US 7,943,743 B2Granted

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

AssigneeMedarex, Inc.

InventorsAlan J. Korman, Mark J. Selby, Changyu Wang, Mohan Srinivasan, David B. Passmore, Haichun Huang, Haibin Chen

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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-L1 antibodies.

Claims26

Dependent claims

An isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof cross-competes for binding to PD-L1 with a reference antibody or reference antigen-binding portion thereof comprising:

(a) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:1 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:2 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:3 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:4 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:5 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:6 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:7 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:8 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:9 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19;
or
(j) a human heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:10 and a human light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20.

8 more elements

An isolated monoclonal antibody, or antigen binding portion thereof, comprising 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, wherein the heavy chain variable region and light chain variable region CDR3 domains are selected from the group consisting of:
(a) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:41;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:71 and conservative modifications thereof;
(b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:42;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:72 and conservative modifications thereof;
(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:43;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:73 and conservative modifications thereof;
(d) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:44;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:74 and conservative modifications thereof;
(e) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:45;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:75 and conservative modifications thereof;
(f) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:46;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:76 and conservative modifications thereof;
(g) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:47;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:77 and conservative modifications thereof;
(h) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:48;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:78 and conservative modifications thereof;
(i) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:49;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:79 and conservative modifications thereof;
and
(j) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:50;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:80 and conservative modifications thereof;
wherein the antibody specifically binds to human PD-L1.

20 more elements

An isolated monoclonal antibody, or antigen binding portion thereof, comprising 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, wherein the heavy chain variable region and light chain variable region CDR1, CDR2, and CDR3 domains are selected from the group consisting of:
(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:21;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:31;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:41;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:51;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:61;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:71;
(b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:22;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:32;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:42;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:52;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:62;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:72;
(c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:23;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:33;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:43;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:53;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:63;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:73;
(d) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:24;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:34;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:44;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:54;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:64;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:74;
(e) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:25;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:35;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:45;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:55;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:65;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:75;
(f) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:26;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:36;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:46;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:56;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:66;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:76;
(g) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:37;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:47;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:57;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:67;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:77;
(h) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:28;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:38;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:48;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:58;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:68;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:78;
(i) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:29;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:39;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:49;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:59;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:69;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:79;
and
(j) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:30;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:40;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:50;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:60;
a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:70;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:80;
wherein the antibody specifically binds to PD-L1.

60 more elements

An isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and light chain variable region are selected from the group consisting of:

(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;
and
(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;
wherein the antibody specifically binds to PD-L1.

19 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/917,727Filed 30 Jun 2006 · us provisional application
Priority: 1 Jul 2005
Published: US 2009/0055944 A126 Feb 2009
Granted: 17 May 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification46 codes

C07K 16/2827
Against the immunoglobulin superfamily: against B7 molecules, e.g. CD80, CD86
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61K 47/6817
The drug being a protein or peptide, e.g. transferrin or bleomycin: toxins
A61K 47/6825
Plant toxins: ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin