PD-L1 antibody, antigen-binding fragment thereof and medical application thereof

Patent metadata

Field	Value
Publication number	US-11780923-B2
Application number	US-202016947583-A
Country	US
Kind code	B2
Filing date	Aug 7, 2020
Priority date	Nov 17, 2015
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

The present invention relates to a PD-L1 antibody, antigen-binding fragments, and medical application thereof. Further, the present invention relates to chimeric antibodies and humanized antibodies comprising the CDR regions of the present PD-L1 antibody, as well as a pharmaceutical composition comprising the present PD-L1 antibody and the antigen-binding fragments thereof, and their use as anti-cancer drugs. In particular, the present invention relates to a humanized PD-L1 antibody and its use in preparation of a medicament for the treatment of PD-L1 mediated disease or disorder.

First claim

It is claimed:

1. A method for treating a PD-L1 mediated cancer in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
(i) the heavy chain variable region comprises a heavy chain CDR1 (HCDR1) of NDYWX 1 (SEQ ID NO: 10), a heavy chain CDR2 (HCDR2) of YISYTGSTYYNPSLKS (SEQ ID NO: 11) and a heavy chain CDR3 (HCDR3) of SGGWLAPFDY (SEQ ID NO: 12); and the light chain variable region comprises a light chain CDR1 (LCDR1) of KSSQSLFYX 2 SNQKX 3 SLA (SEQ ID NO: 13), a light chain CDR2 (LCDR2) of GASTRES (SEQ ID NO: 14) and a light chain CDR3 (LCDR3) of QQYYGYPYT (SEQ ID NO: 15);
wherein X 1 is N or T, X 2 is R or H, and X 3 is N or H;

or
(ii) the heavy chain variable region comprises a heavy chain CDR1 (HCDR1) of SYWMH (SEQ ID NO: 16), a heavy chain CDR2 (HCDR2) of RIX 4 PNSG X 5 TSYNEKFKN (SEQ ID NO: 17) and a heavy chain CDR3 (HCDR3) of GGSSYDYFDY (SEQ ID NO: 18); and the light chain variable region comprises a light chain CDR1 (LCDR1) of RASESVSIHGTHLMH (SEQ ID NO: 19), a light chain CDR2 (LCDR2) of AASNLES (SEQ ID NO: 20) and a light chain CDR3 (LCDR3) of QQSFEDPLT (SEQ ID NO: 21);
wherein X 4 is H or G, and X 5 is G or F.

2. The method according to claim 1 , wherein the cancer is a PD-L1-expressing cancer selected from the group consisting of breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma, non-small cell lung cancer, glioblastoma and bladder cancer.

3. The method according to claim 1 , wherein the antibody light chain variable region further comprises a light chain framework (FR) region derived from murine κ chain, or murine λ-chain; and the antibody heavy chain variable region further comprises a heavy chain FR region derived from murine IgG1, murine IgG2 or murine IgG3.

4. The method according to claim 3 , wherein the antibody heavy chain variable region contains the heavy chain FR region derived from a murine heavy chain variable region having the amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 8, and the antibody light chain variable region contains a light chain FR region derived from a murine light chain variable region having the amino acid sequence selected from the group consisting of SEQ ID NOs: 7 and 9.

5. The method according to claim 3 , wherein the antibody light chain further comprises a light chain constant region derived from murine [k] kappa chain, or a light chain constant region derived from murine [Y] lambda chain; wherein the antibody heavy chain further comprises a heavy chain constant region derived from murine IgG1, or a heavy chain constant region derived from murine IgG2, or a heavy chain constant region derived from murine IgG3.

6. The method according to claim 1 , wherein the antibody or the antigen-binding fragment thereof is a chimeric antibody or a humanized antibody or a fragment thereof.

7. The method according to claim 6 , wherein the antibody is the humanized antibody 9-2 or the humanized antibody 24D5, wherein the heavy chain framework (FR) sequence on the heavy chain variable region of the humanized antibody 9-2 is derived from a combination sequence of a human germline heavy chain IGHV4-30-4*01 and human germline heavy chain hjh2, and comprises FR1, FR2, and FR3 from human germline heavy chain IGHV4-30-4*01 and FR4 from hjh2; or
the heavy chain FR sequence on the heavy chain variable region of the humanized antibody 24D5 is derived from a combination sequence of human germline heavy chain IGHV1-46*01 and human germline heavy chain hjh6.1, and comprises FR1, FR2 and FR3 from human germline heavy chain IGHV1-46*01 and FR4 from hjh6.1.

