Methods and compositions comprising a combination of a VEGF antagonist and an anti-CTLA-4 antibody

Patent metadata

Field	Value
Publication number	US-10532096-B2
Application number	US-201815959595-A
Country	US
Kind code	B2
Filing date	Apr 23, 2018
Priority date	Oct 18, 2013
Publication date	Jan 14, 2020
Grant date	Jan 14, 2020

Abstract

The present invention provides pharmaceutical compositions comprising a VEGF antagonist and an anti-CTLA-4 antibody, and methods of use thereof. The compositions and methods of the present invention are useful for the treatment of cancers and other diseases and disorders in which anti-angiogenic therapies and/or targeted immune responses may be beneficial.

First claim

What is claimed is:

1. A pharmaceutical composition, comprising:
(i) a VEGF antagonist comprising an Ig-like domain 2 of VEGFR1, Ig-like domain 3 of VEGFR2, and a multimerizing domain;
(ii) an anti-CTLA-4 antibody; and
(iii) a pharmaceutically acceptable carrier or diluent.

2. The pharmaceutical composition of claim 1 , wherein the VEGF antagonist-comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2.

3. The pharmaceutical composition of claim 2 , wherein the VEGF Trap comprises VEGFR1R2-FcΔC1(a) encoded by the nucleic acid sequence of SEQ ID NO:1.

4. The pharmaceutical composition of claim 1 , wherein the anti-CTLA-4 antibody is an antagonist antibody.

5. The pharmaceutical composition of claim 4 , wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

6. The pharmaceutical composition of claim 4 , wherein the anti-CTLA-4 antibody has an Fc isotype that provides ADCC and CDC effector activity.

7. The pharmaceutical composition of claim 6 , wherein the anti-CTLA-4 antibody is of the IgG1 isotype.

8. The pharmaceutical composition of claim 4 , wherein the anti-CTLA-4 antibody has an Fc isotype that provides ADCC and CDC effector activity.

9. The pharmaceutical composition of claim 4 , wherein the anti-CTLA-4 antibody is of the IgG1 isotype.

10. A method for extending or prolonging the survival of a subject afflicted with a tumor, the method comprising:
administering to the subject a therapeutically effective amount of a VEGF antagonist and a therapeutically effective amount of an anti-CTLA-4 antibody.
wherein the VEGF antagonist is a VEGF Trap comprising Ig-like domain 2 of VEGFR1, Ig-like domain 3 of VEGFR2, and a multimerizing domain.

11. The method of claim 10 , wherein the VEGF antagonist and the anti-CTLA-4 antibody are administered to the subject in separate dosage forms.

12. The method of claim 11 , wherein the separate dosage forms are administered to the subject simultaneously.

13. The method of claim 11 , wherein the separate dosage forms are administered to the subject sequentially.

14. The method of claim 10 , wherein the VEGF antagonist and the anti-CTLA-4 antibody are administered to the subject in a single dosage form.

15. The method of claim 10 , wherein the VEGF antagonist is administered to the subject intravenously or subcutaneously.

16. The method of claim 10 , wherein the anti-CTLA-4 antibody is administered to the subject intravenously or subcutaneously.

17. The method of claim 10 , wherein the VEGF Trap comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2.

18. The method of claim 17 , wherein the VEGF Trap comprises VEGFR1R2-FcΔC1 (a) encoded by the nucleic acid sequence of SEQ ID NO:1.

19. The method of claim 10 , wherein the anti-CTLA-4 antibody is an antagonist antibody.

20. The method of claim 19 , wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

21. A method for inducing tumor immunity in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a VEGF antagonist and a therapeutically effective amount of an anti-CTLA-4 antibody
wherein the VEGF antagonist is a VEGF Trap comprising Ig-like domain 2 of VEGFR1, Ig-like domain 3 of VEGFR2, and a multimerizing domain.

22. The method of claim 21 , wherein the subject is afflicted with a tumor prior to administration of the VEGF antagonist and anti-CTLA-4 antibody to the subject.

23. The method of claim 21 , wherein the VEGF antagonist and the anti-CTLA-4 antibody are administered to the subject in separate dosage forms.

24. The method of claim 23 , wherein the separate dosage forms are administered to the subject simultaneously.

25. The method of claim 23 , wherein the separate dosage forms are administered to the subject sequentially.

26. The method of claim 21 , wherein the VEGF antagonist and the anti-CTLA-4 antibody are administered to the subject in a single dosage form.

27. The method of claim 21 , wherein the VEGF antagonist is administered to the subject intravenously or subcutaneously.

28. The method of claim 21 , wherein the anti-CTLA-4 antibody is administered to the subject intravenously or subcutaneously.

29. The method of claim 21 , wherein the VEGF Trap comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2.

30. The method of claim 29 , wherein the VEGF Trap comprises VEGFR1R2-FcΔC1 (a) encoded by the nucleic acid sequence of SEQ ID NO:1.

31. The method of claim 21 , wherein the anti-CTLA-4 antibody is an antagonist antibody.

32. The method of claim 21 , wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

Assignees

• Regeneron Pharma

Inventors

• Ioffe Ella
• Lowy Israel
• Thurston Gavin
• Burova Elena

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/71

  for growth factors; for growth regulators · CPC title

• A61K38/1793 Primary

  for cytokines; for lymphokines; for interferons · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K39/39558 Primary

  against tumor tissues, cells, antigens · CPC title