Pd-1/tim-3 bi-specific antibodies, compositions thereof, and methods of making and using the same

Abstract

Provided herein are antibodies that selectively bind to Tim-3 and its isoforms and homologs, and compositions comprising the antibodies. Also provided herein are antibodies that selectively bind to PD-1 and its isoforms and homologs, and compositions comprising the antibodies. In addition, provided herein are bi-specific antibodies and antigen binding constructs that selectively bind to Tim-3 and/or PD-1, their isoforms and homologs, and compositions comprising the antibodies and antigen binding constructs. Also provided are methods of using the antibodies, such as therapeutic and diagnostic methods.

1 . A bi-specific antibody or antigen-binding construct, comprising a first binding domain that specifically binds to Tim-3, and a second binding domain that specifically binds to PD-1, wherein:
 i. the first binding domain comprises:
 i. a CDR-H3 selected from SEQ ID NOs: 111-118; 
 ii. a Chothia CDR-H2 sequence selected from SEQ ID NOs: 63-80, or a Kabat CDR-H2 sequence selected from SEQ ID NOs: 82-109, or both; 
 iii. a Chothia CDR-H1 sequence selected from SEQ ID NOs: 4-23, or a Kabat CDR-H1 sequence selected from SEQ ID NOs: 39-56, or both and 
   ii. the second binding domain comprises:
 i. a CDR-H3 sequence selected from SEQ ID NO: 119, or a CDR-H3 sequence of a V H  sequence selected from SEQ ID NOs: 182-220; 
 ii. a Chothia CDR-H2 sequence selected from SEQ ID NO: 81, and a Chothia CDR-H2 sequence of a V H  sequence selected from SEQ ID NOs: 182-220, or a Kabat CDR-H2 sequence selected from SEQ ID NO: 110, and a Kabat CDR-H2 sequence of a V H  sequence selected from SEQ ID NOs: 182-220 or both; 
 iii. a Chothia CDR-H1 sequence selected from SEQ ID NOs: 24-38, and a Chothia CDR-H1 sequence of a V H  sequence selected from SEQ ID NOs: 182-220, or a Kabat CDR-H1 sequence selected from SEQ ID NOs: 57-62, and a Kabat CDR-H1 sequence of a V H  sequence selected from SEQ ID NOs: 182-220 or both. 
   
     
     
         2 .- 5 . (canceled) 
     
     
         6 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises a CDR-L3 sequence selected from SEQ ID NOs: 140-142. 
     
     
         7 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises a CDR-L2 sequence selected from SEQ ID NOs: 125-133. 
     
     
         8 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises a CDR-L1 sequence selected from SEQ ID NOs: 120-123. 
     
