Bispecific antibodies

Patent metadata

Field	Value
Publication number	US-9334331-B2
Application number	US-201113885421-A
Country	US
Kind code	B2
Filing date	Nov 17, 2011
Priority date	Nov 17, 2010
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

Various bispecific antibodies that specifically bind to both blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X and functionally substitute for the cofactor function of blood coagulation factor VIII, that is, the function to promote activation of blood coagulation factor X by activated blood coagulation factor IX, were produced. From these antibodies, multispecific antigen-binding molecules having a high activity of functionally substituting for blood coagulation factor VIII were successfully discovered.

First claim

The invention claimed is:

1. A bispecific antibody that specifically binds to blood coagulation factor IX and/or activated blood coagulation factor IX, and specifically binds to blood coagulation factor X, wherein the bispecific antibody comprises:
a first antibody H chain comprising a variable region comprising complementarity determining regions (CDRs) 1, 2, and 3 that comprise SEQ ID NOs: 105-107, respectively;
a second antibody H chain comprising a variable region comprising CDRs 1, 2, and 3 that comprise SEQ ID NOs: 126-128, respectively; and
identical first and second antibody L chains, each L chain comprising a variable region comprising CDRs 1, 2, and 3 that comprise SEQ ID NOs: 156-158, respectively.

2. A pharmaceutical composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier.

3. A kit comprising the bispecific antibody of claim 1 , packaged with instructions for use.

4. A bispecific antibody produced by a method comprising culturing a host cell or host cells comprising nucleic acid or nucleic acids encoding a bispecific antibody, wherein the bispecific antibody comprises:
a first antibody H chain comprising a variable region comprising CDRs 1, 2, and 3 that comprise SEQ ID NOs: 105-107, respectively;
a second antibody H chain comprising a variable region comprising CDRs 1, 2, and 3 that comprise SEQ ID NOs: 126-128, respectively; and
identical first and second antibody L chains, each L chain comprising a variable region comprising CDRs 1, 2, and 3 that comprise SEQ ID NOs: 156-158, respectively.

5. The bispecific antibody of claim 4 , wherein the method further comprises obtaining the bispecific antibody produced by the cultured host cell or host cells.

6. A pharmaceutical composition comprising the bispecific antibody of claim 5 and a pharmaceutically acceptable carrier.

7. A kit comprising the bispecific antibody of claim 5 , packaged with instructions for use.

8. The bispecific antibody of claim 1 , wherein:
CDRs 1, 2, and 3 of the first antibody H chain consist of SEQ ID NOs: 105-107, respectively;
CDRs 1, 2, and 3 of the second antibody H chain consist of SEQ ID NOs: 126-128, respectively; and
CDRs 1, 2, and 3 of each identical L chain consist of SEQ ID NOs: 156-158, respectively.

9. The bispecific antibody of claim 1 , wherein the first antibody H chain variable region comprises SEQ ID NO: 45.

10. The bispecific antibody of claim 1 , wherein the second antibody H chain variable region comprises SEQ ID NO: 52.

11. The bispecific antibody of claim 1 , wherein the identical first and second antibody L chain variable regions each comprise SEQ ID NO: 62.

12. The bispecific antibody of claim 1 , wherein the first antibody H chain consists of SEQ ID NO: 20.

13. The bispecific antibody of claim 1 , wherein the second antibody H chain consists of SEQ ID NO: 25.

14. The bispecific antibody of claim 1 , wherein the identical first and second antibody L chains each consist of SEQ ID NO: 32.

15. A bispecific antibody produced by a method comprising culturing a host cell or host cells comprising nucleic acid or nucleic acids encoding a bispecific antibody, wherein the bispecific antibody comprises:
a first antibody H chain comprising a variable region comprising CDRs 1, 2, and 3 that consist of SEQ ID NOs: 105-107, respectively;
a second antibody H chain comprising a variable region comprising CDRs 1, 2, and 3 that consist of SEQ ID NOs: 126-128, respectively; and
identical first and second antibody L chains, each L chain comprising a variable region comprising CDRs 1, 2, and 3 that consist of SEQ ID NOs: 156-158, respectively.

