Human antibodies to PD-1

Patent metadata

Field	Value
Publication number	US-9987500-B2
Application number	US-201514603776-A
Country	US
Kind code	B2
Filing date	Jan 23, 2015
Priority date	Jan 23, 2014
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention provides antibodies that bind to the T-cell co-inhibitor programmed death-1 (PD-1) protein, and methods of use. In various embodiments of the invention, the antibodies are fully human antibodies that bind to PD-1. In certain embodiments, the present invention provides multi-specific antigen-binding molecules comprising a first binding specificity that binds to PD-1 and a second binding specificity that binds to an autoimmune tissue antigen, another T-cell co-inhibitor, an Fc receptor, or a T-cell receptor. In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing PD-1 activity, thus providing a means of treating a disease or disorder such as cancer or a chronic viral infection. In other embodiments, the antibodies are useful for enhancing or stimulating PD-1 activity, thus providing a means of treating, for example, an autoimmune disease or disorder.

First claim

What is claimed is:

1. An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human programmed death-1 (PD-1) protein, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) sequence of SEQ ID NO:162; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) sequence of SEQ ID NO:170.

2. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising:
(a) a HCDR1 domain having an amino acid sequence of SEQ ID NO:164;
(b) a HCDR2 domain having an amino acid sequence of SEQ ID NO:166;
(c) a HCDR3 domain having an amino acid sequence of SEQ ID NO:168;
(d) a LCDR1 domain having an amino acid sequence of SEQ ID NO:172;
(e) a LCDR2 domain having an amino acid sequence of SEQ ID NO:174; and
(f) a LCDR3 domain having an amino acid sequence of SEQ ID NO:176.

3. The isolated antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair of SEQ ID NO:162/170.

4. The isolated antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof has one or more of the following properties:
(a) blocks human PD-1 protein binding to PD-L1 with an IC 50 of less than 3 nM as measured in a competition sandwich ELISA assay at 25° C.;
(b) binds monomeric human PD-1 with a binding dissociation equilibrium constant (K D ) of less than about 50 nM as measured in a surface plasmon resonance assay at 37° C.;
(c) binds monomeric human PD-1 with a K D less than about 12 nM in a surface plasmon resonance assay at 25° C.;
(d) binds monomeric cynomolgus PD-1 with a K D less than about 8.5 nM in a surface plasmon resonance assay at 25° C.;
(e) binds monomeric human PD-1 with a dissociative half-life (t½) of greater than about 6.3 minutes as measured in a surface plasmon resonance assay at 25° C.; and
(f) binds monomeric human PD-1 with a dissociative half-life (t½) of greater than about 0.9 minutes as measured in a surface plasmon resonance assay at 37° C.

5. The isolated antibody or antigen-binding fragment of claim 4 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence of SEQ ID NO:330.

6. The isolated antibody or antigen-binding fragment of claim 4 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence of SEQ ID NO:331.

7. The isolated antibody or antigen-binding fragment of claim 6 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain/light chain amino acid sequence pair of SEQ ID NO:330/331.

8. A pharmaceutical composition comprising an isolated human monoclonal antibody or antigen-binding fragment thereof that binds PD-1 according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

9. An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human programmed death-1 (PD-1) protein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 162, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 170.

10. An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human programmed death-1 (PD-1) protein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 330, and a light chain comprising the amino acid sequence of SEQ ID NO: 331.

Assignees

• Regeneron Pharma

Inventors

• Papadopoulos Nicholas J
• Murphy Andrew J
• Thurston Gavin
• Ioffe Ella
• Burova Elena

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P1/14

  Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents · CPC title