     
         9 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises:
 i. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 17 and 52; a CDR-H2 comprising one or more of SEQ ID NOs: 77 and 102; and a CDR-H3 comprising SEQ ID NO: 113;   ii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 89; and a CDR-H3 comprising SEQ ID NO: 113;   iii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 18 and 53; a CDR-H2 comprising one or more of SEQ ID NOs: 77 and 102; and a CDR-H3 comprising SEQ ID NO: 113;   iv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 19 and 54; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 102; and a CDR-H3 comprising SEQ ID NO: 113;   v. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 22 and 53; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 89; and a CDR-H3 comprising SEQ ID NO: 113;   vi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 4 and 39; a CDR-H2 comprising one or more of SEQ ID NOs: 63 and 82; and a CDR-H3 comprising SEQ ID NO: 111;   vii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 4 and 39; a CDR-H2 comprising one or more of SEQ ID NOs: 63 and 83; and a CDR-H3 comprising SEQ ID NO: 111;   viii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 4 and 39; a CDR-H2 comprising one or more of SEQ ID NOs: 63 and 84; and a CDR-H3 comprising SEQ ID NO: 111;   ix. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 4 and 39; a CDR-H2 comprising one or more of SEQ ID NOs: 63 and 85; and a CDR-H3 comprising SEQ ID NO: 111;   x. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 4 and 39; a CDR-H2 comprising one or more of SEQ ID NOs: 63 and 86; and a CDR-H3 comprising SEQ ID NO: 111;   xi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 4 and 39; a CDR-H2 comprising one or more of SEQ ID NOs: 63 and 87; and a CDR-H3 comprising SEQ ID NO: 111;   xii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 5 and 40; a CDR-H2 comprising one or more of SEQ ID NOs: 64 and 88; and a CDR-H3 comprising SEQ ID NO: 112;   xiii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 7 and 42; a CDR-H2 comprising one or more of SEQ ID NOs: 66 and 90; and a CDR-H3 comprising SEQ ID NO: 113;   xiv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 8 and 43; a CDR-H2 comprising one or more of SEQ ID NOs: 67 and 91; and a CDR-H3 comprising SEQ ID NO: 113;   xv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 9 and 44; a CDR-H2 comprising one or more of SEQ ID NOs: 168 and 92; and a CDR-H3 comprising SEQ ID NO: 114;   xvi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 10 and 45; a CDR-H2 comprising one or more of SEQ ID NOs: 69 and 93; and a CDR-H3 comprising SEQ ID NO: 114;   xvii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 8 and 42; a CDR-H2 comprising one or more of SEQ ID NOs: 70 and 94; and a CDR-H3 comprising SEQ ID NO: 114;   xviii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 8 and 42; a CDR-H2 comprising one or more of SEQ ID NOs: 70 and 95; and a CDR-H3 comprising SEQ ID NO: 114;   xix. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 11 and 46; a CDR-H2 comprising one or more of SEQ ID NOs: 71 and 96; and a CDR-H3 comprising SEQ ID NO: 115;   xx. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 12 and 47; a CDR-H2 comprising one or more of SEQ ID NOs: 72 and 97; and a CDR-H3 comprising SEQ ID NO: 113;   xxi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 13 and 48; a CDR-H2 comprising one or more of SEQ ID NOs: 73 and 98; and a CDR-H3 comprising SEQ ID NO: 116;   xxii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 14 and 49; a CDR-H2 comprising one or more of SEQ ID NOs: 74 and 99; and a CDR-H3 comprising SEQ ID NO: 117;   xxiii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 15 and 50; a CDR-H2 comprising one or more of SEQ ID NOs: 75 and 100; and a CDR-H3 comprising SEQ ID NO: 113;   xxiv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 16 and 51; a CDR-H2 comprising one or more of SEQ ID NOs: 76 and 101; and a CDR-H3 comprising SEQ ID NO: 118;   xxv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 103; and a CDR-H3 comprising SEQ ID NO: 113;   xxvi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 104; and a CDR-H3 comprising SEQ ID NO: 113;   xxvii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 78 and 105; and a CDR-H3 comprising SEQ ID NO: 113;   xxviii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 79 and 106; and a CDR-H3 comprising SEQ ID NO: 113;   xxix. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 80 and 107; and a CDR-H3 comprising SEQ ID NO: 113;   xxx. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 108; and a CDR-H3 comprising SEQ ID NO: 113;   xxxi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 6 and 41; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 109; and a CDR-H3 comprising SEQ ID NO: 113;   xxxii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 20 and 55; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 89; and a CDR-H3 comprising SEQ ID NO: 113;   xxxiii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 21 and 56; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 89; and a CDR-H3 comprising SEQ ID NO: 113; or   xxxiv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 23 and 53; a CDR-H2 comprising one or more of SEQ ID NOs: 65 and 89; and a CDR-H3 comprising SEQ ID NO: 113.   
     
     
         10 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises a V H  is selected from SEQ ID NOs: 144-180. 
     
