Humanized monoclonal antibodies against activated protein C and uses thereof

Patent metadata

Field	Value
Publication number	US-9657111-B2
Application number	US-201314443696-A
Country	US
Kind code	B2
Filing date	Nov 27, 2013
Priority date	Nov 29, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Provided are humanized antibodies that selectively bind to and inhibit activated protein C without binding to or inhibiting unactivated protein C. Methods of treatment employing these antibodies are described herein.

First claim

The invention claimed is:

1. A humanized antibody binding to activated protein C comprising:
(a) a heavy chain comprising heavy chain CDRs represented by SEQ ID NOS: 1, 2 and 3; and
(b) a light chain comprising light chain CDRs represented by SEQ ID NOS: 4, 5 and 6.

2. The antibody of claim 1 , wherein the heavy chain framework regions are represented by SEQ ID NOS: 7, 8, 9 and 10, or having 5 or fewer conservative amino acid substitutions.

3. The antibody of claim 1 , wherein the light chain framework regions are represented by SEQ ID NOS: 11, 12, 13 and 14, or having 5 or fewer conservative amino acid substitutions.

4. The antibody of claim 2 , wherein residue 14 of SEQ ID NO: 8 is substituted with Alanine.

5. The antibody of claim 2 , wherein residues 11, 13 and 31 of SEQ ID NO: 9 are is substituted with one or more of Serine (residue 11), Valine (residue 13) and Isoleucine (residue 31).

6. The antibody of claim 1 , wherein said heavy chain comprises SEQ ID NOS: 16-24.

7. The antibody of claim 3 , wherein residue 4 of SEQ ID NO: 11 is substituted with Leucine.

8. The antibody of claim 3 , wherein residue 12 of SEQ ID NO: 13 is substituted with Arginine.

9. The antibody of claim 1 , wherein said light chain comprises SEQ ID NOS: 26-30.

10. The antibody of claim 1 , wherein the antibody is a single-chain antibody or antibody fragment binding activated protein C.

11. The antibody of claim 10 , wherein the antibody fragment is further defined as Fab′, Fab, F(ab′) 2 , a single domain antibody, Fv, or scFv.

12. A cell or cell line comprising a nucleic acid encoding a humanized antibody binding to activated protein C comprising:
(a) a heavy chain comprising heavy chain CDRs represented by SEQ ID NOS: 1, 2 and 3; and
(b) a light chain comprising light chain CDRs represented by SEQ ID NOS: 4, 5 and 6.

13. The antibody of claim 1 , dispersed in a pharmaceutically acceptable carrier.

14. A method of inhibiting activated protein C anticoagulant activity and/or amidolytic activity in a subject, comprising administering an effective amount of an antibody according to claim 1 to said subject.

15. A method of treating a subject in need of blood coagulation comprising administering an effective amount of an antibody according to claim 1 to said subject.

16. The method of claim 15 , wherein said subject is suffering from hemophilia.

17. A method of promoting hemostasis or thrombosis in a subject, comprising administrating an effective amount of an antibody according to claim 1 to said subject.

18. The method of claim 17 , wherein the subject is a trauma patient.

19. A kit comprising an antibody according to claim 1 .

Assignees

• Bayer Healthcare Llc

Inventors

• Zhao Xiao-Yan
• Wang Zhuozhi
• Kim Ji-Yun
• Zhu Ying
• Tebbe Jan

Classifications

• A61P7/04

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

• C07K16/40 Primary

  against enzymes · CPC title

• C07K2317/515

  Complete light chain, i.e. VL + CL · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• A61P7/00

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