc Methods and compositions for treating triple-negative breast cancer.
CN115916348A (en) 2020-06-18 2023-04-04 基因泰克公司 Treatment with Anti-TIGIT Antibodies and PD-1 Axis Binding Antagonists
WO2021258010A1 (en) 2020-06-19 2021-12-23 Gossamer Bio Services, Inc. Oxime compounds useful as t cell activators
AR122644A1 (en) 2020-06-19 2022-09-28 Onxeo NEW CONJUGATED NUCLEIC ACID MOLECULES AND THEIR USES
CN111925434B (en) * 2020-06-22 2023-06-27 南昌大学 A screening method for monoclonal antibodies
CN115916199A (en) 2020-06-23 2023-04-04 诺华股份有限公司 Dosage regimens comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2021262969A1 (en) 2020-06-24 2021-12-30 The General Hospital Corporation Materials and methods of treating cancer
CN115916191A (en) 2020-06-25 2023-04-04 新基公司 Methods of treating cancer with combination therapies
MX2022016548A (en) 2020-06-26 2023-03-14 Amgen Inc Il-10 muteins and fusion proteins thereof.
JP2023532339A (en) 2020-06-29 2023-07-27 フラグシップ パイオニアリング イノベーションズ ブイ，インコーポレーテッド Viruses engineered to promote sanotransmission and their use in treating cancer
CN115997123A (en) 2020-06-30 2023-04-21 国家医疗保健研究所 Method for predicting risk of recurrence and/or death in patients with solid cancer following preoperative adjuvant therapy
JP7741831B2 (en) 2020-06-30 2025-09-18 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル Method for predicting the risk of recurrence and/or death in patients with solid tumors after neoadjuvant therapy and curative surgery - Patent Application 20070122997
US20230250173A1 (en) 2020-07-01 2023-08-10 Pfizer Inc. Biomarkers for pd-1 axis binding antagonist therapy
JP2023532304A (en) 2020-07-01 2023-07-27 エーアールエス ファーマシューティカルズ オペレーションズ，インク． Anti-ASGR1 antibody conjugates and uses thereof
US12472176B2 (en) 2020-07-07 2025-11-18 Celgene Corporation Pharmaceutical compositions comprising (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same
MX2023000197A (en) 2020-07-07 2023-02-22 BioNTech SE THERAPEUTIC RNA FOR HPV POSITIVE CANCER.
TW202216778A (en) 2020-07-15 2022-05-01 美商安進公司 Tigit and cd112r blockade
US11787775B2 (en) 2020-07-24 2023-10-17 Genentech, Inc. Therapeutic compounds and methods of use
WO2022023379A1 (en) 2020-07-28 2022-02-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for preventing and treating a cancer
TW202221031A (en) 2020-07-30 2022-06-01 英商阿法克塔生命科學有限公司 Serum half-life extended pd-l1 inhibitory polypeptides
US11857535B2 (en) 2020-07-30 2024-01-02 Kymera Therapeutics, Inc. Methods of treating mutant lymphomas
US20230271940A1 (en) 2020-08-03 2023-08-31 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
IL300248A (en) 2020-08-03 2023-03-01 Bicycletx Ltd Peptide-based linkers
JP7743500B2 (en) 2020-08-05 2025-09-24 シンセカイン インコーポレイテッド IL10 receptor binding molecules and methods of use
BR112023001723A2 (en) 2020-08-05 2023-05-02 Synthekine Inc GP130 BINDING MOLECULES AND METHODS OF USE
JP7819178B2 (en) 2020-08-05 2026-02-24 シンセカイン インコーポレイテッド IL10Rb binding molecules and methods of use
KR20230061394A (en) 2020-08-05 2023-05-08 신테카인, 인크. IL10Ra Binding Molecules and Methods of Use
US20230272094A1 (en) 2020-08-05 2023-08-31 Synthekine, Inc. Il2rb/il2rg synthetic cytokines
CN116724051A (en) 2020-08-10 2023-09-08 上海寻百会生物技术有限公司 Compositions and methods for treating autoimmune diseases and cancer by targeting IGSF8
EP4196612A1 (en) 2020-08-12 2023-06-21 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2022038158A1 (en) 2020-08-17 2022-02-24 Bicycletx Limited Bicycle conjugates specific for nectin-4 and uses thereof
EP4199947A4 (en) 2020-08-18 2024-10-16 Onchilles Pharma, Inc. MODIFIED PORCINE PANCREATIC ELASTASE PROTEINS
JP2023540217A (en) 2020-08-26 2023-09-22 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Method of treating cancer by administering a PD-1 inhibitor
KR20230074487A (en) 2020-08-26 2023-05-30 마렝고 테라퓨틱스, 인크. How to detect TRBC1 or TRBC2
BR112023003427A2 (en) 2020-08-28 2023-03-21 Bristol Myers Squibb Co LAG-3 ANTAGONIST THERAPY FOR HEPATOCELLULAR CARCINOMA
US11999752B2 (en) 2020-08-28 2024-06-04 Incyte Corporation Vinyl imidazole compounds as inhibitors of KRAS
AU2021334361A1 (en) 2020-08-31 2023-05-11 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
KR20230087451A (en) 2020-09-02 2023-06-16 주식회사 파멥신 Combination therapy of a PD-1 antagonist and an antagonist to VEGFR-2 for treating cancer patients
JP2023542490A (en) 2020-09-03 2023-10-10 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Method of treating cancer pain by administering a PD-1 inhibitor
CN114316045B (en) * 2020-09-29 2024-07-12 英诺欧奇生物医药(苏州)有限公司 Anti-PD-L1 antibodies and uses thereof
US20230340132A1 (en) * 2020-09-30 2023-10-26 Na Biotech Corp ANTI-ADENOSINE RECEPTOR (A2aR) ANTIBODIES
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
US20230374064A1 (en) 2020-10-05 2023-11-23 Bristol-Myers Squibb Company Methods for concentrating proteins
WO2022076596A1 (en) 2020-10-06 2022-04-14 Codiak Biosciences, Inc. Extracellular vesicle-aso constructs targeting stat6
US20230372397A1 (en) 2020-10-06 2023-11-23 Iovance Biotherapeutics, Inc. Treatment of nsclc patients with tumor infiltrating lymphocyte therapies
IL300024A (en) 2020-10-20 2023-03-01 Hoffmann La Roche Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors
AR123855A1 (en) 2020-10-20 2023-01-18 Genentech Inc PEG-CONJUGATED ANTI-MERTK ANTIBODIES AND METHODS OF USE
WO2022084531A1 (en) 2020-10-23 2022-04-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating glioma
IL302346A (en) 2020-10-28 2023-06-01 Ikena Oncology Inc Combination of an AHR inhibitor with a PDX inhibitor or doxorubicin
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
KR20230100732A (en) 2020-11-04 2023-07-05 제넨테크, 인크. Subcutaneous Administration of Anti-CD20/Anti-CD3 Bispecific Antibodies
AU2021374594B2 (en) 2020-11-04 2026-03-05 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates
CA3196539A1 (en) 2020-11-04 2022-05-12 Chi-Chung Li Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US20240025993A1 (en) 2020-11-06 2024-01-25 Novartis Ag Cd19 binding molecules and uses thereof
WO2022099075A1 (en) 2020-11-06 2022-05-12 Incyte Corporation Crystalline form of a pd-1/pd-l1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
IL302402A (en) 2020-11-08 2023-06-01 Seagen Inc Combination therapy
CA3200878A1 (en) 2020-11-12 2022-05-19 Inserm (Institut National De La Sante Et De La Recherche Medicale) Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes
US20230390303A1 (en) 2020-11-13 2023-12-07 Ono Pharmaceutical Co., Ltd. Cancer treatment by combination of ep4 antagonist and immune checkpoint inhibitor
US12171763B2 (en) 2020-11-13 2024-12-24 Genentech, Inc. Methods and compositions comprising a KRASG12C inhibitor and a PD-L1 binding antagonist for treating lung cancer
WO2022101463A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death
WO2022101481A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
US20230416838A1 (en) 2020-11-16 2023-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
WO2022108931A2 (en) 2020-11-17 2022-05-27 Seagen Inc. Methods of treating cancer with a combination of tucatinib and an anti-pd-1/anti-pd-l1 antibody
WO2022120353A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
KR20230117162A9 (en) 2020-12-02 2024-03-21 제넨테크, 인크. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
EP4255895A1 (en) 2020-12-02 2023-10-11 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
PH12023500013A1 (en) 2020-12-04 2024-03-11 Tidal Therapeutics Inc Ionizable cationic lipids and lipi nanoparticles, and methods of synthesis and use thereof
EP4259149A1 (en) 2020-12-08 2023-10-18 Infinity Pharmaceuticals, Inc. Eganelisib for use in the treatment of pd-l1 negative cancer
WO2022121846A1 (en) * 2020-12-08 2022-06-16 博际生物医药科技(杭州)有限公司 Pd-l1 antibody and application thereof
EP4259144A4 (en) 2020-12-09 2025-08-20 Kymera Therapeutics Inc SMARCA DECORATORS AND USES THEREOF
TW202237119A (en) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Alk-5 inhibitors and uses thereof
EP4262986A1 (en) 2020-12-16 2023-10-25 Gossamer Bio Services, Inc. Compounds useful as t cell activators
EP4262858A1 (en) 2020-12-16 2023-10-25 Molecular Templates, Inc. Clinical methods for use of a pd-l1-binding molecule comprising a shiga toxin effector
ES2967381T3 (en) 2020-12-18 2024-04-30 Lamkap Bio Beta Ag Bispecific antibodies against CEACAM5 and CD47
TW202245808A (en) 2020-12-21 2022-12-01 德商拜恩迪克公司 Therapeutic rna for treating cancer
WO2022135666A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022135667A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
SMT202500208T1 (en) 2020-12-28 2025-07-22 Bristol Myers Squibb Co Antibody compositions and methods of use thereof
JP2024501029A (en) 2020-12-28 2024-01-10 ブリストル－マイヤーズ スクイブ カンパニー Subcutaneous administration of PD1/PD-L1 antibodies
MX2023007850A (en) 2020-12-29 2023-09-11 Incyte Corp Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies.
