Methods for treating cancer using anti-PD-1 antibodies in combination with anti-CTLA-4 antibodies

Patent metadata

Field	Value
Publication number	US-9358289-B2
Application number	US-201414227733-A
Country	US
Kind code	B2
Filing date	Mar 27, 2014
Priority date	May 9, 2005
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

The present invention provides isolated monoclonal antibodies, particularly human monoclonal antibodies, that specifically bind to PD-1 with high affinity. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for detecting PD-1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-1 antibodies. The present invention further provides methods for using a combination immunotherapy, such as the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat hyperproliferative disease, such as cancer. The invention also provides methods for altering adverse events related to treatment with such antibodies individually.

First claim

What is claimed is:

1. A method of inhibiting tumor growth in a subject having a tumor that does not express PD-L1 comprising administering to the subject a combination of a dose of an anti-PD-1 monoclonal antibody or an antigen-binding portion thereof and a dose of an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof, wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof inhibits growth of the tumor in the subject.

2. The method of claim 1 , wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic effect on inhibiting tumor growth compared to the tumor growth inhibition exhibited by administering a therapeutic dose of the anti-PD-1 antibody or antigen-binding portion thereof alone or a therapeutic dose of the anti-CTLA-4 antibody or antigen-binding portion thereof alone.

3. A method of reducing the size of a tumor that does not express PD-L1 in a subject having said tumor comprising administering to the subject a combination of a dose of an anti-PD-1 monoclonal antibody or an antigen-binding portion thereof and a dose of an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof, wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof reduces the size of the tumor in the subject.

4. The method of claim 3 , wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic effect on reducing the tumor size compared to the tumor size reduction exhibited by administering a therapeutic dose of the anti-PD-1 antibody or antigen-binding portion thereof alone or a therapeutic dose of the anti-CTLA-4 antibody or antigen-binding portion thereof alone.

5. A method of treating cancer in a subject having a tumor that does not express PD-L1 comprising administering to the subject a combination of a dose of an anti-PD-1 monoclonal antibody or an antigen-binding portion thereof and a dose of an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof, wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof treats cancer in the subject.

6. The method of claim 5 , wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic therapeutic effect on cancer treatment compared to the cancer treatment effect exhibited by administering a therapeutic dose of the anti-PD-1 antibody or antigen-binding portion thereof alone or a therapeutic dose of the anti-CTLA-4 antibody or antigen-binding portion thereof alone.

7. The method of claim 5 , wherein the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof is a subtherapeutic dose.

8. The method of claim 7 , wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof is a subtherapeutic dose.

9. A method of inhibiting tumor growth in a subject in need thereof comprising administering to the subject a combination of a dose of an anti-PD-1 monoclonal antibody or an antigen-binding portion thereof and a dose of an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof; wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof, the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof, or both doses are subtherapeutic doses; and wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof inhibits tumor growth in the subject.

10. The method of claim 9 , wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic effect on inhibiting tumor growth compared to the tumor growth inhibition exhibited by administering a therapeutic dose of the anti-PD-1 antibody or antigen-binding portion thereof alone or a therapeutic dose of the anti-CTLA-4 antibody or antigen-binding portion thereof alone.

11. The method of claim 9 , wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof is a therapeutic dose and the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof is a subtherapeutic dose.

12. The method of claim 9 , wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof is a subtherapeutic dose and the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof is a subtherapeutic dose.

13. A method of reducing the size of a tumor in a subject in need thereof comprising administering to the subject a combination of a dose of an anti-PD-1 monoclonal antibody or an antigen-binding portion thereof and a dose of an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof; wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof, the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof, or both doses are subtherapeutic doses; and wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof reduces the tumor size in the subject.

14. The method of claim 13 , wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic effect on reducing the tumor size compared to the tumor size reduction exhibited by administering a therapeutic dose of the anti-PD-1 antibody or antigen-binding portion thereof alone or a therapeutic dose of the anti-CTLA-4 antibody or antigen-binding portion thereof alone.

15. The method of claim 13 , wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof is a therapeutic dose and the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof is a subtherapeutic dose.

16. The method of claim 13 , wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof is a subtherapeutic dose and the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof is a subtherapeutic dose.

17. A method of treating cancer comprising administering to a subject in need thereof a combination of a dose of an anti-PD-1 monoclonal antibody or an antigen-binding portion thereof and a dose of an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof; wherein the dose of the anti-PD-1 antibody or antigen-binding portion thereof, the dose of the anti-CTLA-4 antibody or antigen-binding portion thereof, or both doses are subtherapeutic doses; and wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof treats cancer in the subject.

18. The method of claim 17 , wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic therapeutic effect on cancer treatment compared to the cancer treatment effect exhibited by administering a therapeutic dose of the anti-PD-1 antibody or antigen-binding portion thereof alone or a therapeutic dose of the anti-CTLA-4 antibody or antigen-binding portion thereof alone.

Assignees

• Squibb & Sons Llc
• Ono Pharmaceutical Co
• Squibb & Sons Llc

Inventors

• Korman Alan J
• Srinivasan Mohan
• Wang Changyu
• Selby Mark J
• Chen Bingliang
• Cardarelli Josephine M
• Huang Haichun

Classifications

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• C07K16/2803

  against the immunoglobulin superfamily · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title

• C07K16/28 Primary

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