Monoclonal antibodies to programmed death 1 (PD-1)

Patent metadata

Field	Value
Publication number	US-9387247-B2
Application number	US-201414244405-A
Country	US
Kind code	B2
Filing date	Apr 3, 2014
Priority date	May 9, 2005
Publication date	Jul 12, 2016
Grant date	Jul 12, 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 monoclonal antibody or an antigen-binding portion thereof that cross-competes for binding to human PD-1 with a reference antibody or antigen-binding portion thereof, wherein the reference antibody or antigen-binding portion thereof comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains selected from:
(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: 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; and
(d) 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;
wherein the monoclonal antibody or antigen-binding portion thereof comprises a heavy chain variable region, which comprises CDR1, CDR2, CDR3, framework region (FR) 1, FR2, FR3, and FR4, and a light chain variable region, which comprises CDR1, CDR2, CDR3, FR1 FR2, FR3, and FR4,
wherein the monoclonal antibody or antigen-binding portion thereof binds to human PD-1 with a K D of 1×10 −8 M or less, wherein the K D is measured by surface plasmon resonance (Biacore) analysis, and
wherein the light chain variable region FR1 of the monoclonal antibody or antigen-binding portion thereof comprises the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 75) or EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 75) containing one amino acid mutation.

2. The monoclonal antibody or the antigen-binding portion thereof of claim 1 , wherein the light chain variable region FR2 of the monoclonal antibody or the antigen-binding portion thereof comprises the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 76) or WYQQKPGQAPRLLIY (SEQ ID NO: 76) containing one amino acid mutation.

3. The monoclonal antibody or the antigen-binding portion thereof of claim 1 , wherein the light chain variable region FR3 of the monoclonal antibody or the antigen-binding portion thereof comprises the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 77) or GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 77) containing one amino acid mutation.

4. The monoclonal antibody or the antigen-binding portion thereof of claim 1 , wherein the light chain variable region FR4 of the monoclonal antibody or the antigen-binding portion thereof comprises the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 78) or FGGGTKVEIK (SEQ ID NO: 78) containing one amino acid mutation.

5. The monoclonal antibody or the antigen-binding portion thereof of claim 1 , wherein the light chain variable region FR2 and FR4 of the monoclonal antibody or the antigen-binding portion thereof comprises the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 76) and the amino acid sequence of FGGGTKVEIK (SEQ ID NO 78), respectively.

6. The monoclonal antibody or the antigen-binding portion thereof of claim 5 , wherein the heavy chain variable region FR4 of the monoclonal antibody or the antigen-binding portion thereof comprises the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 82) or WGQGTLVTVSS (SEQ ID NO:82) containing one amino acid mutation.

7. The monoclonal antibody or the antigen-binding portion thereof of claim 1 , wherein the light chain variable regions FR2, FR3, and FR4 of the monoclonal antibody or the antigen-binding portion thereof comprises (i) the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 76) or WYQQKPGQAPRLLIY (SEQ ID NO: 76) containing one amino acid mutation, (ii) the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 77) or GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 77) containing one amino acid mutation, and (iii) the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 78) or FGGGTKVEIK (SEQ ID NO: 78) containing one amino acid mutation, respectively.

8. The monoclonal antibody or the antigen-binding portion thereof of claim 7 , wherein the heavy chain variable region FR4 of the monoclonal antibody or the antigen-binding portion thereof comprises the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 82) or WGQGTLVTVSS (SEQ ID NO: 82) containing one amino acid mutation.

9. The monoclonal antibody or antigen-binding portion thereof of claim 8 , wherein the K D is 5×10 −9 M or less and wherein the K D is measured by surface plasmon resonance (Biacore) analysis.

10. The monoclonal antibody or antigen-binding portion thereof of claim 8 , wherein the K D is 1×10 −9 or less and wherein the K D is measured by surface plasmon resonance (Biacore) analysis.

11. The monoclonal antibody or antigen-binding portion thereof of claim 8 , which mediates neither ADCC activity nor CDC activity.

12. The monoclonal antibody of claim 8 , comprising a heavy chain constant region which is of a human IgG1, IgG2, IgG3, or IgG4 isotype.

13. The monoclonal antibody of claim 12 , wherein the heavy chain constant region is of a human IgG4 isotype.

14. A monoclonal antibody or an antigen-binding portion thereof that cross-competes for binding to PD-1 with a reference antibody or antigen-binding portion thereof, wherein the reference antibody or antigen-binding portion thereof comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains selected from:
(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 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

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title