Anti-tim-3 antibodies, compositions comprising anti-tim-3 antibodies and methods of making and using anti-tim-3 antibodies

Abstract

Provided herein are antibodies that selectively bind to Tim-3 and its isoforms and homologs, and compositions comprising the antibodies. Also provided are methods of using the antibodies, such as therapeutic and diagnostic methods.

1 .- 64 . (canceled) 
     
     
         65 . A method of treating cancer that expresses Tim-3 in a subject in need thereof, comprising administering to the subject an effective amount of an antibody or fragment thereof comprising:
 a. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 130, and the V L  region SEQ ID NO: 151;   b. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 131, and the V L  region SEQ ID NO: 152;   c. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 132, and the V L  region SEQ ID NO: 153;   d. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 133, and the V L  region SEQ ID NO: 154;   e. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 134, and the V L  region SEQ ID NO: 155;   f. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 135, and the V L  region SEQ ID NO: 156;   g. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 136, and the V L  region SEQ ID NO: 157;   h. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 137, and the V L  region SEQ ID NO: 158;   i. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 138, and the V L  region SEQ ID NO: 158;   j. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 139, and the V L  region SEQ ID NO: 158;   k. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 140, and the V L  region SEQ ID NO: 158;   l. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 141, and the V L  region SEQ ID NO: 158;   m. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 142, and the V L  region SEQ ID NO: 158;   n. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 143, and the V L  region SEQ ID NO: 158;   o. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 144, and the V L  region SEQ ID NO: 158;   p. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 145, and the V L  region SEQ ID NO: 158;   q. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 146, and the V L  region SEQ ID NO: 158;   r. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 147, and the V L  region SEQ ID NO: 158;   s. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 148, and the V L  region SEQ ID NO: 158;   t. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 149, and the V L  region SEQ ID NO: 158; or   u. three heavy chain CDRs and three light chain CDRs of the V H  region SEQ ID NO: 150, and the V L  region SEQ ID NO: 158.   
     
