Anti-sclerostin antibody, antigen binding fragment and medical use thereof

• US 10,449,250 B2
• Filed: 02/16/2016
• Issued: 10/22/2019
• Est. Priority Date: 03/13/2015
• Status: Active Grant

• Current Assignee: Jiangsu Hengrui Medicine Company Limited, Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.)
• Original Assignee: Jiangsu Hengrui Medicine Company Limited
• Inventors: Liu, Jiajian, Fu, Yayuan, Zhang, Haoying, Wang, Yifang, Zhang, Zhen, Zhang, Ling, Cui, Dongbing, Zhang, Lianshan, Tao, Weikang
• Primary Examiner(s): Xie, Xiaozhen
• Application Number:
  US15/556,488
• Publication Number:
  US 20180099046A1
• Time in Patent Office: 1,344 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• 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
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C12N 15/63 Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression

Abstract

Provided is a humanized antibody and chimeric antibody that specifically binds human sclerostin. The antibodies can be used for treating human bone metabolism related diseases such as osteoporosis (OP).

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to human sclerostin, comprising:

(I) a heavy chain variable region comprising a heavy chain complementarity determining region 1 (CDR1), a heavy chain CDR2, and a heavy chain CDR3 having the amino acid sequences of SEQ ID NO;

7, SEQ ID NO;

8, and SEQ ID NO;

9, respectively; and

a light chain variable region comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3 having the amino acid sequences of SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12, respectively;

or

(II) a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 having the amino acid sequences of SEQ ID NO;

7, SEQ ID NO;

13, and SEQ ID NO;

9, respectively; and

a light chain variable region comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3 having the amino acid sequences of SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12, respectively.

2. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 1, wherein the antibody or the antigen-binding fragment thereof is a murine antibody or fragment thereof.

3. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 2, wherein the heavy chain variable region sequence of the murine antibody comprises SEQ ID NO:

5, or a sequence having at least 95% identity to SEQ ID NO;

5.

4. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 2, wherein the light chain variable region sequence of the murine antibody comprises SEQ ID NO:

6, or a sequence having at least 95% identity to SEQ ID NO;

6.

5. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 1, wherein the antibody or the antigen-binding fragment thereof is a chimeric antibody or humanized antibody, or a fragment thereof.

6. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 5 being a humanized antibody, wherein the humanized antibody comprises framework regions FR1, FR2, FR3, and FR4 of human germline heavy chain IGHV1-18*01, or a mutant sequence thereof.

7. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 6, wherein the humanized antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

14-16, a mutant sequence thereof, and sequences having at least 95% identity to SEQ ID NOs;

14-16.

8. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 5 being a humanized antibody, wherein the humanized antibody comprises framework regions FR1, FR2, FR3, and FR4 of human germline light chain IGK V1-39*01 or IGK V4-1*01, or a mutant sequence thereof.

9. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 8, wherein the humanized antibody comprises a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOs:

17-19, a mutant sequence thereof, and sequences having at least 95% identity to SEQ ID NOs;

17-19.

10. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 5 being a humanized antibody, wherein the humanized antibody comprises:

a heavy chain variable region sequence of SEQ ID NO;

14 and a light chain variable region sequence of SEQ ID NO;

17;

a heavy chain variable region sequence of SEQ ID NO;

15 and a light chain variable region sequence of SEQ ID NO;

18;

or

a heavy chain variable region sequence of SEQ ID NO;

16 and a light chain variable region sequence of SEQ ID NO;

19.

11. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 5, wherein the heavy chain constant region of the humanized antibody comprises a constant region derived from human IgG1 or a variant thereof, human IgG2 or a variant thereof, human IgG3 or a variant thereof, or human IgG4 or a variant thereof.

12. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 11, comprising a full-length heavy chain sequence selected from the group consisting of SEQ ID NOs:

24-26 and sequences having at least 90% identity to SEQ ID NOs;

24-26.

13. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 5, wherein the light chain constant region of the humanized antibody comprises a constant region selected from the group consisting of human κ

and human λ

, or a variant thereof.

14. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 13, comprising a full-length light chain sequence selected from the group consisting of SEQ ID NOs:

27-29 and sequences having at least 90% identity to SEQ ID NOs;

27-29.

15. The antibody or antigen-binding fragment thereof that specifically binds to human sclerostin according to claim 5, comprising:

a full-length heavy chain sequence of SEQ ID NO;

24 and a full-length light chain sequence of SEQ ID NO;

27;

a full-length heavy chain sequence of SEQ ID NO;

25 and a full-length light chain sequence of SEQ ID NO;

28;

or

a full-length heavy chain sequence of SEQ ID NO;

26 and a full-length light chain sequence of SEQ ID NO;

29.

16. A pharmaceutical composition, comprising the antibody or antigen-binding fragment thereof according to claim 1, and one or more pharmaceutically acceptable excipients, diluents or carriers.

17. A pharmaceutical composition, comprising the antibody or antigen-binding fragment thereof according to claim 15, and one or more pharmaceutically acceptable excipients, diluents or carriers.

18. A method of increasing at least one of bone mass, bone mineral density, bone mineral content, and bone strength in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 16.

19. A method of treating a sclerostin (SOST)-mediated bone disease or disorder in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 16, wherein the SOST-mediated bone disease or disorder is selected from the group consisting of osteoporosis, osteopenia, osteoarthritis, rheumatoid arthritis, periodontal disease, and multiple myeloma.

20. A method of increasing at least one of bone mass, bone mineral density, bone mineral content, and bone strength in a subject in need thereof, or a method of treating a sclerostin (SOST)-mediated bone disease or disorder in a subject in need thereof, wherein the SOST-mediated bone disease or disorder is selected from the group consisting of osteoporosis, osteopenia or osteoarthritis, rheumatoid arthritis, periodontal disease, and multiple myeloma, the method comprising administering to the subject the pharmaceutical composition according to claim 17.