PD-1 antibody, antigen-binding fragment thereof, and medical application thereof

• US 10,344,090 B2
• Filed: 11/14/2014
• Issued: 07/09/2019
• 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: Yuan, Jijun, Qu, Xiangdong, Lin, Jufang, Ye, Xin, Cao, Guoqing, Tao, Weikang, Zhang, Lianshan, Zhang, Lei, Yang, Li
• Primary Examiner(s): Ouspenski, Ilia I
• Application Number:
  US15/103,758
• Publication Number:
  US 20160376367A1
• Time in Patent Office: 1,698 Days
• Field of Search: None
• 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. An anti-PD-1 antibody or an antigen-binding fragment thereof, comprising a light chain variable region comprising at least one of a LCDR1, a LCDR2 and a LCDR3 having the amino acid sequences of SEQ ID NO:

6, SEQ ID NO;

7 and SEQ ID NO;

8, respectively; and

a heavy chain variable region comprising a HCDR3 having the amino acid sequence of SEQ ID NO;

5.

2. The anti-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 the HCDR3 having the amino acid sequences of SEQ ID NO:

3, SEQ ID NO;

4 and SEQ ID NO;

5, respectively.

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

4. A host cell transformed with an expression vector comprising the DNA molecule according to claim 3.

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

6. 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, wherein the PD-1 mediated disease or disorder is a cancer.

7. An anti-PD-1 antibody or an antigen-binding fragment thereof, comprising a light chain variable region comprising a LCDR1, a LCDR2 and a LCDR3 having the amino acid sequences of SEQ ID NO:

6, SEQ ID NO;

7 and SEQ ID NO;

8, respectively, and a heavy chain variable region comprising at least one of a HCDR1, a HCDR2 and a HCDR3 having the amino acid sequences of SEQ ID NO;

3, SEQ ID NO;

4 and SEQ ID NO;

5, respectively.

8. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 7, wherein the heavy chain variable region comprises the HCDR3 having the amino acid sequence of SEQ ID NO:

5.

9. An anti-PD-1 antibody or an antigen-binding fragment thereof, comprising a light chain variable region comprising a LCDR1, a LCDR2 and a LCDR3 having the amino acid sequences of SEQ ID NO:

6, SEQ ID NO;

7 and SEQ ID NO;

8, respectively; and

a heavy chain variable region comprising a HCDR1, a HCDR2 and a HCDR3 having the amino acid sequences of SEQ ID NO;

3, SEQ ID NO;

4 and SEQ ID NO;

5, respectively.

10. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 9, wherein the antibody or the antigen-binding fragment thereof is a murine antibody or a fragment thereof.

11. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 9, wherein the antibody or the antigen-binding fragment thereof is a chimeric antibody or a fragment thereof.

12. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 11, wherein the chimeric antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO:

10.

13. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 11, wherein the chimeric antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:

9.

14. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 9, wherein the antibody or the antigen-binding fragment is a humanized antibody or a fragment thereof.

15. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 14, wherein the light chain variable region of the humanized antibody comprises a light chain FR sequence derived from a combination sequence of human germline light chains IGKV1-39 and JK4 as shown in SEQ ID NO:

14, and the light chain FR sequence comprises FR1, FR2 and FR3 of the light chain IGKV 1-39 and FR4 of the light chain JK4.

16. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 14, wherein the humanized antibody comprises a light chain having the amino acid sequence of SEQ ID NO:

12 or a variant thereof.

17. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 14, wherein the heavy chain variable region of the humanized antibody further comprises a heavy chain FR sequence of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof.

18. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 14, wherein the heavy chain variable region of the humanized antibody comprises a heavy chain FR sequence derived from a combination sequence of human germline heavy chains IgHV3-7 and JH6 as shown in SEQ ID NO:

13, and the heavy chain FR sequence comprises FR1, FR2 and FR3 of the heavy chain IgHV3-7 and FR4 of the heavy chain JH6.

19. The anti-PD-1 antibody or the antigen-binding fragment thereof according to claim 14, wherein the humanized antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:

11 or a variant thereof.

20. A DNA molecule encoding the anti-PD-1 antibody or the antigen-binding fragment according to claim 9.

21. An expression vector comprising the DNA molecule according to claim 20.

22. A host cell transformed with the expression vector according to claim 21.

23. The host cell according to claim 22, wherein the host cell is a bacterial cell.

24. The host cell according to claim 22, wherein the host cell is a yeast cell.

25. A pharmaceutical composition comprising the anti-PD-1 antibody or the antigen-binding fragment according to claim 9 and a pharmaceutically acceptable excipient, diluent or carrier.

26. 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 9, wherein the PD-1 mediated disease or disorder is a cancer.

27. The method of claim 26, wherein the cancer is breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma or non-small cell lung cancer.