     
         66 . The method of  claim 65 , wherein the antibody or fragment thereof comprises:
 a. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 4 or 25, a CDR-H2 comprising SEQ ID NOs: 46 or 67, and a CDR-H3 comprising SEQ ID NO: 88; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 112, a CDR-L2 comprising SEQ ID NO: 119, and a CDR-L3 comprising SEQ ID NO: 126;   b. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 5 or 26, a CDR-H2 comprising SEQ ID NOs: 47 or 68, and a CDR-H3 comprising SEQ ID NO: 89; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 111, a CDR-L2 comprising SEQ ID NO: 118, and a CDR-L3 comprising SEQ ID NO: 125;   c. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 6 or 27, a CDR-H2 comprising SEQ ID NOs: 48 or 69, and a CDR-H3 comprising SEQ ID NO: 90; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 113, a CDR-L2 comprising SEQ ID NO: 120, and a CDR-L3 comprising SEQ ID NO: 127;   d. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 7 or 28, a CDR-H2 comprising SEQ ID NOs: 49 or 70, and a CDR-H3 comprising SEQ ID NO: 91; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 109, a CDR-L2 comprising SEQ ID NO: 116, and a CDR-L3 comprising SEQ ID NO: 123;   e. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 8 or 29, a CDR-H2 comprising SEQ ID NOs: 50 or 71, and a CDR-H3 comprising SEQ ID NO: 92; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 114, a CDR-L2 comprising SEQ ID NO: 121, and a CDR-L3 comprising SEQ ID NO: 128 or 28;   f. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 9 or 30, a CDR-H2 comprising SEQ ID NOs: 51 or 72, and a CDR-H3 comprising SEQ ID NO: 93; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 110, a CDR-L2 comprising SEQ ID NO: 117, and a CDR-L3 comprising SEQ ID NO: 124;   g. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 10 or 31, a CDR-H2 comprising SEQ ID NOs: 52 or 73, and a CDR-H3 comprising SEQ ID NO: 94; and the V L  comprising: a CDR-L1 comprising SEQ ID NO: 115, a CDR-L2 comprising SEQ ID NO: 122, and a CDR-L3 comprising SEQ ID NO: 129;   h. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 11 or 32, a CDR-H2 comprising SEQ ID NOs: 53 or 74, and a CDR-H3 comprising SEQ ID NO: 95; and the V L  region comprising: a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   i. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 12 or 33, a CDR-H2 comprising SEQ ID NOs: 54 or 75, and a CDR-H3 comprising SEQ ID NO: 96; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176; a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   j. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 13 or 34, a CDR-H2 comprising SEQ ID NOs: 55 or 76, and a CDR-H3 comprising SEQ ID NO: 97; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   k. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 14 or 35, a CDR-H2 comprising SEQ ID NOs: 56 or 77, and a CDR-H3 comprising SEQ ID NO: 98; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   l. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 15 or 36, a CDR-H2 comprising SEQ ID NOs: 57 or 78, and a CDR-H3 comprising SEQ ID NO: 99; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   m. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 16 or 37, a CDR-H2 comprising SEQ ID NOs: 58 or 79, and a CDR-H3 comprising SEQ ID NO: 100; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   n. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 17 or 38, a CDR-H2 comprising SEQ ID NOs: 59 or 80, and a CDR-H3 comprising SEQ ID NO: 101; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   o. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 18 or 39, a CDR-H2 comprising SEQ ID NOs: 60 or 81, and a CDR-H3 comprising SEQ ID NO: 102; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   p. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 19 or 40, a CDR-H2 comprising SEQ ID NOs: 61 or 82, and a CDR-H3 comprising SEQ ID NO: 103; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   q. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 20 or 41, a CDR-H2 comprising SEQ ID NOs: 62 or 83, and a CDR-H3 comprising SEQ ID NO: 104; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   r. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 21 or 42, a CDR-H2 comprising SEQ ID NOs: 63 or 84, and a CDR-H3 comprising SEQ ID NO: 105; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   s. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 22 or 43, a CDR-H2 comprising SEQ ID NOs: 64 or 85, and a CDR-H3 comprising SEQ ID NO: 106; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178;   t. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 23 or 44, a CDR-H2 comprising SEQ ID NOs: 65 or 86, and a CDR-H3 comprising SEQ ID NO: 107; and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178; or   u. the V H  comprising: a CDR-H1 comprising SEQ ID NOs: 24 or 45, a CDR-H2 comprising SEQ ID NOs: 66 or 87, and a CDR-H3 comprising SEQ ID NO: 108 and the V L  region comprises a CDR-L1 comprising SEQ ID NO: 176, a CDR-L2 sequence comprising SEQ ID NO: 177, and a CDR-L3 sequence comprising SEQ ID NO: 178.   
     
     
         67 . The method of  claim 65 , wherein the antibody or fragment thereof comprises:
 a. the V H  region is SEQ ID NO: 130, and the V L  region is SEQ ID NO: 151;   b. the V H  region is SEQ ID NO: 131, and the V L  region is SEQ ID NO: 152;   c. the V H  region is SEQ ID NO: 132, and the V L  region is SEQ ID NO: 153;   d. the V H  region is SEQ ID NO: 133, and the V L  region is SEQ ID NO: 154;   e. the V H  region is SEQ ID NO: 134, and the V L  region is SEQ ID NO: 155;   f. the V H  region is SEQ ID NO: 135, and the V L  region is SEQ ID NO: 156;   g. the V H  region is SEQ ID NO: 136, and the V L  region is SEQ ID NO: 157;   h. the V H  region is SEQ ID NO: 137, and the V L  region is SEQ ID NO: 158;   i. the V H  region is SEQ ID NO: 138, and the V L  region is SEQ ID NO: 158;   j. the V H  region is SEQ ID NO: 139, and the V L  region is SEQ ID NO: 158;   l. the V H  region is SEQ ID NO: 140, and the V L  region is SEQ ID NO: 158;   m. the V H  region is SEQ ID NO: 141, and the V L  region is SEQ ID NO: 158;   n. the V H  region is SEQ ID NO: 142, and the V L  region is SEQ ID NO: 158;   o. the V H  region is SEQ ID NO: 143, and the V L  region is SEQ ID NO: 158;   p. the V H  region is SEQ ID NO: 144, and the V L  region is SEQ ID NO: 158;   q. the V H  region is SEQ ID NO: 145, and the V L  region is SEQ ID NO: 158;   r. the V H  region is SEQ ID NO: 146, and the V L  region is SEQ ID NO: 158;   s. the V H  region is SEQ ID NO: 147, and the V L  region is SEQ ID NO: 158;   t. the V H  region is SEQ ID NO: 148, and the V L  region is SEQ ID NO: 158;   u. the V H  region is SEQ ID NO: 149, and the V L  region is SEQ ID NO: 158; or   v. the V H  region is SEQ ID NO: 150, and the V L  region is SEQ ID NO: 158.   
     
