Bispecific antagonist comprising a LAG-3 binding domain

1. A bispecific antagonist, comprising a first targeting domain and a second targeting domain:

wherein the first targeting domain binds specifically to human LAG-3 and comprises:

(1) an immunoglobulin HCVR comprising three HCDRs: HCDR1, HCDR2 and HCDR3,

wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 163, 166 and 169,

wherein the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 164, 167 and 170, and

wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 165, 168 and 171; and

(2) an immunoglobulin LCVR comprising three LCDRs: LCDR1, LCDR2 and LCDR3,

wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 172, 175 and 177,

wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 173 and 178, and

wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS; 174, 176 and 179.

2. The bispecific antagonist of claim 1 , wherein the second targeting domain binds specifically to human TIGIT.

3. The bispecific antagonist of claim 2 , wherein the second targeting domain comprises:

(I) au immunoglobulin HCVR comprising three HCDRs: HCDR1, HCDR2 and HCDR3,

wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:1, 6, 11, 15, 17, 20 and 23,

wherein the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 7, 9, 12, 13, 16, 18, 21 and 24, and

wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 5, 8, 10, 14, 19, 22 and 25; and

(2) an immunoglobulin LCVR comprising three LCDRs: LCDR1, LCDR2 and LCDR3,

wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 26, 29, 31, 33, 35, 39, 42 and 45,

wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 27, 30, 36, 37, 40, 43 and 46, and

wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 28, 32, 34, 38, 41, 44 and 47.

4. The bispecific antagonist of claim 3 , wherein the second targeting domain comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:23, an HCDR2 comprising the amino acid sequence of SEQ ID NO:24, an HCDR3 comprising the amino acid sequence of SEQ ID NO:25, an LCDR1 comprising the amino acid sequence of SEQ ID NO:45, an LCDR2 comprising the amino acid sequence of SEQ ID NO:46, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:47.

5. The bispecific antagonist of claim 4 , wherein the second targeting domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:66 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:67.

6. The bispecific antagonist of claim 1 , wherein the second targeting domain binds specifically to human PD-1.

7. The bispecific antagonist of claim 6 , wherein the second targeting domain comprises:

(1) an immunoglobulin HCVR comprising three complementarity determining regions (HCDRs): HCDR1, HCDR2 and HCDR3,

wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:68, 71, 74, 76 and 79,

wherein the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:69, 72, 77 and 80, and

wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:70, 73, 75, 78 and 81; and

(2) an immunoglobulin LCVR comprising three complementarity determining regions (LCDRs): LCDR1, LCDR2 and LCDR3,

wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:82, 85, 88, 89, 90 and 93,

wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:83, 86.91 and 94, and

wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:84, 87, 92 and 95.

8. The bispecific antagonist of claim 7 , wherein the second targeting domain comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:76, an HCDR2 comprising the amino acid sequence oaf SEQ ID NO:77, an HCDR3 comprising the amino acid sequence of SEQ ID NO:78, a LCDR1 comprising the amino acid sequence of SEQ ID NO:90, a LCDR2 comprising the amino acid sequence of SEQ ID NO:9f, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:92.

9. The bispecific antagonist of claim 8 , wherein the second targeting domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:105.

10. The bispecific antagonist of claim 7 , wherein the second targeting domain comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:79, an HCDR2 comprising the amino acid sequence of SEQ ID NO:80, an HCDR3 comprising the amino acid sequence of SEQ ID NO:81, a LCDR1 comprising the amino acid sequence of SEQ ID NO:93, a LCDR2 comprising the amino acid sequence of SEQ ID NO;94, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:95.

11. The bispecific antagonist of claim 10 , wherein the second targeting domain comprises a heavy chain variable region comprising the amino acid sequence f SEQ ID NO:106 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:107.

12. The bispecific antagonist of claim 1 , wherein the second targeting domain binds specifically to human PD-L1.

13. The bispecific antagonist of claim 12 , wherein the second targeting domain comprises:

(1) an immunoglobulin HCVR comprising three complementarity determining regions (HCDRs): HCDR1, HCDR2 and HCDR3,

wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 108, 111, 117 and 120,

wherein the HCDR2 comprises an amino acid sequence selected from the group consisting SEQ ID NOS: 109, 112, 114, 116, 118, 121 and 125, and

wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 110, 113, 115, 119 and 122; and

(2) an immunoglobulin LCVR comprising three LCDRs: LCDR1, LCDR2 and LCDR3,

wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 123, 126, 130, 133 and 136,

wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 126, 127, 131, 134 and 137, and

wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 125, 128, 129, 132, 135 and 138.

14. The bispecific antagonist of claim 13 , wherein the second targeting domain comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:111, an HCDR2 comprising the amino acid sequence of SEQ ID NO:114, an HCDR3 comprising the amino acid sequence of SEQ ID NO:115, a LCDR1 comprising the amino acid sequence of SEQ ID NO:123, a LCDR2 comprising the amino acid sequence of SEQ ID NO:124, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:125.

15. The bispecific antagonist of claim 14 , wherein the second targeting domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:154.

16. A method of treating a cell proliferative disorder in a subject, comprising:

administering to a subject in need thereof an effective amount of the antagonist of claim 1 .

17. A method of treating a cell proliferative disorder in a subject, comprising:

administering to a subject in need thereof an effective amount of the antagonist of claim 1 .

18. A method of treating a cell proliferative disorder in a subject, comprising:

administering to a subject in need thereof an effective amount of the antagonist of claim 6 .

19. A method of treating a cell proliferative disorder in a subject, comprising:

administering to a subject in need thereof an effective amount of the antagonist of claim 12 .