     
         11 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises:
 i. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 354; a CDR-L2 comprising SEQ ID NO: 355; and a CDR-L3 comprising SEQ ID NO: 356;   ii. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 133; and a CDR-L3 comprising SEQ ID NO: 142;   iii. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 127; and a CDR-L3 comprising SEQ ID NO: 142;   iv. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 128; and a CDR-L3 comprising SEQ ID NO: 142;   v. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 129; and a CDR-L3 comprising SEQ ID NO: 142;   vi. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 130; and a CDR-L3 comprising SEQ ID NO: 142;   vii. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 131; and a CDR-L3 comprising SEQ ID NO: 142;   viii. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 123; a CDR-L2 comprising SEQ ID NO: 132; and a CDR-L3 comprising SEQ ID NO: 142;   ix. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 120; a CDR-L2 comprising SEQ ID NO: 125; and a CDR-L3 comprising SEQ ID NO: 140;   x. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 121; a CDR-L2 comprising SEQ ID NO: 125; and a CDR-L3 comprising SEQ ID NO: 140; or   xi. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 122; a CDR-L2 comprising SEQ ID NO: 126; and a CDR-L3 comprising SEQ ID NO: 141.   
     
     
         12 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises a V L  sequence selected from SEQ ID NOs: 221-235. 
     
     
         13 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises:
 i. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   ii. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   iii. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   iv. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   v. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 235, or a variant thereof;   vi. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 235, or a variant thereof;   vii. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 235, or a variant thereof;   viii. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 235, or a variant thereof;   ix. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 229, or a variant thereof;   x. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 229, or a variant thereof;   xi. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 229, or a variant thereof;   xii. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 229, or a variant thereof;   xiii. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 230, or a variant thereof;   xiv. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 230, or a variant thereof;   xv. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 230, or a variant thereof;   xvi. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 230, or a variant thereof;   xvii. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 231, or a variant thereof;   xviii. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 231, or a variant thereof;   xix. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 231, or a variant thereof;   xx. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 231, or a variant thereof;   xxi. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 232, or a variant thereof;   xxii. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 232, or a variant thereof;   xxiii. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 232, or a variant thereof;   xxiv. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 232, or a variant thereof;   xxv. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 233, or a variant thereof;   xxvi. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 233, or a variant thereof;   xxvii. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 233, or a variant thereof;   xxviii. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 233, or a variant thereof;   xxix. the V H  region SEQ ID NO: 165, or a variant thereof, and the V L  region is SEQ ID NO: 234, or a variant thereof;   xxx. the V H  region SEQ ID NO: 151, or a variant thereof, and the V L  region is SEQ ID NO: 234, or a variant thereof;   xxxi. the V H  region SEQ ID NO: 166, or a variant thereof, and the V L  region is SEQ ID NO: 234, or a variant thereof;   xxxii. the V H  region SEQ ID NO: 167, or a variant thereof, and the V L  region is SEQ ID NO: 234, or a variant thereof;   xxxiii. the V H  region SEQ ID NO: 179, or a variant thereof, and the V L  region is SEQ ID NO:228, or a variant thereof;   xxxiv. the V H  region SEQ ID NO: 179, or a variant thereof, and the V L  region is SEQ ID NO:235, or a variant thereof;   xxxv. the V H  region SEQ ID NO: 179, or a variant thereof, and the V L  region is SEQ ID NO:229, or a variant thereof;   xxxvi. the V H  region SEQ ID NO: 152, or a variant thereof, and the V L  region is SEQ ID NO:228, or a variant thereof;   xxxvii. the V H  region SEQ ID NO: 153, or a variant thereof, and the V L  region is SEQ ID NO:228, or a variant thereof;   xxxviii. the V H  region SEQ ID NO: 154, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   xxxix. the V H  region SEQ ID NO: 155, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   xl. the V H  region SEQ ID NO: 156, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   xli. the V H  region SEQ ID NO: 157, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   xlii. the V H  region SEQ ID NO: 158, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   xliii. the V H  region SEQ ID NO: 159, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof;   xliv. the V H  region SEQ ID NO: 160, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof; or   xlv. the V H  region SEQ ID NO: 161, or a variant thereof, and the V L  region is SEQ ID NO: 228, or a variant thereof.   
     