     
         68 . The method of  claim 65 , wherein the antibody or fragment thereof comprises at least one constant region domain. 
     
     
         69 . The method of  claim 68 , wherein the constant region comprises a sequence selected from SEQ ID NOs: 159, 160, and 161. 
     
     
         70 . The method of  claim 65 , wherein the antibody or fragment thereof is a monoclonal antibody. 
     
     
         71 . The method of  claim 65 , wherein the antibody or fragment thereof is an IgA, an IgD, an IgE, an IgG, or an IgM. 
     
     
         72 . The method of  claim 65 , wherein the antibody or fragment thereof is humanized or human. 
     
     
         73 . The method of  claim 65 , wherein the antibody or fragment thereof is aglycosylated. 
     
     
         74 . The method of  claim 73 , wherein the antibody or fragment thereof is selected from an Fv fragment, a Fab fragment, a F(ab′) 2  fragment, a Fab′ fragment, an scFv (sFv) fragment, and an scFv-Fc fragment. 
     
     
         75 . The method of  claim 74 , wherein the antibody or fragment thereof is an scFv fragment. 
     
     
         76 . The method of  claim 75 , wherein the scFv fragment comprises an scFv sequence selected from SEQ ID NO: 169, with or without the N-terminal M residue. 
     
     
         77 . The method of  claim 74 , wherein the antibody or fragment thereof is an scFv-Fc fragment. 
     
     
         78 . The method of  claim 77 , wherein the scFv-Fc fragment comprises a sequence selected from SEQ ID NO: 169, with or without the N-terminal M residue. 
     
     
         79 . The method of  claim 65 , wherein the antibody or fragment thereof has a k a  of about 6.71×10 4  sec −1  to about 2.81×10 5  sec −1  when associating with human Tim-3 at a temperature of 25° C. 
     
     
         80 . The method of  claim 65 , wherein the antibody or fragment thereof has a k d  of about 2.05×10 −2  sec −1  to about 4.25×10 −4  sec −1  when dissociating from human Tim-3 at a temperature of 25° C. 
     
     
         81 . The method of  claim 65 , wherein the antibody or fragment thereof has a K D  of about 9.1×10 −9 M to about 4.3×10 −1 ° M when bound to human Tim-3 at a temperature of 25° C. 
     
     
         82 . The method of  claim 65 , wherein the antibody or fragment thereof specifically binds cynomolgus Tim-3. 
     
     
         83 . The method of  claim 82 , wherein the antibody or fragment thereof has a K D  of about 13.2 nM to about 0.5 nM when bound to cynomolgus Tim-3 at a temperature of 25° C. 
     
     
         84 . The method of  claim 83 , wherein the ratio of K D  for human Tim-3 to K D  for cynomolgus Tim-3 is about 0.33 to about 18.2. 
     
     
         85 . The method of  claim 65 , wherein the cancer is a cancer of epithelial origin. 
     
     
         86 . The method of  claim 65 , wherein the cancer is a carcinoma. 
     
     
         87 . The method of  claim 65 , wherein the antibody or fragment thereof is formulated as a pharmaceutical composition, and the pharmaceutical composition is administered to the subject in need subcutaneously, intravenously, intramuscularly, or intraarterially. 
     
     
         88 . The method of  claim 87 , wherein the pharmaceutical composition is administered to the subject in need thereof at least once a week.