PD-1 ANTIBODY, ANTIGEN-BINDING FRAGMENT THEREOF, AND MEDICAL APPLICATION THEREOF

• US 20160376367A1
• Filed: 11/14/2014
• Published: 12/29/2016
• Est. Priority Date: 12/12/2013
• Status: Active Grant

• Current Assignee: Jiangsu Hengrui Medicine Company Limited, Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.), Suzhou Suncadia Biopharmaceuticals Co., Ltd.
• Original Assignee: Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.)
• Inventors: Qu, Xiangdong, Lin, Jufang, Ye, Xin, Cao, Guoqing, Tao, Weikang, Yuan, Jijun, Zhang, Lianshan, Zhang, Lei, Yang, Li
• Granted Patent: US 10,344,090 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/20 characterized by taxonomic origin
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention provides a human PD-1 antibody, an antigen-binding fragment thereof, and medical use thereof, and further provides a chimeric antibody and humanized antibodies comprising a complementarity-determining region (CDR) of the antibody, a pharmaceutical composition comprising the human PD-1 antibody and the antigen-binding fragment thereof, and use of the antibody in preparing medicines for treating diseases or disorders.

Claims

1. APD-1 antibody or an antigen-binding fragment thereof, comprising:

a light chain variable region comprising at least one LCDR selected from those sequences as shown in;

SEQ ID NO;

6, SEQ ID NO;

7 or SEQ ID NO;

8; and

a heavy chain variable region comprising at least one HCDR region selected from those sequences as shown in;

SEQ ID NO;

3, SEQ ID NO;

4 or SEQ ID NO;

5.

2. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the light chain variable region comprises a LCDR1 as shown in SEQ ID NO:

6.

3. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the light chain variable region comprises a LCDR2 as shown in SEQ ID NO:

7.

4. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the light chain variable region comprises a LCDR3 as shown in SEQ ID NO:

8.

5. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a HCDR1 as shown in SEQ ID NO:

3.

6. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a HCDR2 as shown in SEQ ID NO:

4.

7. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a HCDR3 as shown in SEQ ID NO:

5.

8. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the light chain variable region comprises a LCDR1, a LCDR2 and a LCDR3 as shown in SEQ ID NO:

6, SEQ ID NO;

7 and SEQ ID NO;

8, respectively.

9. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a HCDR1, a HCDR2 and a HCDR3 as shown in SEQ ID NO:

3, SEQ ID NO;

4 and SEQ ID NO;

5, respectively.

10. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the light chain variable region comprises a LCDR1, a LCDR2 and a LCDR3 as shown in SEQ ID NO:

6, SEQ ID NO;

7 and SEQ ID NO;

8, respectively; and

wherein the heavy chain variable region comprises a HCDR1, a HCDR2 and a HCDR3 as shown in SEQ ID NO;

3, SEQ ID NO;

4 and SEQ ID NO;

5, respectively.

11. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the antibody or the antigen-binding fragment thereof is a murine antibody or a fragment thereof.

12. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the antibody or the antigen-binding fragment thereof is a chimeric antibody or a fragment thereof.

13. The PD-1 antibody or the antigen-binding fragment thereof according to claim 12, wherein the light chain variable region sequence of the chimeric antibody is:

SEQ ID NO;

10.

14. The PD-1 antibody or the antigen-binding fragment thereof according to claim 12, wherein the heavy chain variable region sequence of the chimeric antibody is:

SEQ ID NO;

9

15. The PD-1 antibody or the antigen-binding fragment thereof according to claim 1, wherein the antibody or the antigen-binding fragment is a humanized antibody or a fragment thereof.

16. The PD-1 antibody or the antigen-binding fragment thereof according to claim 15, wherein the light chain FR sequence of the light chain variable region of the humanized antibody is derived from a combination sequence of human germline light chains IGKV1-39 and JK4 as shown in SEQ ID NO:

14, comprising FR1, FR2 and FR3 of IGKV 1-39 and FR4 of JK4.

17. The PD-1 antibody or the antigen-binding fragment thereof according to claim 15, wherein the sequence of the humanized antibody light chain is a sequence as shown in SEQ ID NO:

12 or a variant thereof.

18. The PD-1 antibody or the antigen-binding fragment thereof according to claim 15, wherein the heavy chain variable region of the humanized antibody further comprises a heavy chain FR of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof.

19. The PD-1 antibody or the antigen-binding fragment thereof according to claim 15, wherein the heavy chain FR sequence of the heavy chain variable region of the humanized antibody is derived from a combination sequence of human germline heavy chains IgHV3-7 and JH6 as shown in SEQ ID NO:

13, comprising FR1, FR2 and FR3 of IgHV3-7 and FR4 of JH6.

20. The PD-1 antibody or the antigen-binding fragment thereof according to claim 15, wherein the sequence of the humanized antibody heavy chain is a sequence as shown in SEQ ID NO:

11 or a variant thereof.

21. A DNA molecule encoding the antibody or the antigen-binding fragment according to claim 1.

22. An expression vector comprising the DNA molecule according to claim 21.

23. A host cell transformed with the expression vector according to claim 22.

24. The host cell according to claim 23, wherein the host cell is bacteria.

25. The host cell according to claim 23, wherein the host cell is yeast.

26. A pharmaceutical composition comprising the PD-1 antibody or the antigen-binding fragment according to claim 1 and a pharmaceutically acceptable excipient, diluent or carrier.

27. A method for treating a PD-1 mediated disease or disorder in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody or the antigen-binding fragment according to claim 1.

28. The method of claim 27, wherein the PD-1 mediated disease or disorder is a cancer.

29. The method of claim 28, wherein the cancer is breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma or non-small cell lung cancer.