     
         14 .- 17 . (canceled) 
     
     
         18 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises a CDR-L3 sequence selected from SEQ ID NO: 143 or a CDR-L3 sequence of a V L  sequence selected from SEQ ID NOs: 237-269. 
     
     
         19 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises a CDR-L2 sequence selected from SEQ ID NOs: 134-139 or a CDR-L2 sequence of a V L  sequence selected from SEQ ID NOs: 237-269. 
     
     
         20 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain comprises a CDR-L1 sequence selected from SEQ ID NO: 124 or a CDR-L1 sequence of a V L  sequence selected from SEQ ID NOs: 237-269. 
     
     
         21 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises:
 i. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 24 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   ii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 38 and 62; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   iii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 37 and 62; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   iv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 36 and 58; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   v. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 35 and 62; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   vi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 34 and 58; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   vii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 33 and 58; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   viii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 32 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   ix. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 31 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   x. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 30 and 59; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 29 and 58; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 28 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xiii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 27 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xiv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 26 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xv. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 25 and 57; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xvi. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 24 and 60; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xvii. a V H  comprising: a CDR-H1 comprising one or more of SEQ ID NOs: 24 and 61; a CDR-H2 comprising one or more of SEQ ID NOs: 81 and 110; and a CDR-H3 comprising SEQ ID NO: 119;   xviii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 198; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 198; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 198;   xix. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 199; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 199; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 199;   xx. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 200; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 200; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 200;   xxi. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 201; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 201; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 201;   xxii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 202; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 202; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 202;   xxiii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 203; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 203; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 203;   xxiv. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 204; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 204; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 204;   xxv. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 205; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 205; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 205;   xxvi. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 206; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 206; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 206;   xxvii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 207; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 207; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 207;   xxviii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 208; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 208; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 208;   xxix. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 209; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 209; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 209;   xxx. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 210; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 210; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 210;   xxxi. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 211; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 211; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 211;   xxxii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 212; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 212; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 212;   xxxiii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 213; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 213; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 213;   xxxiv. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 214; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 214; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 214;   xxxv. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 215; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 215; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 215   xxxvi. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 216; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 216; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 216;   xxxvii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 217; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 217; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 217;   xxxviii. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 218; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 218; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 218;   xxxix. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 219; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 219; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 219; or   xl. a V H  comprising: a CDR-H1 comprising a Chothia and/or Kabat CDR-H1 sequence of SEQ ID NO: 220; a CDR-H2 comprising a Chothia and/or Kabat CDR-H2 sequence of SEQ ID NO: 220; and a CDR-H3 comprising a CDR-H3 sequence of SEQ ID NO: 220.   
     
     
         22 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises a V H  is selected from SEQ ID NOs: 181-220. 
     
     
         23 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises:
 i. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 125; a CDR-L2 comprising SEQ ID NO: 134; and a CDR-L3 comprising SEQ ID NO: 143;   ii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 244; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 244; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 244;   iii. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 125; a CDR-L2 comprising SEQ ID NO: 135; and a CDR-L3 comprising SEQ ID NO: 143;   iv. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 125; a CDR-L2 comprising SEQ ID NO: 136; and a CDR-L3 comprising SEQ ID NO: 143;   v. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 125; a CDR-L2 comprising SEQ ID NO: 137; and a CDR-L3 comprising SEQ ID NO: 143;   vi. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 125; a CDR-L2 comprising SEQ ID NO: 138; and a CDR-L3 comprising SEQ ID NO: 143;   vii. a V L  comprising: a CDR-L1 comprising SEQ ID NO: 125; a CDR-L2 comprising SEQ ID NO: 139; and a CDR-L3 comprising SEQ ID NO: 143;   viii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 242; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 242; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 242;   ix. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 243; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 243; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 243;   x. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 245; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 245; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 245;   xi. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 246; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 246; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 246;   xii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 247; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 247; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 247;   xiii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 248; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 248; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 248;   xiv. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 249; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 249; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 249;   xv. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 250; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 250; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 250;   xvi. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 251; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 251; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 251;   xvii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 252; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 252; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 252;   xviii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 253; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 253; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 253;   xix. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 254; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 254; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 254;   xx. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 255; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 255; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 255;   xxi. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 256; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 256; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 256;   xxii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 257; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 257; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 257;   xxiii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 258; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 258; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 258;   xxiv. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 259; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 259; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 259;   xxv. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 260; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 260; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 260;   xxvi. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 261; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 261; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 261;   xxvii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 262; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 262; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 262;   xxviii. a V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 263; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 263; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 263;   xxix. V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 264; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 264; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 264;   xxx. V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 265; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 265; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 265;   xxxi. V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 266; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 266; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 266;   xxxii. V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 267; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 267; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 267;   xxxiii. V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 268; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 268; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 268; or   xxxiv. V L  comprising: a CDR-L1 comprising a CDR-L1 sequence of SEQ ID NO: 269; a CDR-L2 comprising a CDR-L2 sequence of SEQ ID NO: 269; and a CDR-L3 comprising a CDR-L3 sequence of SEQ ID NO: 269.   
     
