Anti-PD-1 antibodies

1. An antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen binding fragment comprises:

(i) a heavy chain variable region comprising:

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:8, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:9, 91, 79 or 86, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:10; and

(ii) a light chain variable region comprising light chain CDRs selected from the group consisting of:

a. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:4, 15, 18, 29, 32 or 35, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:5;

b. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22; and

c. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:25, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:26.

2. An antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment comprises:

(i) a heavy chain variable region comprising:

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:8, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:91, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:10; and

(ii) a light chain variable region comprising:

a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22.

3. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises:

(i) a heavy chain variable region comprising:

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:8, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:86, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:10; and

(ii) a light chain variable region comprising:

a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22.

4. An antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7 or 88 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14, 17, 20, 24, 28, 31, 34 or 76.

5. The antibody or antigen-binding fragment of claim 4 , is an antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 6 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 13, 16, 19, 23, 27, 30, or 33.

6. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 92 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 20.

7. An antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 85 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 20.

8. The antibody or antigen-binding fragment of claim 7 , is an antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 84 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 19.

9. An antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment comprises:

(i) a heavy chain variable region comprising:

a. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:8,

b. a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:9, 79, 86, or 91, and

c. a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41 or 10, and

(ii) a light chain variable region comprising:

d. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3,

e. a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 4, and

f. a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:5.

10. The antibody or antigen-binding fragment of claim 9 , wherein the antibody or antigen-binding fragment comprises:

a. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:8,

b. a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:86,

c. a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41,

d. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3,

e. a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:4, and

f. a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:5.

11. The antibody or antigen-binding fragment of claim 9 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 75, 78, 81 or 88 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 76.

12. The antibody or antigen-binding fragment of claim 9 , that is an antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 74, 77, 80, 82, or 89 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 2.

13. The antibody or antigen-binding fragment of claim 9 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 95 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 76.

14. The antibody or antigen-binding fragment of claim 13 , is an antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 83 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 2.

15. An antibody or antigen-binding fragment thereof that binds to human PD-1, wherein the antibody or antigen-binding fragment comprises:

a. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:40 or 53,

b. a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:9 or 54,

c. a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41,

d. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3,

e. a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:4, 42, 47, or 60, and

f. a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:5, 48, or 55.

16. The antibody or antigen-binding fragment of claim 15 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the CDRs of the heavy and light chain variable regions are selected from the group consisting of:

a. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:42, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:5;

b. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:47, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:48;

c. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:53, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:54, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

d. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:41; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:60, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:5.

17. The antibody or antigen-binding fragment of claim 15 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region selected from the group consisting of:

a. a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 37 or 119 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 39;

b. a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 44 or 121 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 46;

c. a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 50 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 52; and

d. a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 57 or 123 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 59.

18. The antibody or antigen-binding fragment claim 7 , which is an antibody comprising two heavy chains and two light chains.

19. The antibody or antigen-binding fragment of claim 18 , which is an antibody comprising a heavy chain region of the IgG4 subtype with an S228P mutation.

20. The antibody or antigen-binding fragment of claim 18 , which is an antibody comprising a heavy chain region of the IgG1 subtype.

21. The antibody or antigen-binding fragment of claim 3 , wherein the antibody or antigen-binding fragment thereof comprises a glycosylation pattern characteristic of expression by a CHO cell.

22. An isolated polynucleotide encoding the antibody or antigen-binding fragment of claim 3 .

23. An expression vector comprising the isolated polynucleotide of claim 22 .

24. A host cell comprising the expression vector of claim 23 .

25. A composition comprising the antibody or antigen-binding fragment of claim 3 and a pharmaceutically acceptable carrier or diluent.

26. The composition of claim 25 , further comprising an agent selected from the group consisting of:

a. an anti-LAG3 antibody or an antigen-binding fragment thereof;

b. an anti-TIGIT antibody or an antigen-binding fragment thereof;

c. an anti-VISTA antibody or an antigen-binding fragment thereof;

d. an anti-BTLA antibody or an antigen-binding fragment thereof;

e. an anti-TIM3 antibody or an antigen-binding fragment thereof;

f. an anti-CTLA4 antibody or an antigen-binding fragment thereof;

g. an anti-HVEM antibody or an antigen-binding fragment thereof;

h. an anti-CD70 antibody or an antigen-binding fragment thereof;

i. an anti-OX40 antibody or an antigen-binding fragment thereof;

j. an anti-CD28 antibody or an antigen-binding fragment thereof;

k. an anti-PDL1 antibody or an antigen-binding fragment thereof;

l. an anti-PDL2 antibody or an antigen-binding fragment thereof;

m. an anti-GITR antibody or an antigen-binding fragment thereof;

n. an anti-ICOS antibody or an antigen-binding fragment thereof;

o. an anti-SIRPα antibody or an antigen-binding fragment thereof;

p. an anti-ILT2 antibody or an antigen-binding fragment thereof;

q. an anti-ILT3 antibody or an antigen-binding fragment thereof;

r. an anti-ILT4 antibody or an antigen-binding fragment thereof;

s. an anti-ILT5 antibody or an antigen-binding fragment thereof;

t. an anti-4-1BB antibody or an antigen-binding fragment thereof;

u. an anti-NK2GA antibody or an antigen-binding fragment thereof;

v. an anti-NK2GC antibody or an antigen-binding fragment thereof;

w. an anti-NK2GE antibody or an antigen-binding fragment thereof;

x. an anti-TSLP antibody or an antigen-binding fragment thereof;

y. an anti-IL10 antibody or an antigen-binding fragment thereof;

z. a STING agonist;

aa. a CXCR2 antagonist; and

bb. a PARP inhibitor.

27. A method of producing an antibody or antigen-binding fragment comprising:

a. culturing a host cell comprising a polynucleotide encoding the heavy chain and/or the light chain of the antibody or antigen-binding fragment of claim 3 under conditions for expression of the polynucleotide; and

b. recovering the antibody or antigen-binding fragment from the host cell and/or culture medium.