Methods for treating cancer using anti-PD-1 antibodies

Patent metadata

Field	Value
Publication number	US-9492540-B2
Application number	US-201414270750-A
Country	US
Kind code	B2
Filing date	May 6, 2014
Priority date	May 9, 2005
Publication date	Nov 15, 2016
Grant date	Nov 15, 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 for treating a cancer in a subject comprising administering to the subject an anti-PD-1 monoclonal antibody, or an antigen-binding portion thereof, which cross-competes for binding to PD-1 with a reference antibody, or antigen-binding portion thereof, comprising:
(a) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 15; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 22; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 29; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 36; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 43; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 50;
(b) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 16; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 23; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 30; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 37; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 44; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 51;
(c) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 17; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 24; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 31; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 38; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 45; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 52;
(d) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 18; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 25; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 32; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 39; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 46; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 53;
(e) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 19; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 26; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 33; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 40; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 47; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 54;
(f) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 20; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 27; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 34; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 41; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 48; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 55; or
(g) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 21; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 28; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 42; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 49; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 56,
wherein the anti-PD-1 monoclonal antibody or antigen-binding portion thereof exhibits at least one of the following properties:
(i) binds to human PD-1 with a K D of 1×10 −7 M or less, wherein the K D is measured by surface plasmon resonance (Biacore) analysis;
(ii) binds to human PD-1 with an on rate (k on ) of about 0.76×10 5 l/Ms or more, wherein the on rate (k on ) is measured by surface plasmon resonance (Biacore) analysis; and
(iii) binds to human PD-1 with an off rate (k off ) of about 4.5×10 l/s or less, wherein the off rate (k off ) is measured by surface plasmon resonance (Biacore) analysis.

2. The method of claim 1 , wherein the reference antibody or antigen-binding portion thereof comprises a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 18; a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 25; a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 32; a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 39; a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 46; and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 53.

3. The method of claim 1 , wherein the reference antibody or antigen-binding portion thereof comprises:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: I and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 8;
(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 2 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 9;
(c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 3 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 10;
(d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 4 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 11;
(e) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 5 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 12;
(f) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 6 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 13; or
(g) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 7 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 14.

4. The method of claim 3 , wherein the reference antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 4 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 11.

5. A method for treating a cancer in a subject comprising administering to the subject an anti-PD-1 monoclonal antibody, or an antigen-binding portion thereof, which binds to the same epitope on human PD-1 as does a reference antibody, or antigen-binding portion thereof, comprising:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: I and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 8;
(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 2 and a

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

• C07K2317/75

  Agonist effect on antigen · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title