US 8,008,449 B2Granted

Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics

AssigneesMedarex, Inc., Ono Pharmaceutical Co., Ltd.

InventorsAlan J. Korman, Mohan Srinivasan, Changyu Wang, Mark J. Selby, Bingliana Chen, Josephine M. Cardarelli

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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.

Claims23

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-1 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:
8;
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:
9;
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:
10;
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:
11;
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:
12;
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:
13;
or
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 SEO ID NO:
14.

19 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 CDR3domains, 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:
15;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:
22;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
29;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
36;
a light chain variable region CDR2 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:
50;
b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
16;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:
23;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
30;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
37;
a light chain variable region CDR2 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:
51;
c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
17;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:
24;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
31;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
38;
a light chain variable region CDR2 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:
52;
d) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
18;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:
25;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
32;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
39;
a light chain variable region CDR2 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:
53;
e) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
19;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:
26;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
33;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
40;
a light chain variable region CDR2 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:
54;
f) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
20;
a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:
27;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
34;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
41;
a light chain variable region CDR2 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:
55;
and
g) 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:
28;
a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
35;
a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:
42;
a light chain variable region CDR2 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:
56,
wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

91 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:
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;
and
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,
wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

27 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:
29;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
50 and conservative modifications thereof;
b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
30;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
51 and conservative modifications thereof;
c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
31;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
52 and conservative modifications thereof;
d) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
32;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
53 and conservative modifications thereof;
e) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
33;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
54 and conservative modifications thereof;
f) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
34;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
55 and conservative modifications thereof;
and
g) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
35;
and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:
56 and conservative modifications thereof;
wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/913,217Filed 2 May 2006 · us provisional application
Priority: 9 May 2005
Published: US 2009/0217401 A127 Aug 2009
Granted: 30 Aug 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07K 16/2818
Against the immunoglobulin superfamily: against CD28 or CD152
A61K 39/00
Medicinal preparations containing antigens or antibodies
A61K 39/3955
Against materials from animals: against proteinaceous materials, e.g. enzymes, hormones, lymphokines
A61K 39/39558
Against materials from animals: against tumor tissues, cells, antigens

Family

Application60/679,466Us provisional application · filed 9 May 2005
Application60/738,434Us provisional application · filed 21 Nov 2005
Application60/748,919Us provisional application · filed 8 Dec 2005
US 2009/0217401 A1Pre-grant publication · published 27 Aug 2009
US 8,008,449 B2This patent

From the US filing history. Foreign family members aren’t listed.