Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)

Abstract

The disclosure provides antibody agents that bind to a T Cell Immunoglobulin and Mucin Protein-3 (TIM-3) protein. Particular immunoglobulin heavy chain polypeptide and immunoglobulin light chain polypeptide sequences are explicitly provided. Also provided are related nucleic acids, vectors, compositions, and methods of using the anti-TIM-3 antibody agent to treat a disorder or disease that is responsive to TIM-3 inhibition, such as cancer, an infectious disease, or an autoimmune disease.

1 . A polypeptide that is capable of binding T Cell Immunoglobulin and Mucin Protein 3 (TIM-3), wherein the polypeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96% 97%, 98%, or 99% sequence identity to SEQ ID NO: 1. 
     
     
         2 . A heavy chain polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1. 
     
     
         3 . The heavy chain polypeptide of  claim 2 , wherein the polypeptide binds T Cell Immunoglobulin and Mucin Protein 3 (TIM-3). 
     
     
         4 . A polypeptide that is capable of binding T Cell Immunoglobulin and Mucin Protein 3 (TIM-3), wherein the polypeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to SEQ ID NO: 2. 
     
     
         5 . A light chain polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2. 
     
     
         6 . The heavy chain polypeptide of  claim 5 , wherein the polypeptide binds T Cell Immunoglobulin and Mucin Protein 3 (TIM-3). 
     
     
         7 . A polypeptide comprising a polypeptide of anyone of  claims 1 - 3  and/or a polypeptide of any one of  claims 4 - 6 , wherein the polypeptide comprises at least one disulfide bond formed by a first cysteine and a second cysteine, and wherein:
 i) the first cysteine is selected from residue 22, 96, 127, 140, 196, 219, 222, 254, 314, 360 and 418 of SEQ ID NO: 1, and the second cysteine is selected from residue 23, 88, 134, 194, and 214 of SEQ ID NO: 2; 
 ii) the first cysteine is selected from residue 22, 96, 127, 140, 196, 219, 222, 254, 314, 360 and 418 of SEQ ID NO: 1, and the second cysteine is selected from 22, 96, 127, 140, 196, 219, 222, 254, 314, 360 and 418 of SEQ ID NO: 1; 
 iii) the first cysteine is selected from residue 23, 88, 134, 194, and 214 of SEQ ID NO: 2, and the second cysteine is selected from residue 23, 88, 134, 194, and 214 of SEQ ID NO: 2; 
 iv) the first residue is residue 23 of SEQ ID NO: 2, and the second residue is residue 88 of SEQ ID NO: 2; 
 v) the first residue is residue 134 of SEQ ID NO: 2, and the second residue is residue 194 of SEQ ID NO: 2; 
 vi) the first residue is residue 214 of SEQ ID NO: 2, and the second residue is residue 127 of SEQ ID NO: 1; 
 vii) the first residue is residue 22 of SEQ ID NO: 1, and the second residue is residue 97 of SEQ ID NO: 1; 
 viii) the first residue is residue 140 of SEQ ID NO: 1, and the second residue is residue 196 of SEQ ID NO: 1; 
 ix) the first residue is residue 219 of SEQ ID NO: 1, and the second residue is residue 222 of SEQ ID NO: 1; 
 x) the first residue is residue 254 of SEQ ID NO: 1, and the second residue is residue 314 of SEQ ID NO: 1; or 
 xi) the first residue is residue 360 of SEQ ID NO: 1, and the second residue is residue 418 of SEQ ID NO: 1. 
 
     
     
         8 . The polypeptide of any one of  claims 1 - 7 , wherein the polypeptide contains at least one asparagine that is glycosylated. 
     
     
         9 . An isolated nucleic acid sequence encoding a polypeptide comprising an amino acid sequence of SEQ ID NO: 1. 
     
     
         10 . An isolated nucleic acid sequence encoding a polypeptide comprising an amino acid sequence of SEQ ID NO: 2. 
     
     
         11 . An isolated nucleic acid whose sequence comprises SEQ ID NO:3. 
     
     
         12 . An isolated nucleic acid whose sequence comprises SEQ ID NO:4. 
     
     
         13 . A vector comprising the isolated nucleic acid sequence of any one of  claims 9 - 12 . 
     
     
         14 . An isolated cell comprising the vector of  claim 13 . 
     
     
         15 . An antibody agent comprising the polypeptide of any one of  claims 1 - 8 . 
     
     
         16 . The antibody agent of  claim 15 , wherein the antibody agent comprises a polypeptide whose amino acid sequence comprises SEQ ID NO: 1 and a polypeptide whose amino acid sequence comprises SEQ ID NO: 2. 
     
     
         17 . The antibody agent of  claim 15  or  16 , wherein the antibody agent binds TIM-3. 
     
     
         18 . The antibody agent of any one of  claims 15 - 17 , wherein the antibody agent binds to TIM-3 with a K D  between about 1 picomolar (pM) and about 100 micromolar (μM). 
     