     
         24 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises a V L  sequence selected from SEQ ID NOs: 236-269. 
     
     
         25 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the second binding domain comprises:
 i. the V H  region SEQ ID NO: 181 and the V L  region SEQ ID NO: 244;   ii. the V H  region SEQ ID NO: 197 and the V L  region SEQ ID NO: 236;   iii. the V H  region SEQ ID NO: 197 and the V L  region SEQ ID NO: 244;   iv. the V H  region SEQ ID NO: 181 and the V L  region SEQ ID NO: 236;   v. the V H  region SEQ ID NO: 196 and the V L  region SEQ ID NO: 236;   vi. the V H  region SEQ ID NO: 195 and the V L  region SEQ ID NO: 236;   vii. the V H  region SEQ ID NO: 194 and the V L  region SEQ ID NO: 236;   viii. the V H  region SEQ ID NO: 193 and the V L  region SEQ ID NO: 236;   ix. the V H  region SEQ ID NO: 192 and the V L  region SEQ ID NO: 236;   x. the V H  region SEQ ID NO: 191 and the V L  region SEQ ID NO: 236;   xi. the V H  region SEQ ID NO: 190 and the V L  region SEQ ID NO: 236;   xii. the V H  region SEQ ID NO: 189 and the V L  region SEQ ID NO: 236;   xiii. the V H  region SEQ ID NO: 188 and the V L  region SEQ ID NO: 236;   xiv. the V H  region SEQ ID NO: 187 and the V L  region SEQ ID NO: 236;   xv. the V H  region SEQ ID NO: 186 and the V L  region SEQ ID NO: 236;   xvi. the V H  region SEQ ID NO: 185 and the V L  region SEQ ID NO: 236;   xvii. the V H  region SEQ ID NO: 184 and the V L  region SEQ ID NO: 236;   xviii. the V H  region SEQ ID NO: 183 and the V L  region SEQ ID NO: 236;   xix. the V H  region SEQ ID NO: 182 and the V L  region SEQ ID NO: 236;   xx. the V H  region SEQ ID NO: 196 and the V L  region SEQ ID NO: 244;   xxi. the V H  region SEQ ID NO: 195 and the V L  region SEQ ID NO: 244;   xxii. the V H  region SEQ ID NO: 194 and the V L  region SEQ ID NO: 244;   xxiii. the V H  region SEQ ID NO: 193 and the V L  region SEQ ID NO: 244;   xxiv. the V H  region SEQ ID NO: 192 and the V L  region SEQ ID NO: 244;   xxv. the V H  region SEQ ID NO: 191 and the V L  region SEQ ID NO: 244;   xxvi. the V H  region SEQ ID NO: 190 and the V L  region SEQ ID NO: 244;   xxvii. the V H  region SEQ ID NO: 189 and the V L  region SEQ ID NO: 244;   xxviii. the V H  region SEQ ID NO: 188 and the V L  region SEQ ID NO: 244;   xxix. the V H  region SEQ ID NO: 187 and the V L  region SEQ ID NO: 244;   xxx. the V H  region SEQ ID NO: 186 and the V L  region SEQ ID NO: 244;   xxxi. the V H  region SEQ ID NO: 185 and the V L  region SEQ ID NO: 244;   xxxii. the V H  region SEQ ID NO: 184 and the V L  region SEQ ID NO: 244;   xxxiii. the V H  region SEQ ID NO: 183 and the V L  region SEQ ID NO: 244;   xxxiv. the V H  region SEQ ID NO: 182 and the V L  region SEQ ID NO: 244; or   xxxv. the V H  region SEQ ID NO: 181 and the V L  region SEQ ID NO: 244.   
     