PH12023500015A1 (en) 2020-12-30 2024-03-11 Kymera Therapeutics Inc Irak degraders and uses thereof
JP2024501894A (en) 2021-01-04 2024-01-16 メルサナ セラピューティクス インコーポレイテッド B7H4 targeting antibody-drug conjugates and methods of use thereof
US20250186539A2 (en) 2021-01-11 2025-06-12 Bicycletx Limited Methods for treating cancer
WO2022150788A2 (en) 2021-01-11 2022-07-14 Synthekine, Inc. Compositions and methods related to receptor pairing
EP4277707A1 (en) 2021-01-14 2023-11-22 Askgene Pharma, Inc. Interferon prodrugs and methods of making and using the same
CN116963773A (en) 2021-01-21 2023-10-27 浙江养生堂天然药物研究所有限公司 Compositions and methods for treating tumors
WO2022162569A1 (en) 2021-01-29 2022-08-04 Novartis Ag Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof
US20240423972A1 (en) 2021-02-01 2024-12-26 Yale University Chemotherapeutic bioadhesive particles with immunostimulatory molecules for cancer treatment
EP4288427A1 (en) 2021-02-02 2023-12-13 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
JP2024506858A (en) 2021-02-02 2024-02-15 リミナル・バイオサイエンシーズ・リミテッド GPR84 antagonists and their uses
AR124800A1 (en) 2021-02-03 2023-05-03 Genentech Inc LACTAMS AS CBL-B INHIBITORS
WO2022169998A1 (en) 2021-02-03 2022-08-11 Genentech, Inc. Amides as cbl-b inhibitors
WO2022171121A1 (en) 2021-02-10 2022-08-18 同润生物医药(上海)有限公司 Method and combination for treating tumors
BR112023016025A2 (en) * 2021-02-10 2023-10-31 Jiangxi Jemincare Group Co Ltd ANTI-PD-L1 ANTIBODY AND USE THEREOF
CN117120090A (en) 2021-02-12 2023-11-24 林伯士萨顿公司 HPK1 antagonists and uses thereof
JP7821808B2 (en) 2021-02-12 2026-02-27 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Bicyclic tetrahydroazepine derivatives for the treatment of cancer
WO2022174268A1 (en) 2021-02-15 2022-08-18 Kymera Therapeutics, Inc. Irak4 degraders and uses thereof
CN116867494A (en) 2021-02-15 2023-10-10 凯麦拉医疗公司 IRAK4 degraders and their uses
GB202102396D0 (en) 2021-02-19 2021-04-07 Adc Therapeutics Sa Molecular adjuvant
CN116917273A (en) 2021-03-02 2023-10-20 葛兰素史克知识产权发展有限公司 Substituted pyridines as DNMT1 inhibitors
EP4301756A4 (en) 2021-03-05 2025-02-26 Nimbus Saturn, Inc. HPK1 ANTAGONISTS AND USES THEREOF
WO2022184937A1 (en) 2021-03-05 2022-09-09 Leadartis, S.L. Trimeric polypeptides and uses thereof in the treatment of cancer
JP2024510176A (en) 2021-03-08 2024-03-06 ブループリント メディシンズ コーポレイション MAP4K1 inhibitor
US11918582B2 (en) 2021-03-15 2024-03-05 Rapt Therapeutics, Inc. Pyrazole pyrimidine compounds and uses thereof
CN115073599B (en) * 2021-03-16 2023-04-28 北京天广实生物技术股份有限公司 Antibodies that bind PD-L1 and uses thereof
WO2022194908A1 (en) 2021-03-17 2022-09-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
CN117321418A (en) 2021-03-18 2023-12-29 诺华股份有限公司 Cancer biomarkers and how to use them
CN118459539B (en) 2021-03-19 2026-01-06 生物治疗探索股份有限公司 Compounds for modulating trained immunity and their methods of use
EP4313123A1 (en) 2021-03-23 2024-02-07 Regeneron Pharmaceuticals, Inc. Methods of treating cancer in immunosuppressed or immunocompromised patients by administering a pd-1 inhibitor
US20240344138A1 (en) 2021-03-25 2024-10-17 Feng Biosciences, Inc Targeted therapies in cancer
TW202304506A (en) 2021-03-25 2023-02-01 日商安斯泰來製藥公司 Combination therapy involving antibodies against claudin 18.2 for treatment of cancer
AU2022246174A1 (en) 2021-03-25 2023-09-14 Iovance Biotherapeutics, Inc. Methods and compositions for t-cell coculture potency assays and use with cell therapy products
MX2023011310A (en) 2021-03-26 2023-10-05 Innate Pharma Multispecific proteins comprising an nkp46-binding site, a cancer antgienge binding site fused to a cytokine for nk cell engaging.
US20240181052A1 (en) 2021-03-29 2024-06-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022213062A1 (en) 2021-03-29 2022-10-06 Nimbus Saturn, Inc. Hpk1 antagonists and uses thereof
JP2024511831A (en) 2021-03-31 2024-03-15 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド Antigen binding proteins and combinations thereof
JP2024512669A (en) 2021-03-31 2024-03-19 フラグシップ パイオニアリング イノベーションズ ブイ，インコーポレーテッド Tanotransmission polypeptides and their use in the treatment of cancer
JP2024514530A (en) 2021-04-02 2024-04-02 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Antibodies against truncated CDCP1 and uses thereof
BR112023020410A2 (en) 2021-04-05 2023-11-28 Bristol Myers Squibb Co OXOISOINDOLINE COMPOUNDS REPLACED BY PYRIDINILE FOR CANCER TREATMENT
BR112023020077A2 (en) 2021-04-06 2023-11-14 Bristol Myers Squibb Co OXOISOINDOLINE COMPOUNDS REPLACED BY PYRIDINYL
TW202304979A (en) 2021-04-07 2023-02-01 瑞士商諾華公司 USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
CA3214757A1 (en) 2021-04-08 2022-10-13 Andreas Loew Multifuntional molecules binding to tcr and uses thereof
US12016860B2 (en) 2021-04-08 2024-06-25 Nurix Therapeutics, Inc. Combination therapies with Cbl-b inhibitor compounds
AU2022253351A1 (en) 2021-04-09 2023-10-12 Boehringer Ingelheim International Gmbh New scaffold for bifunctional molecules with improved properties
MX2023011796A (en) 2021-04-09 2024-01-08 Seagen Inc Methods of treating cancer with anti-tigit antibodies.
KR20230167097A (en) 2021-04-09 2023-12-07 제넨테크, 인크. Combination therapy with RAF inhibitors and PD-1 axis inhibitors
CA3215047A1 (en) 2021-04-09 2022-10-13 Lan Huang Therapeutic compositions and methods for treating tumors
AU2022256074A1 (en) 2021-04-09 2023-11-02 Nimbus Clio, Inc. Cbl-b modulators and uses thereof
EP4320156A1 (en) 2021-04-09 2024-02-14 Ose Immunotherapeutics Scaffold for bifunctioanl molecules comprising pd-1 or cd28 and sirp binding domains
TW202304459A (en) 2021-04-12 2023-02-01 美商英塞特公司 Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent
EP4323356A1 (en) 2021-04-13 2024-02-21 Nuvalent, Inc. Amino-substituted heterocycles for treating cancers with egfr mutations
BR112023021318A2 (en) 2021-04-14 2023-12-19 Aro Biotherapeutics Company FN3-SIRNA DOMAIN CONJUGATES AND USES THEREOF
WO2022219080A1 (en) 2021-04-14 2022-10-20 INSERM (Institut National de la Santé et de la Recherche Médicale) New method to improve nk cells cytotoxicity
CA3214552A1 (en) 2021-04-14 2022-10-20 Russell C. Addis Cd71 binding fibronectin type iii domains
CN113150153B (en) * 2021-04-15 2022-05-10 博奥信生物技术（南京）有限公司 Anti-human PDL1 monoclonal antibody and application thereof
CA3235132A1 (en) 2021-04-16 2022-10-20 Novartis Ag Antibody drug conjugates and methods for making thereof
JP2024514879A (en) 2021-04-16 2024-04-03 イケナ オンコロジー， インコーポレイテッド MEK inhibitors and their uses
AU2022262600A1 (en) 2021-04-20 2023-10-05 Seagen Inc. Modulation of antibody-dependent cellular cytotoxicity
US20240158861A1 (en) 2021-04-23 2024-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cell senescence accumulation related disease
EP4330436A1 (en) 2021-04-30 2024-03-06 Genentech, Inc. Therapeutic and diagnostic methods and compositions for cancer
CA3213632A1 (en) 2021-04-30 2022-11-03 F. Hoffmann-La Roche Ag Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate
WO2022227015A1 (en) 2021-04-30 2022-11-03 Merck Sharp & Dohme Corp. Il4i1 inhibitors and methods of use
AU2022271290A1 (en) 2021-05-07 2023-11-23 Kymera Therapeutics, Inc. Cdk2 degraders and uses thereof
US12577299B2 (en) 2021-05-07 2026-03-17 Surface Oncology, LLC Anti-IL-27 antibodies and uses thereof
US12291575B2 (en) 2021-05-14 2025-05-06 Genentech, Inc. Methods for treatment of CD20-positive proliferative disorder with mosunetuzumab and polatuzumab vedotin
US20220396623A1 (en) 2021-05-18 2022-12-15 Kymab Limited Uses of anti-icos antibodies
AR125874A1 (en) 2021-05-18 2023-08-23 Novartis Ag COMBINATION THERAPIES
JP2024521712A (en) 2021-05-21 2024-06-04 アーカス バイオサイエンシーズ，インコーポレーテッド AXL Inhibitor Compounds
CN117295741A (en) 2021-05-21 2023-12-26 艾库斯生物科学有限公司 AXL compounds
US20250282871A1 (en) 2021-05-21 2025-09-11 Tianjin Lipogen Technology Co., Ltd Pharmaceutical combination and use thereof
AU2022281461A1 (en) 2021-05-25 2024-01-04 Edelweiss Immune Inc C-x-c motif chemokine receptor 6 (cxcr6) binding molecules, and methods of using the same
