Anti-OX40 antibody and use thereof

1. An anti-OX40 antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein:

1) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:106, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:130;

2) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:106, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:131;

3) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:107, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:130;

4) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:108, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:130;

5) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:109, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:130;

6) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:110, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:130; and

7) The HCVR comprises three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the HCVR as shown in SEQ ID NO:111, and the LCVR comprises the LCDR1, LCDR2 and LCDR3 sequences contained in the LCVR as shown in SEQ ID NO:130.

2. An anti-OX40 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises a complementarity determining region HCDR1, HCDR2 and HCDR3 and the LCVR comprises LCDR1, LCDR2 and LCDR3, wherein the combinations of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprised in said antibody or its antigen-binding fragment are represented in the following table:

the amino acid

the amino acid

the amino acid

the amino acid

the amino acid

the amino acid

sequence of

sequence of

sequence of

sequence of

sequence of

sequence of

combination

HCDR1

HCDR2

HCDR3

LCDR1

LCDR2

LCDR3

(1)

SEQ ID NO: 1

SEQ ID NO: 17

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

SEQ ID NO: 53

(2)

SEQ ID NO: 1

SEQ ID NO: 17

SEQ ID NO: 34

SEQ ID NO: 42

SEQ ID NO: 48

SEQ ID NO: 54

(3)

SEQ ID NO: 2

SEQ ID NO: 18

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

SEQ ID NO: 53

(4)

SEQ ID NO: 3

SEQ ID NO: 19

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

SEQ ID NO: 53

(5)

SEQ ID NO: 4

SEQ ID NO: 20

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

SEQ ID NO: 53

(6)

SEQ ID NO: 4

SEQ ID NO: 21

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

SEQ ID NO: 53

(7)

SEQ ID NO: 5

SEQ ID NO: 22

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

SEQ ID NO: 53

(8)

SEQ ID NO: 6

SEQ ID NO: 23

SEQ ID NO: 34

SEQ ID NO: 41

SEQ ID NO: 47

 SEQ ID NO: 53.

3. An anti-OX40 antibody or antigen-binding fragment thereof, which comprises a heavy chain variable region HCVR and a light chain variable region LCVR, wherein the combinations of the heavy chain variable region HCVR and light chain variable region LCVR comprised in said antibody or its antigen-binding fragment are represented in the following table:

HCVR, which comprises

LCVR, which comprises

or consists of the amino

or consists of the amino

acid sequence as

acid sequence as

represented in the

represented in the

combination

following SEQ ID NO

following SEQ ID NO

(1)

SEQ ID NO: 106

SEQ ID ND: 130

(2)

SEQ ID NO: 106

SEQ ID NO: 131

(3)

SEQ ID NO: 107

SEQ ID NO: 130

(4)

SEQ ID NO: 108

SEQ ID NO: 130

(5)

SEQ ID NO: 109

SEQ ID NO: 130

(6)

SEQ ID NO: 110

SEQ ID NO: 130

(7)

SEQ ID NO: 111

 SEQ ID NO: 130.

4. An antibody or antigen-binding fragment thereof of claim 1 , which comprises a heavy chain and a light chain, wherein the combinations of the heavy chain and light chain comprised in said antibody or its antigen-binding fragment are in the following table:

Heavy chain, which

Light chain,, which

comprises or consists of

comprises or consists of

the amino acid sequence

the amino acid sequence

represented by the

represented by the

combination

following SEQ ID NO

following SEQ ID NO

 (1)

SEQ ID NO: 189

SEQ ID NO: 168

 (2)

SEQ ID NO: 139

SEQ ID NO: 168

 (3)

SEQ ID NO: 140

SEQ ID NO: 168

 (4)

SEQ ID NO: 141

SEQ ID NO: 168

 (5)

SEQ ID NO: 142

SEQ ID NO: 168

 (6)

SEQ ID NO: 143

SEQ ID NO: 168

 (7)

SEQ ID NO: 144

SEQ ID NO: 168

 (8)

SEQ ID NO: 145

SEQ ID NO: 168

 (9)

SEQ ID NO: 146

SEQ ID NO: 168

(10)

SEQ ID NO: 147

SEQ ID NO: 168

(11)

SEQ ID NO: 148

SEQ ID NO: 168

(12)

SEQ ID NO: 149

 SEQ ID NO: 168.

5. The anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody is an antibody in IgG1 format or an antibody in IgG2 format or an antibody in IgG4 format or antigen-binding fragment thereof.

6. The anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody is a monoclonal antibody.

7. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antigen-binding fragment is an antibody fragment selected from the group consisting of Fab, Fab′, Fab′-SH, Fv, single chain antibody (scFv) or (Fab′)2, diabodies (dAb) or linear antibody.

8. The antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody is a bispecific or multispecific antibody molecule.

9. An isolated nucleic acid encoding an anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 .

10. An expression vector comprising the nucleic acid according to claim 9 .

11. A mammalian host cell comprising the nucleic acid according to claim 9 .

12. A method of preparing an anti-OX40 antibody or antigen-binding fragment thereof comprising culturing the host cell according to claim 11 under conditions suitable for expression of a nucleic acid encoding an anti-OX40 antibody or antigen-binding fragment thereof, optionally isolating the antibody or antigen-binding fragment thereof, and optionally said method further comprises recovering the anti-OX40 antibody or antigen-binding fragment thereof from the host cell.

13. An immunoconjugate comprising the anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 conjugated to a cytotoxic agent.

14. A pharmaceutical composition comprising the anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 , and optionally a pharmaceutically acceptable adjuvant, and optionally further comprising one or more other therapeutic agents.

15. A method of activating T cells or inducing T cell mediated antitumor activity or increasing T cell proliferation, survival, effector function, or migration in a subject comprising administering to said subject an effective amount of the anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 .

16. A method of treating cancer in a subject comprising administering to said subject an effective amount of the anti-OX40 antibody or antigen-binding fragment thereof according to claim 1 .

17. The method of claim 16 , further comprising administering to said subject in combination with one or more therapies.

18. The anti-OX40 antibody or antigen-binding fragment thereof according to claim 2 , wherein the antibody is a monoclonal antibody.

19. The antibody or antigen-binding fragment thereof according to claim 2 , wherein the antigen-binding fragment is an antibody fragment selected from the group consisting of Fab, Fab′, Fab′-SH, Fv, single chain antibody (scFv) or (Fab′)2, diabodies (dAb) or linear antibody.

20. The antibody or antigen-binding fragment thereof according to claim 8 , wherein the bispecific antibody molecule binds to OX40 and PD-1.

21. A pharmaceutical composition according to claim 14 , wherein the other therapeutic agent is an anti-PD-1 antibody.

22. The method according to claim 16 , wherein said cancer is lung cancer, non-small cell lung cancer, liver cancer, stomach cancer, or colon cancer.

23. The method according to claim 17 , wherein the therapies comprise surgery, radiation therapy, and/or administration of another therapeutic agent selected from the group consisting of a chemotherapeutic agent, an anti-angiogenic agent, an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

24. The method according to claim 23 , wherein the anti-angiogenic agent is bevacizumab.