     
         19 . A composition comprising (a) the polypeptide of any one of  claims 1 - 8 , (b) the isolated nucleic acid of any one of  claims 9 - 12 , (c) the vector of  claim 13 , (d) the isolated cell of  claim 14 , or (e) the antibody agent of any one of  claims 15 - 18 . 
     
     
         20 . The composition of  claim 19 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         21 . A method of treating a disorder in a mammal that is responsive to TIM-3 inhibition, which method comprises administering an effective amount of the polypeptide of any one of  claims 1 - 8 , the isolated nucleic acid of any one of  claims 9 - 12 , the vector of  claim 13 , the isolated cell of  claim 14 , the antibody agent of any one of  claims 15 - 18 , or the composition of  claim 19  or  20  to a mammal having a disorder that is responsive to TIM-3 inhibition, whereupon the disorder is treated in the mammal. 
     
     
         22 . A method of inducing an immune response in a mammal having a disorder that is responsive to TIM-3 inhibition, comprising administering to said mammal an effective amount of a TIM-3 agent selected from the group consisting of: the polypeptide of any one of  claims 1 - 8 , the isolated nucleic acid of any one of  claims 9 - 12 , the vector of  claim 13 , the isolated cell of  claim 14 , the antibody agent of any one of  claims 15 - 18 , or the composition of  claim 19  or  20 , whereupon an immune response is induced in the mammal. 
     
     
         23 . A method of enhancing an immune response or increasing the activity of an immune cell in a mammal having a disorder that is responsive to TIM-3 inhibition, comprising administering to said mammal an effective amount of a TIM-3 agent selected from the group consisting of: the polypeptide of any one of  claims 1 - 8 , the isolated nucleic acid of any one of  claims 9 - 12 , the vector of  claim 13 , the isolated cell of  claim 14 , the antibody agent of any one of  claims 15 - 18 , or the composition of  claim 19  or  20 , whereupon an immune response or immune cell activity is enhanced or increased in the mammal. 
     
     
         24 . The method of  claim 22  or  23 , wherein the immune response is a humoral or cell mediated immune response. 
     
     
         25 . The method of  claim 24 , wherein the immune response is a CD4 or CD8 T cell response. 
     
     
         26 . The method of  claim 24 , wherein the immune response is a B cell response. 
     
     
         27 . The method of any one of  claims 21 - 26 , wherein the disorder is cancer. 
     
     
         28 . The method of  claim 27 , wherein the cancer is:
 i) a cancer associated with a high tumor mutation burden (TMB);   ii) a cancer that is microsatellite stable (MSS),   iii) a cancer that is characterized by microsatellite instability,   iv) a cancer that has a high microsatellite instability status (MSI-H),   v) a cancer that has a low microsatellite instability status (MSI-L),   vi) a cancer associated with high TMB and MSI-H,   vii) a cancer associated with high TMB and MSI-L or MSS,   viii) a cancer that has a defective DNA mismatch repair system,   ix) a cancer that has a defect in a DNA mismatch repair gene,   x) a hypermutated cancer,   xi) a cancer comprising a mutation in polymerase epsilon (POLE),   xii) adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, stomach cancer, small intestine cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, a hematological cancer, multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma/primary mediastinal B-cell lymphoma, or chronic myelogenous leukemia, or   xiii) a cancer of xii), wherein the cancer is MSS or MSI-L, is characterized by microsatellite instability, is MSI-H, has high TMB, has high TMB and is MSS or MSI-L, has high TMB and is MSI-H, has a defective DNA mismatch repair system, has a defect in a DNA mismatch repair gene, is a hypermutated cancer, or comprises a mutation in polymerase epsilon (POLE).   
     
     
         29 . The method of any one of  claims 21 - 26 , wherein the disorder is an infectious disease. 
     
     
         30 . The method of  claim 29 , wherein the infectious disease is caused by a virus or a bacterium. 
     
     
         31 . The method of  claim 30 , wherein the virus is human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), influenza virus, dengue virus, or hepatitis B virus (HBV). 
     
     
         32 . The method of any one of  claims 21 - 26 , wherein the disorder is an autoimmune disease. 
     
     
         33 . The method of  claim 32 , wherein the autoimmune disease is multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis, scleroderma, Crohn's disease, psoriasis, systemic lupus erythematosus (SLE), or ulcerative colitis. 
     
     
         34 . The method of any one of  claims 21 - 33 , wherein the mammal has been administered or will be administered an agent that inhibits PD-1, such that the mammal receives both. 
     
     
         35 . The method of  claim 34 , wherein the agent that inhibits PD-1 is a PD-1-binding agent. 
     
     
         36 . The method of  claim 35 , wherein the PD-1-binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. 
     