WO2022251359A1 (en) 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Bicyclic inhibitors of alk5 and methods of use
WO2022247972A2 (en) 2021-05-26 2022-12-01 Centro De Inmunologia Molecular Use of therapeutic compositions for the treatment of patients with tumours of epithelial origin
TW202307210A (en) 2021-06-01 2023-02-16 瑞士商諾華公司 Cd19 and cd22 chimeric antigen receptors and uses thereof
EP4346904A1 (en) 2021-06-03 2024-04-10 Synthorx, Inc. Head and neck cancer combination therapy comprising an il-2 conjugate and cetuximab
CN113234152B (en) * 2021-06-03 2023-05-02 天津科技大学 Programmed death receptor-ligand 1 (PD-L1) specific binding polypeptide and application thereof
BR112023025194A2 (en) 2021-06-04 2024-02-27 Boehringer Ingelheim Int ANTI-SIRP-ALPHA ANTIBODIES
GB202107994D0 (en) 2021-06-04 2021-07-21 Kymab Ltd Treatment of cancer
CA3218590A1 (en) 2021-06-07 2022-12-15 Providence Health & Services - Oregon Cxcr5, pd-1, and icos expressing tumor reactive cd4 t cells and their use
WO2022258691A1 (en) 2021-06-09 2022-12-15 Innate Pharma Multispecific proteins binding to nkg2d, a cytokine receptor, a tumour antigen and cd16a
BR112023025331A2 (en) 2021-06-09 2024-02-27 Innate Pharma MULTI-SPECIFIC PROTEIN, PHARMACEUTICAL COMPOSITION, RECOMBINANT CELL, NUCLEIC ACID OR NUCLEIC ACID SET, USE OF A PROTEIN OR COMPOSITION, METHODS OR USE
WO2022261159A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
EP4352059A1 (en) 2021-06-09 2024-04-17 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
WO2022258678A1 (en) 2021-06-09 2022-12-15 Innate Pharma Multispecific proteins binding to nkp30, a cytokine receptor, a tumour antigen and cd16a
US20240254226A1 (en) 2021-06-10 2024-08-01 Ono Pharmaceutical Co., Ltd. Cancer treatment method by combined use of cd47 inhibitory substance, immune checkpoint inhibitory substance, and standard therapy
US20230034659A1 (en) * 2021-06-17 2023-02-02 Sparx Bioscience Limited Anti-pdl1 antibodies and uses thereof
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US20240316104A1 (en) 2021-06-29 2024-09-26 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
EP4363449A2 (en) 2021-07-02 2024-05-08 Genentech, Inc. Methods and compositions for treating cancer
EP4367269A1 (en) 2021-07-05 2024-05-15 Inserm (Institut National De La Sante Et De La Recherche Medicale) Gene signatures for predicting survival time in patients suffering from renal cell carcinoma
MX2024000357A (en) 2021-07-07 2024-02-12 Incyte Corp Tricyclic compounds as inhibitors of kras.
JP2024525758A (en) 2021-07-13 2024-07-12 ビオンテック・ソシエタス・エウロパエア Multispecific binding agents to CD40 and CD137 in combination therapy for cancer - Patents.com
KR20240083168A (en) 2021-07-14 2024-06-11 블루프린트 메디신즈 코포레이션 Heterocyclic compounds as MAP4K1 inhibitors
CA3226163A1 (en) 2021-07-14 2023-01-19 Synthekine, Inc. Methods and compositions for use in cell therapy of neoplastic disease
US12600717B2 (en) 2021-07-14 2026-04-14 Incyte Corporation Tricyclic compounds as inhibitors of KRAS
US20240336630A1 (en) 2021-07-15 2024-10-10 Blueprint Medicines Corporation Map4k1 inhibitors
MX2024000406A (en) 2021-07-19 2024-04-18 Regeneron Pharma Combination of checkpoint inhibitors and an oncolytic virus for treating cancer.
WO2023004431A2 (en) * 2021-07-23 2023-01-26 The Trustees Of Columbia University In The City Of New York Characterization of potent and broadly neutralizing monoclonal antibodies against sars-cov-2, its variants, and related coronaviruses and methods of use
CN118871463A (en) 2021-07-28 2024-10-29 基因泰克公司 Methods and compositions for treating cancer
AU2022317820A1 (en) 2021-07-28 2023-12-14 F. Hoffmann-La Roche Ag Methods and compositions for treating cancer
EP4377348A1 (en) 2021-07-30 2024-06-05 Seagen Inc. Treatment for cancer
AU2022320051A1 (en) 2021-07-30 2024-01-25 ONA Therapeutics S.L. Anti-cd36 antibodies and their use to treat cancer
EP4380980A1 (en) 2021-08-03 2024-06-12 F. Hoffmann-La Roche AG Bispecific antibodies and methods of use
WO2023015198A1 (en) 2021-08-04 2023-02-09 Genentech, Inc. Il15/il15r alpha heterodimeric fc-fusion proteins for the expansion of nk cells in the treatment of solid tumours
MX2024002281A (en) 2021-08-23 2024-05-20 Immunitas Therapeutics Inc Anti-cd161 antibodies and uses thereof.
JP2024534127A (en) 2021-08-25 2024-09-18 ピク セラピューティクス， インコーポレイテッド eIF4E inhibitors and uses thereof
US12157732B2 (en) 2021-08-25 2024-12-03 PIC Therapeutics, Inc. eIF4E inhibitors and uses thereof
US12441742B2 (en) 2021-08-31 2025-10-14 Incyte Corporation Naphthyridine compounds as inhibitors of KRAS
WO2023034530A1 (en) 2021-09-02 2023-03-09 Teon Therapeutics, Inc. Methods of improving growth and function of immune cells
US20240368280A1 (en) 2021-09-02 2024-11-07 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Anti-cecam6 antibodies with reduced side-effects
CA3231180A1 (en) 2021-09-08 2023-03-16 Redona Therapeutics, Inc. Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives
WO2023049697A1 (en) 2021-09-21 2023-03-30 Incyte Corporation Hetero-tricyclic compounds as inhibitors of kras
WO2023051926A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
TW202321308A (en) 2021-09-30 2023-06-01 美商建南德克公司 Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists
CA3234375A1 (en) 2021-10-01 2023-04-06 Incyte Corporation Pyrazoloquinoline kras inhibitors
WO2023057882A1 (en) 2021-10-05 2023-04-13 Pfizer Inc. Combinations of azalactam compounds with a pd-1 axis binding antagonist for the treatment of cancer
TW202333802A (en) 2021-10-11 2023-09-01 德商拜恩迪克公司 Therapeutic rna for lung cancer
WO2023064857A1 (en) 2021-10-14 2023-04-20 Incyte Corporation Quinoline compounds as inhibitors of kras
JP2024539139A (en) 2021-10-20 2024-10-28 シンセカイン インコーポレイテッド Heterodimeric FC cytokines and uses thereof
WO2023066322A1 (en) 2021-10-21 2023-04-27 杭州阿诺生物医药科技有限公司 Fusion polypeptide and use thereof
WO2023077034A1 (en) 2021-10-28 2023-05-04 Lyell Immunopharma, Inc. Methods for culturing immune cells
KR20240099362A (en) 2021-10-29 2024-06-28 브리스톨-마이어스 스큅 컴퍼니 LAG-3 antagonist therapy for hematologic malignancies
US12187744B2 (en) 2021-10-29 2025-01-07 Kymera Therapeutics, Inc. IRAK4 degraders and synthesis thereof
WO2023081730A1 (en) 2021-11-03 2023-05-11 Teon Therapeutics, Inc. 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer
WO2023079428A1 (en) 2021-11-03 2023-05-11 Pfizer Inc. Combination therapies using tlr7/8 agonist
US20240426823A1 (en) 2021-11-03 2024-12-26 Institut National de la Santé et de la Recherche Médicale Methods and compositions for treating triple negative breast cancer (tnbc)
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
EP4429769A1 (en) 2021-11-09 2024-09-18 Sensei Biotherapeutics, Inc. Anti-vista antibodies and uses thereof
WO2023083439A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
KR20240103030A (en) 2021-11-17 2024-07-03 인스티튜트 내셔날 드 라 싼테 에 드 라 리셰르셰 메디칼르 Universal Sarbecovirus Vaccine
WO2023091746A1 (en) 2021-11-22 2023-05-25 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a kras inhibitor
TW202340212A (en) 2021-11-24 2023-10-16 美商建南德克公司 Therapeutic compounds and methods of use
EP4436957A1 (en) 2021-11-24 2024-10-02 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023097211A1 (en) 2021-11-24 2023-06-01 The University Of Southern California Methods for enhancing immune checkpoint inhibitor therapy
TW202329937A (en) 2021-12-03 2023-08-01 美商英塞特公司 Bicyclic amine cdk12 inhibitors
WO2023107705A1 (en) 2021-12-10 2023-06-15 Incyte Corporation Bicyclic amines as cdk12 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
JP2025500922A (en) 2021-12-16 2025-01-15 ヴァレリオ・セラピューティクス Novel conjugated nucleic acid molecules and uses thereof
WO2023114984A1 (en) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US20250302950A1 (en) 2021-12-20 2025-10-02 Synthorx, Inc. Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab
WO2023118165A1 (en) 2021-12-21 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2023122778A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators
CA3244187A1 (en) 2021-12-22 2023-06-29 Incyte Corporation Salts and solid forms of an fgfr inhibitor and processes of preparing thereof
WO2023122772A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122777A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023129438A1 (en) 2021-12-28 2023-07-06 Wisconsin Alumni Research Foundation Hydrogel compositions for use for depletion of tumor associated macrophages
KR20240130705A (en) 2021-12-30 2024-08-29 네오이뮨텍, 인코퍼레이티드 Method for treating tumors with a combination of IL-7 protein and VEGF antagonist
WO2023137161A1 (en) 2022-01-14 2023-07-20 Amgen Inc. Triple blockade of tigit, cd112r, and pd-l1
CA3249004A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
JP2025504020A (en) 2022-01-28 2025-02-06 ジョージアミューン・インコーポレイテッド Antibodies against programmed cell death protein 1, which are PD-1 agonists
WO2023142996A1 (en) 2022-01-28 2023-08-03 上海岸阔医药科技有限公司 Method for preventing or treating disease or disorder associated with antineoplastic agent
EP4472967A4 (en) 2022-01-31 2026-04-15 Kymera Therapeutics Inc IRAQ-DECORDERS AND USES OF THEM
WO2023144423A1 (en) 2022-01-31 2023-08-03 LockBody Therapeutics Ltd Activatable bispecific anti-cd47 and anti-pd-l1 proteins and uses thereof
EP4472963A1 (en) 2022-02-01 2024-12-11 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
EP4479388A1 (en) 2022-02-14 2024-12-25 Gilead Sciences, Inc. Antiviral naphthyridinone compounds
WO2023154799A1 (en) 2022-02-14 2023-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Combination immunotherapy for treating cancer
US20250152643A1 (en) 2022-02-17 2025-05-15 Regeneron Pharmaceuticals, Inc. Combinations of checkpoint inhibitors and oncolytic virus for treating cancer
WO2023155905A1 (en) 2022-02-21 2023-08-24 上海岸阔医药科技有限公司 Compound and use thereof
US20230277669A1 (en) 2022-02-24 2023-09-07 Amazentis Sa Uses of urolithins
WO2023164638A1 (en) 2022-02-25 2023-08-31 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma
US20240117030A1 (en) 2022-03-03 2024-04-11 Pfizer Inc. Multispecific antibodies and uses thereof
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
EP4490151A1 (en) 2022-03-07 2025-01-15 Incyte Corporation Solid forms, salts, and processes of preparation of a cdk2 inhibitor
CN119156403A (en) 2022-03-08 2024-12-17 阿伦蒂斯治疗股份公司 Use of anti-claudin-1 antibodies to increase T cell availability
WO2023173053A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023173057A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
US20250177352A1 (en) 2022-03-14 2025-06-05 Laekna Limited Combination treatment for cancer
EP4493575A1 (en) 2022-03-18 2025-01-22 Bristol-Myers Squibb Company Methods of isolating polypeptides
CA3246893A1 (en) 2022-03-30 2023-10-05 Centessa Pharmaceuticals (Uk) Limited Activatable bispecific anti-cd3 and anti-pd-l1 proteins and uses thereof
IL315770A (en) 2022-04-01 2024-11-01 Genentech Inc Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023192478A1 (en) 2022-04-01 2023-10-05 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2023196988A1 (en) 2022-04-07 2023-10-12 Modernatx, Inc. Methods of use of mrnas encoding il-12
US20260042840A1 (en) 2022-04-07 2026-02-12 Bristol-Myers Squibb Company Methods of treating tumor
WO2023194656A1 (en) 2022-04-08 2023-10-12 Tilt Biotherapeutics Oy Monoclonal pd-l1 antibodies
US20230326022A1 (en) 2022-04-08 2023-10-12 Bristol-Myers Squibb Company Machine Learning Identification, Classification, and Quantification of Tertiary Lymphoid Structures
TWI882313B (en) 2022-04-13 2025-05-01 美商建南德克公司 Pharmaceutical compositions of therapeutic proteins and methods of use
CA3247048A1 (en) 2022-04-13 2023-10-19 Genentech, Inc. Pharmaceutical compositions of mosunetuzumab and methods of use
CA3248034A1 (en) 2022-04-15 2023-10-19 Iovance Biotherapeutics, Inc. Til expansion processes using specific cytokine combinations and/or akti treatment
WO2023211889A1 (en) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Polymorphic compounds and uses thereof
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
CN119317641A (en) 2022-05-11 2025-01-14 基因泰克公司 Administration for treatment with anti-FCRH5/anti-CD3 bispecific antibodies
WO2023220703A1 (en) 2022-05-12 2023-11-16 Genentech, Inc. Methods and compositions comprising a shp2 inhibitor and a pd-l1 binding antagonist
US20250340641A1 (en) 2022-05-18 2025-11-06 Kymab Limited Uses of anti-icos antibodies
IL316768A (en) 2022-05-25 2025-01-01 Ikena Oncology Inc Mek inhibitors and uses thereof
WO2023230554A1 (en) 2022-05-25 2023-11-30 Pfizer Inc. Combination of a braf inhibitor, an egfr inhibitor, and a pd-1 antagonist for the treatment of braf v600e-mutant, msi-h/dmmr colorectal cancer
AR129423A1 (en) 2022-05-27 2024-08-21 Viiv Healthcare Co USEFUL COMPOUNDS IN HIV THERAPY
EP4531916A1 (en) 2022-06-02 2025-04-09 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
EP4537107A2 (en) 2022-06-07 2025-04-16 Genentech, Inc. Method for determining the efficacy of a lung cancer treatment comprising an anti-pd-l1 antagonist and an anti-tigit antagonist antibody
PE20250927A1 (en) 2022-06-08 2025-04-02 Incyte Corp Tricyclic triazolo compounds as DGK inhibitors
WO2023240156A1 (en) 2022-06-08 2023-12-14 Tidal Therapeutics, Inc. Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
US20250230256A1 (en) 2022-06-16 2025-07-17 Lamkap Bio Beta Ltd Combination therapy of bispecific antibodies against ceacam5 and cd47 and bispecific antibodies against ceacam5 and cd3
AR129675A1 (en) 2022-06-22 2024-09-18 Incyte Corp CDK12 INHIBITORS OF BICYCLIC AMINES
EP4543923A1 (en) 2022-06-22 2025-04-30 Juno Therapeutics, Inc. Treatment methods for second line therapy of cd19-targeted car t cells
WO2024015731A1 (en) 2022-07-11 2024-01-18 Incyte Corporation Fused tricyclic compounds as inhibitors of kras g12v mutants
WO2024015803A2 (en) 2022-07-11 2024-01-18 Autonomous Therapeutics, Inc. Encrypted rna and methods of its use
JP2025523057A (en) 2022-07-12 2025-07-17 ホットスポット セラピューティクス インコーポレイテッド CBL-B INHIBITORS AND ANTI-PD1/ANTI-PD-L1 FOR USE IN CANCER TREATMENT - Patent application
JP2025523020A (en) 2022-07-13 2025-07-17 ジェネンテック， インコーポレイテッド Administration for Treatment with Anti-FcRH5/Anti-CD3 Bispecific Antibody
EP4554943A1 (en) 2022-07-14 2025-05-21 Teon Therapeutics, Inc. Adenosine receptor antagonists and uses thereof
US12600722B2 (en) 2022-07-18 2026-04-14 Incyte Corporation Tetracyclic compounds as DGK inhibitors
US12600723B2 (en) 2022-07-18 2026-04-14 Incyte Corporation Tetracyclic compounds as DGK inhibitors
CA3261510A1 (en) 2022-07-19 2024-01-25 F. Hoffmann-La Roche Ag Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
KR20250044313A (en) 2022-07-27 2025-03-31 아스트라제네카 아베 Combination of a PD-1/PD-L1 inhibitor and a recombinant virus expressing interleukin-12
JP2025527247A (en) 2022-08-02 2025-08-20 リミナル・バイオサイエンシーズ・リミテッド Aryl-triazolyl and related gpr84 antagonists and their uses
CN120051456A (en) 2022-08-02 2025-05-27 里米诺生物科学有限公司 Substituted pyridone GPR84 antagonists and uses thereof
IL318575A (en) 2022-08-02 2025-03-01 Liminal Biosciences Ltd Heteroaryl carboxamide and related gpr84 antagonists and uses thereof
CA3263560A1 (en) 2022-08-05 2024-02-08 Juno Therapeutics, Inc. Chimeric antigen receptors specific for gprc5d and bcma
US20260049068A1 (en) 2022-08-08 2026-02-19 Bristol-Myers Squibb Company Substituted Tetrazolyl Compounds Useful as T Cell Activators
KR20250046310A (en) 2022-08-09 2025-04-02 브리스톨-마이어스 스큅 컴퍼니 Tertiary amine-substituted bicyclic compounds useful as T cell activators
WO2024033400A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sk2 inhibitor for the treatment of pancreatic cancer
WO2024033399A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sigmar1 ligand for the treatment of pancreatic cancer
CR20250043A (en) 2022-08-11 2025-03-25 Hoffmann La Roche Bicyclic tetrahydrothiazepine derivatives
TW202417001A (en) 2022-08-11 2024-05-01 瑞士商赫孚孟拉羅股份公司 Bicyclic tetrahydroazepine derivatives
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024040175A1 (en) 2022-08-18 2024-02-22 Pulmatrix Operating Company, Inc. Methods for treating cancer using inhaled angiogenesis inhibitor
