Anti-tim-3 antibodies and use thereof

Abstract

Provided are antibodies that specifically bind to T-cell immunoglobulin domain and mucin domain 3 (Tim-3). The anti-Tim-3 antibodies can be used to treat, prevent or diagnose immune, cancerous, infectious diseases or other pathological disorders that may be modulated by Tim-3-mediated functions.

1 .- 33 . (canceled) 
     
     
         34 . A composition comprising an antibody or antigen-binding fragment thereof capable of binding to human Tim-3, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH-CDR1 amino acid sequence of SEQ ID NO 3, a VH-CDR2 amino acid sequence of SEQ ID NO 26, a VH-CDR3 amino acid sequence of SEQ ID NO 5; and a light chain variable region (VL) comprising a VL-CDR1 amino acid sequence of SEQ ID NO 6, a VL-CDR2 amino acid sequence of SEQ ID NO 7, and a VL-CDR3 amino acid sequence of SEQ ID NO 27. 
     
     
         35 . The composition of  claim 34 , wherein the antibody is a humanized antibody molecule. 
     
     
         36 . The composition of  claim 34 , wherein the antigen binding fragment is a Fab, Fab′, F(ab′)2, Fv fragment, diabody, scFv, or nanobody. 
     
     
         37 . The composition of  claim 34 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 28. 
     
     
         38 . The composition of  claim 34 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28. 
     
     
         39 . The composition of  claim 34 , wherein the antibody or antigen binding fragment thereof comprises a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 36. 
     
     
         40 . The composition of  claim 34 , wherein the antibody or antigen binding fragment thereof comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 36. 
     
     
         41 . The composition of  claim 34 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36. 
     
     
         42 . The composition of  claim 34 , wherein the antibody comprises a heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4 or a variant thereof. 
     
     
         43 . The composition of  claim 42 , wherein the antibody comprises a variant heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4, wherein the variant heavy chain constant region provides a reduced or eliminated effector function. 
     
     
         44 . The composition of  claim 43 , wherein the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). 
     
     
         45 . The composition of  claim 43 , wherein the variant heavy chain constant region is a variant heavy chain constant region of human IgG1, comprising one or more mutations selected from a group consisting of E 233 P, L 234 A, L 235 A, L 236 Δ and P 329 A. 
     
     
         46 . The composition of  claim 45 , wherein the variant human IgG1 heavy chain constant region comprises the amino sequence of SEQ ID NO 21. 
     
     
         47 . The composition of  claim 34 , wherein the antibody comprises a light chain constant region of the type of kappa or lambda, or a variant thereof. 
     
     
         48 . The composition of  claim 34 , further comprising a pharmaceutically acceptable excipient. 
     
     
         49 . A method of stimulating an immune response in a subject, comprising administrating to the subject the antibody or antigen binding fragment thereof of  claim 34 . 
     
     
         50 . A method for treating a cancer or a tumor in a subject in need thereof, comprising administrating to the subject the antibody or fragment thereof of  claim 34 . 
     
     
         51 . The method of  claim 50 , wherein the cancer is selected from a lung cancer, a liver cancer, a stomach cancer, a cervical cancer, a melanoma, a renal cancer, a breast cancer, a colorectal cancer, a leukemia, a lymphoma, an ovarian cancer, a head and neck cancer or a metastatic lesion of the cancer. 
     
     
         52 . The method of  claim 50 , wherein the antibody is administrated in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent or procedure is selected from a chemotherapy, a targeted therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, a surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy. 
     
     
         53 . The method of  claim 52 , wherein the antibody is administered in combination with an inhibitor of an immune checkpoint molecule selected from PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. 
     
     
         54 . The method of  claim 52 , wherein the antibody is administered in combination with anti-PD-1 mAb 317-4B6 or 317-4B6/IgG4mt10. 
     
     
         55 . A method of treating an infectious disease in a subject in need thereof, comprising administering to the subject the antibody of  claim 34 . 
     
     
         56 . The method of  claim 55 , wherein the infectious disease is a chronic viral infection selected from HIV infection and HCV infection.