     
         37 . The method of  claim 36 , wherein the anti-PD-1 antibody is an antibody selected from the group consisting of: BGB-A317, BI 754091, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI-0680, MGA-012, nivolumab, PDR001, pembrolizumab, PF-06801591, REGN-2810, TSR-042, and derivatives thereof. 
     
     
         38 . The method of  claim 34 , wherein the agent that inhibits PD-1 is an anti-PD-L1/L2 agent. 
     
     
         39 . The method of  claim 38 , wherein the anti-PD-L1/L2 agent is an anti-PD-Ll antibody. 
     
     
         40 . The method of  claim 39 , wherein the anti-PD-L1 antibody agent is atezolizumab, avelumab, CX-072, durvalumab, FAZ053, LY3300054, PD-L1 millamolecule, or derivatives thereof. 
     
     
         41 . The method of any one of  claims 21 - 40 , wherein the mammal has been administered or will be administered an agent that inhibits LAG-3, such that the mammal receives both. 
     
     
         42 . The method of  claim 41 , wherein the agent that inhibits LAG-3 is a LAG-3-binding agent. 
     
     
         43 . The method of  claim 42 , wherein the LAG-3-binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. 
     
     
         44 . The method of any one of  claim 41 - 43 , wherein the mammal has received or will receive treatment with each of an agent that inhibits TIM-3, an agent that inhibits PD-1 and an agent that inhibits LAG-3, such that the mammal receives all three. 
     
     
         45 . The method of any one of  claims 21 - 44 , wherein the mammal has been administered or will be administered an agent that inhibits PARP, such that the mammal receives both. 
     
     
         46 . The method of  claim 45 , wherein the agent that inhibits PARP is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. 
     
     
         47 . The method of  claim 45  or  46 , wherein the agent that inhibits PARP is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, Simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2-(4-(Trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, and salts or derivatives thereof. 
     
     
         48 . The method of any one of  claims 45 - 47 , wherein the mammal receives treatment with each of the TIM-3 agent, an agent that inhibits PD-1, and an agent that inhibits PARP, such that the mammal receives all three. 
     
     
         49 . The method of  claim 48 , wherein the method further comprises the mammal receiving treatment with an agent that inhibits LAG-3, such that the mammal receives all four. 
     
     
         50 . The method of any one of  claims 21 - 49 , wherein the mammal is resistant to treatment with an agent that inhibits PD-1. 
     
     
         51 . The method of any one of  claims 21 - 50 , wherein the mammal is refractory to treatment with an agent that inhibits PD-1. 
     
     
         52 . The method of any one of  claims 21 - 51 , wherein the method sensitizes the mammal to treatment with an agent that inhibits PD-1. 
     
     
         53 . The method of any one of  claims 50 - 52 , wherein the mammal comprises an exhausted immune cell. 
     
     
         54 . The method of  claim 53 , wherein the exhausted immune cell is an exhausted T cell. 
     
     
         55 . The method of any one of  claims 21 - 54 , wherein the mammal is human. 
     
     
         56 . The method of any one of  claims 21 - 55 , wherein the mammal has previously been treated with one or more different cancer treatment modalities. 
     
     
         57 . The method of  claim 56 , wherein the mammal has previously been treated with one or more of surgery, radiotherapy, chemotherapy, or immunotherapy. 
     
     
         58 . The method of  claim 56  or  57 , wherein the mammal has previously been treated with a cytotoxic therapy. 
     
     
         59 . The method of any one of  claims 21 - 58 , wherein the method further comprises administering another therapeutic agent or treatment. 
     
     
         60 . The method of  claim 59 , wherein the method further comprises administering one or more of surgery, a radiotherapy, a chemotherapy, an immunotherapy, an anti-angiogenic agent, or an anti-inflammatory. 
     
     
         61 . A method of manufacturing the polypeptide of any one of  claims 1 - 8  by expressing a nucleic acid encoding the polypeptide in a host cell culture. 
     
     
         62 . A method of manufacturing the antibody agent of any one of  claims 15 - 18  by expressing a nucleic acid encoding the antibody agent in a host cell culture. 
     
     
         63 . A method of manufacturing the composition of  claim 19  or  20  by combining the polypeptide of any one of  claims 1 - 8 , the isolated nucleic acid of any one of  claims 9 - 12 , the vector of  claim 13 , the isolated cell of  claim 14 , or the antibody agent of any one of  claims 15 - 18  with a pharmaceutically acceptable carrier and formulating for administration to a subject. 
     
     
         64 . The method of  claim 63 , wherein the step of formulating for administration comprises formulating for parenteral delivery. 
     
     
         65 . A method of manufacturing the polypeptide of any one of  claims 1 - 8 , the isolated nucleic acid of any one of  claims 9 - 12 , the vector of  claim 13 , the isolated cell of  claim 14 , the antibody agent of any one of  claims 15 - 18 , or the composition of  claim 19  or  20  for use in one of the methods of anyone of  claims 21 - 60 .