US20260053903A1 (en) 2022-08-19 2026-02-26 Massachusetts Institute Of Technology Compositions and methods for targeting dendritic cell lectins
WO2024043227A1 (en) 2022-08-23 2024-02-29 小野薬品工業株式会社 Bispecific antibody
JP2025531738A (en) 2022-09-01 2025-09-25 ジェネンテック， インコーポレイテッド Bladder cancer treatment and diagnosis methods
US20260071003A1 (en) 2022-09-01 2026-03-12 University Of Georgia Research Foundation, Inc. Compositions and methods for directing apolipoprotein l1 to induce mammalian cell death
EP4583860A1 (en) 2022-09-06 2025-07-16 Institut National de la Santé et de la Recherche Médicale Inhibitors of the ceramide metabolic pathway for overcoming immunotherapy resistance in cancer
EP4587040A1 (en) 2022-09-14 2025-07-23 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy
WO2024069009A1 (en) 2022-09-30 2024-04-04 Alentis Therapeutics Ag Treatment of drug-resistant hepatocellular carcinoma
WO2024077191A1 (en) 2022-10-05 2024-04-11 Flagship Pioneering Innovations V, Inc. Nucleic acid molecules encoding trif and additionalpolypeptides and their use in treating cancer
WO2024077095A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
WO2024077166A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
WO2024081736A2 (en) 2022-10-11 2024-04-18 Yale University Compositions and methods of using cell-penetrating antibodies
EP4606384A1 (en) 2022-10-19 2025-08-27 Astellas Pharma, Inc. Use of anti-cldn4-anti-cd137 bispecific antibody combined with pd-1 signal inhibitor for cancer treatment
WO2024086739A1 (en) 2022-10-20 2024-04-25 Synthekine, Inc. Methods and compositions of il12 muteins and il2 muteins
EP4605422A2 (en) 2022-10-20 2025-08-27 Repertoire Immune Medicines, Inc. Cd8 t cell targeted il2
EP4604939A1 (en) 2022-10-20 2025-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Combination therapy for the treatment of cancer
WO2024084034A1 (en) 2022-10-21 2024-04-25 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of osteoarthritis
AU2023369055A1 (en) 2022-10-24 2025-05-15 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier
WO2024089417A1 (en) 2022-10-24 2024-05-02 Memorial Sloan-Kettering Cancer Center Tumour stratification for responsiveness to an immune checkpoint inhibitor
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
WO2024102722A1 (en) 2022-11-07 2024-05-16 Neoimmunetech, Inc. Methods of treating a tumor with an unmethylated mgmt promoter
EP4615480A1 (en) 2022-11-07 2025-09-17 Alector LLC Uses of siglec-9 ecd fusion molecules in cancer treatment
AR131099A1 (en) 2022-11-18 2025-02-19 Incyte Corp HETEROARYL FLUOROALKENES AS DGK INHIBITORS
EP4623072A2 (en) 2022-11-21 2025-10-01 Iovance Biotherapeutics, Inc. Two-dimensional processes for the expansion of tumor infiltrating lymphocytes and therapies therefrom
US20240208961A1 (en) 2022-11-22 2024-06-27 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
CN120569191A (en) 2022-11-23 2025-08-29 乔治亚大学研究基金公司 Compositions for increasing immune response and methods of use thereof
AU2023404228A1 (en) 2022-11-29 2025-06-19 Adlai Nortye Biopharma Co., Ltd. Fusion polypeptide and use thereof
WO2024118836A1 (en) 2022-11-30 2024-06-06 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes with shortened rep step
JP2025541738A (en) 2022-12-01 2025-12-23 ビオンテック・ソシエタス・エウロパエア Multispecific antibodies against CD40 and CD137 in combination with anti-PD1AB and chemotherapy
AU2023402712A1 (en) 2022-12-01 2025-05-08 Innate Pharma Compositions and methods for neoadjuvant treatment in cancer comprising anti-cd39 antibodies
EP4626552A1 (en) 2022-12-01 2025-10-08 MedImmune Limited Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies
CN120712102A (en) 2022-12-13 2025-09-26 朱诺治疗学股份有限公司 Chimeric antigen receptors specific for BAFF-R and CD19 and methods and uses thereof
KR20250120305A (en) 2022-12-14 2025-08-08 아스텔라스 파마 유럽 비.브이. Combination therapy involving a dual-specificity binding agent that binds to CLDN18.2 and CD3 and an immune checkpoint inhibitor
JP2026501282A (en) 2022-12-20 2026-01-14 ジェネンテック， インコーポレイテッド Methods of treating pancreatic cancer with pd-1 axis binding antagonists and rna vaccines
CN120731228A (en) 2022-12-21 2025-09-30 百时美施贵宝公司 Combination therapy for lung cancer
WO2024137865A1 (en) 2022-12-22 2024-06-27 Gossamer Bio Services, Inc. Compounds useful as t cell activators
CN116063526B (en) * 2022-12-31 2025-03-25 合肥天港免疫药物有限公司 Anti-PDL1 antibodies and uses thereof
IL321948A (en) 2023-01-06 2025-09-01 Lassen Therapeutics Inc Anti-il-18bp antibodies
TW202430560A (en) 2023-01-06 2024-08-01 美商拉森醫療公司 Anti-il-18bp antibodies
WO2024151687A1 (en) 2023-01-09 2024-07-18 Flagship Pioneering Innovations V, Inc. Genetic switches and their use in treating cancer
WO2024150177A1 (en) 2023-01-11 2024-07-18 Advesya Treatment methods for solid tumors
AR131101A1 (en) 2023-01-12 2025-02-19 Incyte Corp HETEROARYLFLUOROALKENES AS DGK INHIBITORS
WO2024151885A1 (en) 2023-01-13 2024-07-18 Iovance Biotherapeutics, Inc. Use of til as maintenance therapy for nsclc patients who achieved pr/cr after prior therapy
WO2024150017A1 (en) 2023-01-13 2024-07-18 Akrivia Biomedics Limited Method of profiling diseases
WO2024160721A1 (en) 2023-01-30 2024-08-08 Kymab Limited Antibodies
JP2026505276A (en) 2023-01-31 2026-02-13 ユニバーシティ オブ ロチェスター Immune checkpoint blockade therapy for treating Staphylococcus aureus infection
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy
JP2026510999A (en) 2023-03-21 2026-04-10 バイオグラフ ５５，インク． CD19/CD38 multispecific antibody
WO2024200571A1 (en) 2023-03-28 2024-10-03 Institut National de la Santé et de la Recherche Médicale Method for discriminating mono-immunotherapy from combined immunotherapy in cancers
TW202502311A (en) 2023-03-29 2025-01-16 美商默沙東有限責任公司 Il4i1 inhibitors and methods of use
WO2024208818A1 (en) 2023-04-04 2024-10-10 Innate Pharma Modular chimeric antigen receptor
WO2024216028A1 (en) 2023-04-12 2024-10-17 Agenus Inc. Methods of treating cancer using an anti-ctla4 antibody and an enpp1 inhibitor
WO2024213767A1 (en) 2023-04-14 2024-10-17 Institut National de la Santé et de la Recherche Médicale Engraftment of mesenchymal stromal cells engineered to stimulate immune infiltration in tumors
WO2024220532A1 (en) 2023-04-18 2024-10-24 Incyte Corporation Pyrrolidine kras inhibitors
WO2024218512A1 (en) * 2023-04-19 2024-10-24 Centessa Pharmaceuticals (Uk) Limited Activatable bispecific anti-cd89 and anti-pd-l1 proteins and uses thereof
GB2644480A (en) 2023-04-24 2026-04-15 King Abdullah Univ Of Science Of Technology Compositions, systems and methods for multiplex detection of target biomarkers in a sample
EP4701650A2 (en) 2023-04-26 2026-03-04 Isabella Pharma B.V. Methods of treating cancer by administering immunogenic compositions and a pd-1 inhibitor
WO2024228167A1 (en) 2023-05-03 2024-11-07 Iox Therapeutics Inc. Inkt cell modulator liposomal compositions and methods of use
WO2024229461A2 (en) 2023-05-04 2024-11-07 Novasenta, Inc. Anti-cd161 antibodies and methods of use thereof
WO2024233341A1 (en) 2023-05-05 2024-11-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024231384A1 (en) 2023-05-10 2024-11-14 Institut National de la Santé et de la Recherche Médicale Compositions for treating senescence related disease
EP4709712A1 (en) 2023-05-10 2026-03-18 Blueprint Medicines Corporation Gsk3a inhibitors and methods of use thereof
IL324490A (en) 2023-05-10 2026-01-01 Genentech Inc Methods and compositions for treating cancer
WO2024245951A1 (en) 2023-05-26 2024-12-05 Institut National de la Santé et de la Recherche Médicale Combination of slc8a1 inhibitor and mitochondria-targeted antioxidant for treating melanoma
US12531162B1 (en) * 2023-05-31 2026-01-20 Northeastern University Multi-dimensional phenotypic space for genotype to phenotype mapping and intelligent design of cancer drug therapies using a deep learning net
EP4724149A1 (en) 2023-06-07 2026-04-15 Bristol-Myers Squibb Company Spirocyclic substituted oxoisoindolinyl piperidine-2,6-dione compound
