US 2014/0212422 A1 · METHODS FOR TREATING CANCER USING ANTI-PD-1 ANTIBODIES IN COMBINATION WITH ANTI-CTLA-4 ANTIBODIES

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.

Claims46

Dependent claims

A method for treating a cancer in a subject comprising administering to the subject a combination of an anti-PD-1 antibody, or an antigen-binding portion thereof, and an anti-CTLA-4 antibody, or an antigen-binding portion thereof, wherein the combination of the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof exhibits a synergistic therapeutic effect on cancer treatment.

A method for treating a cancer in a subject comprising administering to the subject a combination of an anti-PD-1 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-1 monoclonal antibody or antigen-binding portion thereof 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 KD of 1×10−7 M or less, wherein the KD is measured by surface plasmon resonance (Biacore) analysis;
(ii) binds to human PD-1 with an on rate (kon) of about 0.76×105 l/Ms or more, wherein the on rate (kon) is measured by surface plasmon resonance (Biacore) analysis;
and
(iii) binds to human PD-1 with an off rate (koff) of about 4.5×10−4 l/s or less, wherein the off rate (koff) is measured by surface plasmon resonance (Biacore) analysis.

87 more elements

A method for treating a cancer in a subject comprising administering to the subject a combination of an anti-PD-1 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-1 monoclonal antibody or antigen-binding portion thereof 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:
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;
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.

19 more elements

(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.

82 more elements

Dependencies are inferred from the claim text.

Facts

Application

14/227,733Filed 27 Mar 2014

Priority

9 May 2005

Published

31 Jul 2014

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

Application11/913,217Continuation · filed 29 Jan 2009

Application13/210,137Continuation · filed 15 Aug 2011

Application14/227,733Continuation

US 2009/0217401 A1Published application

US 2013/0133091 A1Published application

US 8,008,449 B2Related patent

US 8,779,105 B2Related patent

US 9,358,289 B2Related patent

US 2014/0212422 A1This patent

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

Methods for treating cancer using anti-pd-1 antibodies in combination with anti-ctla-4 antibodies

Life of this patent

Methods for treating cancer using anti-pd-1 antibodies in combination with anti-ctla-4 antibodies

Life of this patent

Abstract

Claims46