16. The bispecific antibody of claim 15 , wherein the method further comprises obtaining the bispecific antibody produced by the cultured host cell or host cells.

17. A pharmaceutical composition comprising the bispecific antibody of claim 16 and a pharmaceutically acceptable carrier.

18. A kit comprising the bispecific antibody of claim 16 , packaged with instructions for use.

19. A bispecific antibody that specifically binds to blood coagulation factor IX and/or activated blood coagulation factor IX, and specifically binds to blood coagulation factor X, wherein the bispecific antibody comprises:
a first antibody H chain comprising a variable region comprising SEQ ID NO: 45;
a second antibody H chain comprising a variable region comprising SEQ ID NO: 52; and
identical first and second antibody L chains, each comprising a variable region comprising SEQ ID NO: 62.

20. A bispecific antibody produced by a method comprising culturing a host cell or host cells comprising a nucleic acid or nucleic acids encoding a bispecific antibody, wherein the bispecific antibody comprises:
a first antibody H chain comprising a variable region comprising SEQ ID NO: 45;
a second antibody H chain comprising a variable region comprising SEQ ID NO: 52; and
identical first and second antibody L chains, each comprising a variable region comprising SEQ ID NO: 62.

21. The bispecific antibody of claim 20 , wherein the method further comprises obtaining the bispecific antibody produced by the cultured host cell or host cells.

22. A pharmaceutical composition comprising the bispecific antibody of claim 21 and a pharmaceutically acceptable carrier.

23. A kit comprising the bispecific antibody of claim 21 , packaged with instructions for use.

24. The bispecific antibody of claim 19 , wherein:
the variable region of the first antibody H chain consists of SEQ ID NO: 45;
the variable region of the second antibody H chain consists of SEQ ID NO: 52; and
the variable regions of the identical first and second antibody L chains each consist of SEQ ID NO: 62.

25. A bispecific antibody that specifically binds to blood coagulation factor IX and/or activated blood coagulation factor IX, and specifically binds to blood coagulation factor X, wherein the bispecific antibody comprises:
a first antibody H chain comprising SEQ ID NO: 20;
a second antibody H chain comprising SEQ ID NO: 25; and
identical first and second antibody L chains, each comprising SEQ ID NO: 32.

26. The bispecific antibody of claim 25 , wherein:
the first antibody H chain consists of SEQ ID NO: 20;
the second antibody H chain consists of SEQ ID NO: 25; and
each of the identical first and second antibody L chains consists of SEQ ID NO: 32.

27. A bispecific antibody produced by a method comprising culturing a host cell or host cells comprising nucleic acid or nucleic acids encoding a bispecific antibody comprising:
a first antibody H chain comprising SEQ ID NO: 20;
a second antibody H chain comprising SEQ ID NO: 25; and
identical first and second antibody L chains, each comprising SEQ ID NO: 32.

28. The bispecific antibody of claim 27 , wherein the method further comprises obtaining the bispecific antibody produced by the cultured host cell or host cells.

29. A pharmaceutical composition comprising the bispecific antibody of claim 28 and a pharmaceutically acceptable carrier.

30. A kit comprising the bispecific antibody of claim 28 , packaged with instructions for use.

31. The bispecific antibody of claim 1 , wherein the bispecific antibody:
(a) has increased activated blood coagulation factor X generation-promoting activity as compared to a reference antibody

Assignees

• Igawa Tomoyuki
• Sampei Zenjiro
• Kojima Tetsuo
• Soeda Tetsuhiro
• Muto Atsushi
• Kitazawa Takehisa
• Nishida Yukiko
• Imai Chifumi
• Suzuki Tsukasa
• Yoshihashi Kazutaka
• Chugai Pharmaceutical Co Ltd

Inventors

• Igawa Tomoyuki
• Sampei Zenjiro
• Kojima Tetsuo
• Soeda Tetsuhiro
• Muto Atsushi
• Kitazawa Takehisa
• Nishida Yukiko
• Imai Chifumi
• Suzuki Tsukasa
• Yoshihashi Kazutaka

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title