PD-1/TIM-3 BI-SPECIFIC ANTIBODIES, COMPOSITIONS THEREOF, AND METHODS OF MAKING AND USING THE SAME

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)