Human monoclonal antibodies to programmed death ligand 1 (PD-L1)

Patent metadata

Field	Value
Publication number	US-9273135-B2
Application number	US-201514796956-A
Country	US
Kind code	B2
Filing date	Jul 10, 2015
Priority date	Jul 1, 2005
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-LI antibodies.

First claim

We claim:

1. A method for enhancing an immune response in a subject comprising administering to the subject a combination of an anti-PD-L1 monoclonal antibody or an antigen-binding portion thereof and an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof, wherein the anti-PD-L1 monoclonal antibody or antigen-binding portion thereof cross-competes for binding to PD-L1 with a reference antibody comprising:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:1 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(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:12;
(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:13;
(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:14;
(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:15;
(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:16;
(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:17;
(h) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:8 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:9 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; or
(j) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:10 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20, and
wherein enhancing the immune response results in inhibition of growth of tumor cells in the subject.

2. The method of claim 1 , wherein the anti-PD-L1 monoclonal antibody or antigen-binding portion thereof comprises a light chain variable region having at least 90% sequence identity to a light chain variable region selected from:
(a) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; and
(j) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20.

3. The method of claim 1 , wherein the anti-PD-L1 monoclonal antibody or antigen-binding portion thereof comprises a heavy chain variable region and a light chain variable region, wherein a framework region of the heavy chain variable region exhibits at least 90% sequence identity to a framework region of a heavy chain variable region selected from:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:1;
(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:2;
(c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:3;
(d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:4;
(e) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:5;
(f) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:6;
(g) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:7;
(h) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:8;
(i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:9; and
(j) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:10; and/or
a framework region of the light chain variable region exhibits at least 90% sequence identity to a framework region of a light chain variable region selected from:
(a) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18; and
(i) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19.

4. The method of claim 1 , wherein the anti-PD-L1 monoclonal antibody or antigen-binding portion thereof comprises a light chain variable region comprising:
(a) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:105;
(b) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:106;
(c) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:107; or
(d) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:108.

5. The method of claim 4 , wherein the anti-PD-L1 monoclonal antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising:
(a) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:101;
(b) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:102;
(c) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:103; or
(d) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR

Assignees

• Squibb & Sons Llc
• Squibb & Sons Llc

Inventors

• Korman Alan J
• Selby Mark J
• Wang Changyu
• Srinivasan Mohan
• Passmore David B
• Huang Haichun
• Chen Haibin

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P39/02

  Antidotes · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P35/00

  Antineoplastic agents · CPC title