WO2024254245A1 (en) 2023-06-09 2024-12-12 Incyte Corporation Bicyclic amines as cdk2 inhibitors
WO2024256635A1 (en) 2023-06-15 2024-12-19 Institut National de la Santé et de la Recherche Médicale Dpm1 inhibitor for treating cancer
WO2024261302A1 (en) 2023-06-22 2024-12-26 Institut National de la Santé et de la Recherche Médicale Nlrp3 inhibitors, pak1/2 inhibitors and/or caspase 1 inhibitors for use in the treatment of rac2 monogenic disorders
AU2024314878A1 (en) 2023-06-23 2026-01-22 Bristol-Myers Squibb Company Substituted oxoisoindolinyl piperidine-2,6-dione compound as anticancer agent
WO2024263195A1 (en) 2023-06-23 2024-12-26 Genentech, Inc. Methods for treatment of liver cancer
IL321486A (en) 2023-06-23 2025-08-01 Kymera Therapeutics Inc Irak degraders and uses thereof
WO2024263904A1 (en) 2023-06-23 2024-12-26 Genentech, Inc. Methods for treatment of liver cancer
WO2025003193A1 (en) 2023-06-26 2025-01-02 Institut National de la Santé et de la Recherche Médicale Sertraline and indatraline for disrupting intracellular cholesterol trafficking and subsequently inducing lysosomal damage and anti-tumor immunity
WO2025006811A1 (en) 2023-06-27 2025-01-02 Lyell Immunopharma, Inc. Methods for culturing immune cells
WO2025012417A1 (en) 2023-07-13 2025-01-16 Institut National de la Santé et de la Recherche Médicale Anti-neurotensin long fragment and anti-neuromedin n long fragment antibodies and uses thereof
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025030002A2 (en) 2023-08-02 2025-02-06 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
CN121712571A (en) 2023-08-15 2026-03-20 百时美施贵宝公司 Ceramic hydroxyapatite chromatographic flow-through method
WO2025042742A1 (en) 2023-08-18 2025-02-27 Bristol-Myers Squibb Company Compositions comprising antibodies that bind bcma and cd3 and methods of treatment
WO2025043151A2 (en) 2023-08-24 2025-02-27 Incyte Corporation Bicyclic dgk inhibitors
WO2025049277A1 (en) 2023-08-25 2025-03-06 Genentech, Inc. Methods and compositions for treating non-small cell lung cancer comprising an anti-tigit antagonist antibody and a pd-1 axis binding antagonist
IL326828A (en) 2023-09-02 2026-04-01 Bristol Myers Squibb Co Substituted azetidinyl oxoisoindolinyl piperidine-2,6-dione compounds
WO2025056180A1 (en) 2023-09-15 2025-03-20 BioNTech SE Methods of treatment using agents binding to epcam and cd137 in combination with pd-1 axis binding antagonists
WO2025073765A1 (en) 2023-10-03 2025-04-10 Institut National de la Santé et de la Recherche Médicale Methods of prognosis and treatment of patients suffering from melanoma
AU2024357850A1 (en) 2023-10-09 2026-04-23 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
US20250114468A1 (en) 2023-10-09 2025-04-10 Regeneron Pharmaceuticals, Inc. Methods of treating cancer with a combination of a pd1 inhibitor and a targeted immunocytokine
WO2025078632A1 (en) 2023-10-12 2025-04-17 Institut National de la Santé et de la Recherche Médicale Methods of prognosis and treatment of patients suffering from cancer
TW202515903A (en) 2023-10-12 2025-04-16 瑞士商百濟神州瑞士有限責任公司 Anti-pd-1-based treatment before and after surgery
WO2025085404A1 (en) 2023-10-16 2025-04-24 Genentech, Inc. Diagnostic and therapeutic methods for treating lung cancer
WO2025085781A1 (en) 2023-10-19 2025-04-24 Genentech, Inc. Combinations of il15/il15r alpha heterodimeric fc-fusion proteins and her2xcd3 bispecific antibodies for the treatment of her2-positive cancers
WO2025096487A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096489A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096488A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
TW202535865A (en) 2023-10-31 2025-09-16 美商必治妥美雅史谷比公司 Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096494A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096505A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096490A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
US20250163079A1 (en) 2023-11-01 2025-05-22 Incyte Corporation Kras inhibitors
WO2025096843A1 (en) 2023-11-03 2025-05-08 Amgen Inc. Bispecific molecules
US12562256B2 (en) * 2023-11-07 2026-02-24 New York University Systems, methods and computer-accessible medium for identifying target pairs for CAR-T therapy
WO2025106278A1 (en) 2023-11-17 2025-05-22 Mersana Therapeutics, Inc. Treatment of cancer using b7-h4-targeted antibody-drug conjugates
TW202523667A (en) 2023-12-05 2025-06-16 美商英塞特公司 Tricyclic triazolo compounds as dgk inhibitors
US20250186450A1 (en) 2023-12-06 2025-06-12 Incyte Corporation COMBINATION THERAPY COMPRISING DGK INHIBITORS and PD-1/PD-L1 INHIBITORS
WO2025120866A1 (en) 2023-12-08 2025-06-12 Astellas Pharma Inc. Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and agents stabilizing or increasing expression of cldn18.2
AR134560A1 (en) 2023-12-08 2026-01-28 Astellas Pharma Inc COMBINATION THERAPY INVOLVING BISPECIFIC BINDING AGENTS THAT BIND TO CLDN18.2 AND CD3 AND AGENTS THAT STABILIZE OR INCREASE CLDN18.2 EXPRESSION
WO2026033885A1 (en) 2024-08-08 2026-02-12 Astellas Pharma Inc. Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and agents stabilizing or increasing expression of cldn18.2
WO2025120867A1 (en) 2023-12-08 2025-06-12 Astellas Pharma Inc. Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and anti-vegfr2 antibodies
US20250195536A1 (en) 2023-12-13 2025-06-19 Incyte Corporation Bicyclooctane kras inhibitors
WO2025132479A1 (en) 2023-12-18 2025-06-26 Institut National de la Santé et de la Recherche Médicale Flt3 inhibitor for modulating macrophages polarization
WO2025132770A1 (en) 2023-12-22 2025-06-26 Institut National de la Santé et de la Recherche Médicale Affitins for the treatment of cancer
WO2025145207A1 (en) 2023-12-29 2025-07-03 Bristol-Myers Squibb Company Combination therapy of kras inhibitor and treg-depleting agent
TW202539700A (en) 2024-01-16 2025-10-16 美商建南德克公司 Methods of treating urothelial carcinoma with a pd-1 axis binding antagonist and an rna vaccine
WO2025153834A1 (en) 2024-01-19 2025-07-24 Institut National de la Santé et de la Recherche Médicale Methods of predicting the risk of recurrence and/or death of patients suffering from a hepatocellular carcinoma (hcc)
TW202545567A (en) 2024-01-30 2025-12-01 美商思進公司 Anti-pd-l1 antibodies and antibody-drug conjugates and their use in the treatment of cancer
TW202543581A (en) 2024-02-12 2025-11-16 美商艾伊拉醫療公司 Delivery compositions
WO2025174933A1 (en) 2024-02-14 2025-08-21 Genentech, Inc. Methods for treatment of pancreatic cancer with anti-pd-l1 ab, anti-tigit ab, gemcitabine and nab-placlitaxel
TW202600608A (en) 2024-02-27 2026-01-01 美商必治妥美雅史谷比公司 Anti-ceacam5 antibodies and uses thereof
EP4658320A1 (en) 2024-02-27 2025-12-10 Bristol-Myers Squibb Company Anti-ceacam5 antibody drug conjugates
WO2025188693A1 (en) 2024-03-05 2025-09-12 Bristol-Myers Squibb Company Bicyclic tlr7 agonists and uses thereof
WO2025188694A1 (en) 2024-03-05 2025-09-12 Bristol-Myers Squibb Company Tricyclic tlr7 agonists and uses thereof
WO2025186778A1 (en) 2024-03-08 2025-09-12 Janssen Biotech, Inc. Combinations of oncolytic viruses and immunomodulators
US20250361297A1 (en) 2024-03-12 2025-11-27 Adaptam Therapeutics, S.L. Anti- siglec-15 binding molecules and methods of use
WO2025191529A1 (en) 2024-03-14 2025-09-18 Biohaven Therapeutics Ltd. Next generation riluzole prodrugs
WO2025202213A1 (en) 2024-03-26 2025-10-02 Institut National de la Santé et de la Recherche Médicale Lipid nanoparticle loaded with antitumoral agent and functionnalized to target immosuppressive cells
WO2025210123A1 (en) 2024-04-03 2025-10-09 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical composition for treating cancers
WO2025210175A1 (en) 2024-04-04 2025-10-09 Centre National De La Recherche Scientifique Mutant csf-1r extracellular domain fusion molecules and therapeutic uses thereof
WO2025213154A1 (en) 2024-04-05 2025-10-09 Amgen Inc. Gastrointestinal cancer treatments using mta-cooperative prmt5 inhibitors
WO2025216894A1 (en) 2024-04-09 2025-10-16 Sensei Biotherapeutics, Inc. Bispecific anti-vista and anti-cd28 binding proteins and uses thereof
WO2025219330A1 (en) 2024-04-15 2025-10-23 Institut National de la Santé et de la Recherche Médicale Detection of ppix for use in methods for melanoma ferroptosis sensitivity and targeted therapy resistance prediction
WO2025219595A1 (en) 2024-04-19 2025-10-23 Biper Therapeutics Method for combination treatments using alkynylbenzenesulphonamides for cancer therapy
WO2025226767A1 (en) 2024-04-24 2025-10-30 Bristol-Myers Squibb Company Substituted 3-(5-(6-aminopyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds for use in the treatment of cancer
WO2025228998A1 (en) 2024-04-30 2025-11-06 Institut National de la Santé et de la Recherche Médicale Use of hdac4 inhibitors for the treatment of melanoma
WO2025232879A1 (en) 2024-05-10 2025-11-13 Cytocares (Shanghai) Inc. Anti-lilrb2 monospecific and bispecific antibody constructs and uses thereof
WO2025233867A1 (en) 2024-05-10 2025-11-13 Adaptam Therapeutics, S.L. Anti-siglec-9 antibodies and uses thereof
WO2025245489A1 (en) 2024-05-24 2025-11-27 Bristol-Myers Squibb Company Treatment of tumors in subjects having fgl-1 positive samples
WO2025247829A1 (en) 2024-05-27 2025-12-04 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical composition for treating prostate cancer
NL2037811B1 (en) 2024-05-29 2025-12-12 Univ Oslo Treatment for Cancer
WO2025254987A1 (en) 2024-06-03 2025-12-11 Alector Llc Siglec-9 ecd fusion molecule variants and methods of use thereof
WO2025252857A1 (en) 2024-06-05 2025-12-11 Institut National de la Santé et de la Recherche Médicale Il-15 muteins with ph-dependent binding for il-15ralpha
WO2025252855A1 (en) 2024-06-05 2025-12-11 Institut National de la Santé et de la Recherche Médicale IL-15 MUTEINS WITH PH-DEPENDENT BINDING FOR IL-15Rbeta
WO2025259515A2 (en) 2024-06-11 2025-12-18 Amgen Inc. Combination treatment
GB202408360D0 (en) 2024-06-11 2024-07-24 Cancer Research Tech Ltd Tumour sensitisation
WO2026003224A2 (en) 2024-06-26 2026-01-02 Iomx Therapeutics Ag Bispecific antigen binding proteins (abp) targeting immune checkpoint molecules and both leukocyte immunoglobulin-like receptor subfamily b1 (lilrb1) and lilrb2; combinations and uses thereof
WO2026006604A1 (en) 2024-06-26 2026-01-02 Lyell Immunopharma, Inc. Feeder cell replacement
WO2026012976A1 (en) 2024-07-08 2026-01-15 Institut National de la Santé et de la Recherche Médicale Use of inhibitor of gasdermind for treatment of rac2 monogenic disorders
WO2026013071A1 (en) 2024-07-09 2026-01-15 Institut National de la Santé et de la Recherche Médicale Setdb1 inhibitor for use in the treatment of uveal melanoma
WO2026019990A1 (en) 2024-07-18 2026-01-22 Genentech, Inc. Methods of treating cancer with anti-ccr8/anti-cd3 bispecific antibodies
WO2026035787A1 (en) 2024-08-07 2026-02-12 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) macrocyles
WO2026035866A1 (en) 2024-08-07 2026-02-12 Iovance Biotherapeutics, Inc. Treatment of cancer patients with tumor infiltrating lymphocyte therapies in combination with a lag-3 inhibitor and a pd-1 inhibitor
WO2026035860A1 (en) 2024-08-07 2026-02-12 Teon Therapeutics, Inc. Formulations of adenosine receptor antagonist
WO2026037839A2 (en) 2024-08-12 2026-02-19 ONA Therapeutics S.L. Anti-fgfr4 molecules and uses thereof
GB202412414D0 (en) 2024-08-23 2024-10-09 Univ Bradford Methods for treating cancer
WO2026050572A2 (en) 2024-08-29 2026-03-05 Marengo Therapeutics, Inc. Multifunctional molecules binding to tcr and uses thereof
WO2026055167A1 (en) 2024-09-05 2026-03-12 Surface Oncology, LLC Anti-il-27 antibodies and use of biomarkers in uses thereof
WO2026055168A1 (en) 2024-09-06 2026-03-12 Surface Oncology, LLC Anti-il-27 antibodies and uses and doses thereof
WO2026052851A2 (en) 2024-09-09 2026-03-12 Institut National de la Santé et de la Recherche Médicale Inhibitor of ciliogenesis for use in a method of preventing therapeutic resistance in cancer
WO2026060143A1 (en) 2024-09-11 2026-03-19 Incyte Corporation Kras inhibitors
WO2026072557A2 (en) 2024-09-24 2026-04-02 Genzyme Corporation Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
WO2026074471A1 (en) 2024-10-02 2026-04-09 Janssen Pharmaceutica Nv Combination therapies with hafnium oxide nanoparticles and pd-l1 antibodies for use in the treatment of non small cell lung cancer
WO2026076207A1 (en) 2024-10-04 2026-04-09 Incyte Corporation Tricyclic heteroaryl compounds as inhibitors of tyk2 and/or jak1
WO2026080794A1 (en) 2024-10-11 2026-04-16 Bristol-Myers Squibb Company Chemical compounds useful for degrading proteins

Family Cites Families (141)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
EP0154316B1 (en) 1984-03-06 1989-09-13 Takeda Chemical Industries, Ltd. Chemically modified lymphokine and production thereof
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US5374548A (en) 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
MX9203291A (en) 1985-06-26 1992-08-01 Liposome Co Inc LIPOSOMAS COUPLING METHOD.
GB8601597D0 (en) 1986-01-23 1986-02-26 Wilson R H Nucleotide sequences
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4954617A (en) 1986-07-07 1990-09-04 Trustees Of Dartmouth College Monoclonal antibodies to FC receptors for immunoglobulin G on human mononuclear phagocytes
US4881175A (en) 1986-09-02 1989-11-14 Genex Corporation Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5260203A (en) 1986-09-02 1993-11-09 Enzon, Inc. Single polypeptide chain binding molecules
WO1988007089A1 (en) 1987-03-18 1988-09-22 Medical Research Council Altered antibodies
US5013653A (en) 1987-03-20 1991-05-07 Creative Biomolecules, Inc. Product and process for introduction of a hinge region into a fusion protein to facilitate cleavage
US5258498A (en) 1987-05-21 1993-11-02 Creative Biomolecules, Inc. Polypeptide linkers for production of biosynthetic proteins
US5132405A (en) 1987-05-21 1992-07-21 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
ATE243754T1 (en) 1987-05-21 2003-07-15 Micromet Ag MULTIFUNCTIONAL PROTEINS WITH PREDEFINED TARGET
US5091513A (en) 1987-05-21 1992-02-25 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
GB8717430D0 (en) 1987-07-23 1987-08-26 Celltech Ltd Recombinant dna product
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
GB8809129D0 (en) 1988-04-18 1988-05-18 Celltech Ltd Recombinant dna methods vectors and host cells
US5476996A (en) 1988-06-14 1995-12-19 Lidak Pharmaceuticals Human immune system in non-human animal
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
EP0401384B1 (en) 1988-12-22 1996-03-13 Kirin-Amgen, Inc. Chemically modified granulocyte colony stimulating factor
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5108921A (en) 1989-04-03 1992-04-28 Purdue Research Foundation Method for enhanced transmembrane transport of exogenous molecules
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5859205A (en) * 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
US6673986B1 (en) 1990-01-12 2004-01-06 Abgenix, Inc. Generation of xenogeneic antibodies
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
EP1690934A3 (en) 1990-01-12 2008-07-30 Abgenix, Inc. Generation of xenogeneic antibodies
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
US6172197B1 (en) 1991-07-10 2001-01-09 Medical Research Council Methods for producing members of specific binding pairs
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US6300129B1 (en) * 1990-08-29 2001-10-09 Genpharm International Transgenic non-human animals for producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5874299A (en) 1990-08-29 1999-02-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
ATE300615T1 (en) 1990-08-29 2005-08-15 Genpharm Int TRANSGENIC MICE CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US6255458B1 (en) 1990-08-29 2001-07-03 Genpharm International High affinity human antibodies and human antibodies against digoxin
US5789650A (en) 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
ES2341666T3 (en) 1991-12-02 2010-06-24 Medimmune Limited PRODUCTION OF AUTHORTIC BODIES OF REPERTORIES OF ANTIQUE RPOS SEGMENTS EXPRESSED ON THE FAGOS SURFACE.