8. The method according to claim 7 , wherein the heavy chain FR sequence of the humanized antibody 9-2 has 1-8 amino acid back-mutations selected from the group consisting of W47Y, V71R, G27Y, I48M, V67L, F78Y, S30T and Q39K; or wherein the heavy chain FR sequence of the humanized antibody 24D5 has 1-8 amino acid back-mutations selected from the group consisting of T74K, R72V, M48I, M70L, R38Q, L83F, V68A, and V79A.

9. The method according to claim 7 , wherein the heavy chain variable region sequence of the humanized antibody 9-2 comprises SEQ ID NO: 22 or a variant thereof, wherein the variant comprises 1-8 amino acid back-mutations selected from the group consisting of W47Y, V71R, G27Y, I48M, V67L, F78Y, S30T and Q39K; or the heavy chain variable region sequence of the humanized antibody 24D5 comprises SEQ ID NO: 24 or a variant thereof, wherein the variant comprises 1-8 amino acid back-mutations selected from the group consisting of T74K, R72V, M48I, M70L, R38Q, L83F, V68A, and V79A.

10. The method according to claim 6 , wherein the antibody is the humanized antibody 9-2 or the humanized antibody 24D5, wherein:
the light chain framework (FR) sequence on the light chain variable region of the humanized antibody 9-2 is derived from a combination sequence of a human germline light chain IGKV4-1*01 and human germline light chain hjk4.1, and comprises FR1, FR2 and FR3 from human germline light chain IGKV4-1*01 and FR4 from hjk4.1, or
the light chain FR sequence of the light chain variable region of the humanized antibody 24D5 is derived from a combination sequence of a human germline light chain IGKV7-3*01 and human germline light chain hjh2.1, and comprises FR1, FR2 and FR3 from IGKV7-3*01 and FR4 from hjk2.1.

11. The method according to claim 10 , wherein the light chain FR sequence of the humanized antibody 9-2 has a P49S amino acid back-mutation; or wherein the light chain FR sequence of the humanized antibody 24D5 has 1-3 amino acid back-mutations selected from the group consisting of Y91F, T22S and G72E, and optionally an N85E deglycosylation mutation.

12. The method according to claim 10 , wherein the light chain variable region sequence of the humanized antibody 9-2 comprises the amino acid sequence of SEQ ID NO: 23 or a variant thereof, wherein the variant comprises a P49S amino acid back-mutation; or the light chain variable region sequence of the humanized antibody 24D5 comprises the amino acid sequence of SEQ ID NO: 25 or a variant thereof, wherein the variant comprises 1-3 amino acid back-mutations selected from the group consisting of Y91F, T22S and G72E, and optionally an N85E deglycosylation mutation.

13. The method according to claim 6 , wherein X 1 is T, X 2 is H, X 3 is H, X 4 is G, and X 5 is F.

14. The method according to claim 13 , wherein the antibody is the humanized antibody 9-2 or the humanized antibody 24D5, and wherein the heavy chain variable region sequence of the humanized antibody 9-2 comprises SEQ ID NO: 26 and the light chain variable region sequence of the humanized antibody 9-2 comprises SEQ ID NO: 27; or
the heavy chain variable region sequence of the humanized antibody 24D5 comprises SEQ ID NO: 28 and the light chain variable region sequence of the humanized antibody 24D5 comprises SEQ ID NO: 29.

15. The method according to claim 14 , wherein the heavy chain of the humanized antibody further comprises a heavy chain constant region derived from human IgG1, IgG2, IgG3, or IgG4; or wherein the light chain of the humanized antibody further comprises a constant region derived from human κ chain, or human λ chain.

16. The method according to claim 15 , wherein the heavy chain constant region comprises IgG4 heavy chain constant region with F234A and L235A mutations.

17. The method according to clai

Assignees

• Suzhou Suncadia Biopharmaceuticals Co Ltd
• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Qu Xiangdong
• Hu Qiyue
• Xu Shaoyu
• Cui Dongbing
• Jin Houcong
• Tao Weikang
• Zhang Lianshan
• Cao Guoqing
• Sun Piaoyang

Classifications

• C07K16/2827 Primary

  against B7 molecules, e.g. CD80, CD86 · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07K16/28 Primary

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61K2039/505

  comprising antibodies · CPC title