     
         26 . A bi-specific antibody or antigen-binding construct, comprising a first binding domain that specifically binds to Tim-3, and a second binding domain that specifically binds to PD-1, wherein the first binding domain comprises:
 i. a V H  region selected from SEQ ID NOs: 144-180, or a variant thereof having 10 or fewer amino acid substitutions;   ii. a V L  region selected from SEQ ID NOs: 221-235, or variant thereof of having 10 or fewer amino acid substitutions
 and the second binding domain comprises:
 i. a V H  region selected from SEQ ID NOs: 181-220, or a variant thereof having 10 or fewer amino acid substitutions; and 
 ii. a V L  region selected from SEQ ID NOs: 236-269, or variant thereof of having 10 or fewer amino acid substitutions. 
 
   
     
     
         27 . (canceled) 
     
     
         28 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the antibody comprises at least one constant region domain. 
     
     
         29 . (canceled) 
     
     
         30 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the bi-specific antibody or antigen binding construct is humanized or human. 
     
     
         31 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the bi-specific antibody or antigen binding construct is aglycosylated. 
     
     
         32 . The bi-specific antibody or antigen binding construct of  claim 1 , wherein the first binding domain or the second binding domain comprises an antibody fragment. 
     
     
         33 .- 35 . (canceled) 
     
     
         36 . The bi-specific antibody or antigen binding construct of  claim 32 , wherein the antibody fragment is selected from the group consisting of: an Fv fragment, a Fab fragment, a F(ab′) 2  fragment, a Fab′ fragment, an scFv (sFv) fragment, and an scFv-Fc fragment. 
     
     
         37 .- 48 . (canceled) 
     
     
         49 . An isolated antibody that specifically binds to human Tim-3, wherein the antibody comprises a CDR-H3 sequence selected from:
 i. a sequence defined by the consensus sequence α 1 -α 2 -α 3 -Y-R-α 6 -α 7 -α 8 -α 9 -α 10 -α 11 -α 12 -α 13 , where α 1  is Q, S or G; α 2  is G, F, Y, or H; α 3  is G, F, V, or I; α 6  is absent or S; α 7  is Y, S, M, or L; α 8  is D, N, or W; α 9  is D; α 10  is A, W, or S; α 11  is M, Y, F, or L; α 12  is D or V; and α 13  is Y or H;   ii. a sequence defined by the consensus sequence G-β 2 -β 3 -Y-R-β 7 -W-D-S-β 11 -D-β 13 , where β 2  is Y or H; β 3  is V or I; β 7  is M, or L; β 11  is Y, F, or L; and β 13  is Y or H; and   iii. a sequence selected from SEQ ID NOs: 111-118, or a variant thereof having three, two, or one amino acid substitution(s).   
     
     
         50 .- 116 . (canceled) 
     
     
         117 . A kit comprising an antibody of  claim 1 , and instructions for use of the antibody. 
     
     
         118 .- 119 . (canceled) 
     
     
         120 . A polynucleotide encoding an antibody of  claim 49 . 
     
     
         121 .- 125 . (canceled) 
     
     
         126 . A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         127 . A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of an antibody of  claim 1 . 
     
     
         128 .- 161 . (canceled)