CA2124967C (en) 1991-12-17 2008-04-08 Nils Lonberg Transgenic non-human animals capable of producing heterologous antibodies
US5714350A (en) 1992-03-09 1998-02-03 Protein Design Labs, Inc. Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region
WO1993022332A2 (en) 1992-04-24 1993-11-11 Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
US5260074A (en) 1992-06-22 1993-11-09 Digestive Care Inc. Compositions of digestive enzymes and salts of bile acids and process for preparation thereof
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
GB9223377D0 (en) 1992-11-04 1992-12-23 Medarex Inc Humanized antibodies to fc receptors for immunoglobulin on human mononuclear phagocytes
CA2161351C (en) 1993-04-26 2010-12-21 Nils Lonberg Transgenic non-human animals capable of producing heterologous antibodies
AU691811B2 (en) 1993-06-16 1998-05-28 Celltech Therapeutics Limited Antibodies
IL108501A (en) 1994-01-31 1998-10-30 Mor Research Applic Ltd Antibodies and pharmaceutical compositions containing them
CA2143491C (en) 1994-03-01 2011-02-22 Yasumasa Ishida A novel peptide related to human programmed cell death and dna encoding it
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US6121022A (en) 1995-04-14 2000-09-19 Genentech, Inc. Altered polypeptides with increased half-life
US6410690B1 (en) 1995-06-07 2002-06-25 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
AU725609C (en) * 1995-08-18 2002-01-03 Morphosys Ag Protein/(poly)peptide libraries
WO1997007671A1 (en) 1995-08-29 1997-03-06 Kirin Beer Kabushiki Kaisha Chimeric animal and method for constructing the same
US6632976B1 (en) 1995-08-29 2003-10-14 Kirin Beer Kabushiki Kaisha Chimeric mice that are produced by microcell mediated chromosome transfer and that retain a human antibody gene
US5922845A (en) 1996-07-11 1999-07-13 Medarex, Inc. Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
US7368531B2 (en) * 1997-03-07 2008-05-06 Human Genome Sciences, Inc. Human secreted proteins
US6261791B1 (en) 1997-03-10 2001-07-17 The Regents Of The University Of California Method for diagnosing cancer using specific PSCA antibodies
WO1998052976A1 (en) 1997-05-21 1998-11-26 Biovation Limited Method for the production of non-immunogenic proteins
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
ES2434961T5 (en) 1998-04-20 2018-01-18 Roche Glycart Ag Antibody glycosylation engineering to improve antibody-dependent cell cytotoxicity
CA2352783C (en) 1998-12-03 2012-04-10 The Regents Of The University Of California Stimulation of t cells against self antigens using ctla-4 blocking agents
US7041474B2 (en) * 1998-12-30 2006-05-09 Millennium Pharmaceuticals, Inc. Nucleic acid encoding human tango 509
US20080213778A1 (en) * 1998-12-30 2008-09-04 Millennium Pharmaceuticals, Inc. Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses
HU230769B1 (en) 1999-01-15 2018-03-28 Genentech Inc. Polypeptide variants with altred effector function
EP1176195B1 (en) 1999-04-09 2013-05-22 Kyowa Hakko Kirin Co., Ltd. Method for controlling the activity of immunologically functional molecule
FR2794025A1 (en) 1999-05-25 2000-12-01 Transgene Sa COMPOSITION FOR IMPLEMENTING ANTI-TUMOR OR ANTIVIRAL TREATMENT IN A MAMMAL
DE60037896D1 (en) 1999-07-29 2008-03-13 Medarex Inc HUMAN ANTIBODIES AGAINST HER2 / NEU
EP1210424B1 (en) * 1999-08-23 2007-02-07 Dana-Farber Cancer Institute, Inc. Novel b7-4 molecules and uses therefor
EP1210428B1 (en) * 1999-08-23 2015-03-18 Dana-Farber Cancer Institute, Inc. Pd-1, a receptor for b7-4, and uses therefor
IL148079A0 (en) 1999-08-24 2002-09-12 Medarex Inc Human ctla-4 antibodies and compositions containing the same
AU1448701A (en) 1999-11-09 2001-06-06 Human Genome Sciences, Inc. 15 human secreted proteins
US6803192B1 (en) * 1999-11-30 2004-10-12 Mayo Foundation For Medical Education And Research B7-H1, a novel immunoregulatory molecule
AU784634B2 (en) 1999-11-30 2006-05-18 Mayo Foundation For Medical Education And Research B7-H1, a novel immunoregulatory molecule
US7030219B2 (en) 2000-04-28 2006-04-18 Johns Hopkins University B7-DC, Dendritic cell co-stimulatory molecules
CA2412377A1 (en) * 2000-06-06 2001-12-13 Bristol-Myers Squibb Company B7-related nucleic acids and polypeptides and their uses for immunomodulation
US20030031675A1 (en) * 2000-06-06 2003-02-13 Mikesell Glen E. B7-related nucleic acids and polypeptides useful for immunomodulation
JP2004501631A (en) 2000-06-28 2004-01-22 ジェネティックス・インスチチュート・リミテッド・ライアビリティ・カンパニー PD-L2 molecule: novel PD-1 ligand and use thereof
US20020025317A1 (en) 2000-07-20 2002-02-28 Schering Ag Bispecific monoclonal antibodies to IL-12 and IL-18
US7132109B1 (en) 2000-10-20 2006-11-07 University Of Connecticut Health Center Using heat shock proteins to increase immune response
WO2002032378A2 (en) 2000-10-20 2002-04-25 Tsuneya Ohno Fusion cells and cytokine compositions for treatment of disease
CN1487996B (en) 2000-11-30 2010-06-16 米德列斯公司 Transgenic transchromosomal rodents for production of human antibodies
US7396917B2 (en) * 2000-12-05 2008-07-08 Alexion Pharmaceuticals, Inc. Rationally designed antibodies
EP2388590A1 (en) 2001-04-02 2011-11-23 Dana Farber Cancer Institute PD-1, a receptor for B7-4, and uses thereof
AR036993A1 (en) * 2001-04-02 2004-10-20 Wyeth Corp USE OF AGENTS THAT MODULATE THE INTERACTION BETWEEN PD-1 AND ITS LINKS IN THE SUBMODULATION OF IMMUNOLOGICAL ANSWERS
AU2002258941A1 (en) 2001-04-20 2002-11-05 Mayo Foundation For Medical Education And Research Methods of enhancing cell responsiveness
EP1421203A4 (en) 2001-05-17 2005-06-01 Diversa Corp Novel antigen binding molecules for therapeutic, diagnostic, prophylactic, enzymatic, industrial, and agricultural applications, and methods for generating and screening thereof
MXPA05000511A (en) * 2001-07-12 2005-09-30 Jefferson Foote Super humanized antibodies.
WO2003006636A1 (en) 2001-07-12 2003-01-23 Genethor Gmbh Reduction of the stimulatory capacity of antigen-presenting cells
WO2003011911A1 (en) 2001-07-31 2003-02-13 Ono Pharmaceutical Co., Ltd. Substance specific to pd-1
IL145926A0 (en) 2001-10-15 2002-07-25 Mor Research Applic Ltd Peptide epitopes of mimotopes useful in immunomodulation
HUP0600342A3 (en) 2001-10-25 2011-03-28 Genentech Inc Glycoprotein compositions
WO2003042402A2 (en) * 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents that modulate immune cell activation and methods of use thereof
AU2003217912A1 (en) 2002-03-01 2003-09-16 Xencor Antibody optimization
EP1532175B1 (en) 2002-03-22 2012-10-17 Aprogen, Inc. Humanized antibody and process for preparing the same
EA200401325A1 (en) 2002-04-09 2005-04-28 Киова Хакко Когио Ко., Лтд. CELLS WITH MODIFIED GENOM
IL149820A0 (en) 2002-05-23 2002-11-10 Curetech Ltd Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency
US7304149B2 (en) 2002-06-20 2007-12-04 Washington University In St. Louis BTLA nucleic acids
ES2350687T3 (en) 2002-07-03 2011-01-26 Ono Pharmaceutical Co., Ltd. IMMUNOPOTENTIAL COMPOSITIONS.
CN1753912B (en) 2002-12-23 2011-11-02 惠氏公司 Anti-PD-1 antibodies and uses thereof
US7563869B2 (en) 2003-01-23 2009-07-21 Ono Pharmaceutical Co., Ltd. Substance specific to human PD-1
US7465446B2 (en) 2003-05-30 2008-12-16 Medarex, Inc. Surrogate therapeutic endpoint for anti-CTLA4-based immunotherapy of disease
WO2006021955A2 (en) 2004-08-23 2006-03-02 Mor Research Applications Ltd. Use of bat monoclonal antibody for immunotherapy
TWI309240B (en) * 2004-09-17 2009-05-01 Hoffmann La Roche Anti-ox40l antibodies
ES2671893T3 (en) 2004-10-06 2018-06-11 Mayo Foundation For Medical Education And Research B7-H1 and PD-1 in the treatment of renal cell carcinoma
RU2494107C2 (en) 2005-05-09 2013-09-27 Оно Фармасьютикал Ко., Лтд. Human monoclonal antibodies specific for programmed cell death 1 (pd1) protein and methods of treating cancer with using anti-pd1 antibodies either individually, or in combination with other immunotherapeutic agents
WO2006124269A2 (en) 2005-05-16 2006-11-23 Amgen Fremont Inc. Human monoclonal antibodies that bind to very late antigen-1 for the treatment of inflammation and other disorders
CN104356236B (en) 2005-07-01 2020-07-03 E.R.施贵宝&圣斯有限责任公司 Human monoclonal antibody against programmed death ligand 1 (PD-L1)
HRP20201595T1 (en) * 2011-11-28 2020-12-11 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
AR091649A1 (en) * 2012-07-02 2015-02-18 Bristol Myers Squibb Co OPTIMIZATION OF ANTIBODIES THAT FIX THE LYMPHOCYTE ACTIVATION GEN 3 (LAG-3) AND ITS USES
MX2016007885A (en) * 2013-12-17 2017-01-11 Genentech Inc Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody.
WO2016191751A1 (en) * 2015-05-28 2016-12-01 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
US11078278B2 (en) * 2015-05-29 2021-08-03 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
EP3307778A1 (en) * 2015-06-12 2018-04-18 Bristol-Myers Squibb Company Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways
JP2019514889A (en) * 2016-04-25 2019-06-06 メディミューン，エルエルシー Composition comprising a co-formulation of anti-PD-L1 and anti-CTLA-4 antibody
WO2018009507A1 (en) * 2016-07-06 2018-01-11 Bristol-Myers Squibb Company Combination of tim-4 antagonist and methods of use

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10988536B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10988535B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11001630B2 (en) 2008-08-11 2021-05-11 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation Gene-3 (LAG-3), and uses thereof
US11236165B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind Lymphocyte Activation Gene-3 (LAG-3), and uses thereof
US11236163B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11236164B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11530267B2 (en) 2008-08-11 2022-12-20 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11512130B2 (en) 2008-08-11 2022-11-29 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11345752B2 (en) 2012-07-02 2022-05-31 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11274152B2 (en) 2013-09-20 2022-03-15 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
US11306143B2 (en) 2016-07-06 2022-04-19 Bristol-Myers Squibb Company Combination of TIM-4 antagonist and PD-1 antagonist and methods of use
US12227575B2 (en) 2016-07-06 2025-02-18 Bristol-Myers Squibb Company Combination of TIM-4 antagonist and PD-1 antagonist and methods of use
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US12049503B2 (en) 2017-05-30 2024-07-30 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US12565528B2 (en) 2020-10-23 2026-03-03 Bristol-Myers Squibb Company LAG-3 antagonist therapy for lung cancer
US12052261B2 (en) 2022-02-15 2024-07-30 Bank Of America Corporation System and method for authenticating the receiving end of data transmission via LiFi and holochain network
US12074641B2 (en) 2022-02-15 2024-08-27 Bank Of America Corporation System and method for secured data transmission using LiFi and holochain network
US12381626B2 (en) 2022-02-15 2025-08-05 Bank Of America Corporation System and method for secured data transmission using LiFi and holochain network

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