Human antibodies to PD-L1

Patent metadata

Field	Value
Publication number	US-11117970-B2
Application number	US-201815905653-A
Country	US
Kind code	B2
Filing date	Feb 26, 2018
Priority date	Jan 23, 2014
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

The present invention provides antibodies that bind to the T-cell co-inhibitor ligand programmed death-ligand1 (PD-L1) protein, and methods of use. In various embodiments of the invention, the antibodies are fully human antibodies that bind to PD-L1. In certain embodiments, the present invention provides multi-specific antigen-binding molecules comprising a first binding specificity that binds to PD-L1 and a second binding specificity that binds to a tumor cell antigen, an infected cell-specific antigen, or a T-cell co-inhibitor. In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing PD-L1 activity, thus providing a means of treating a disease or disorder such as cancer or viral infection.

First claim

What is claimed is:

1. A method of inhibiting a tumor in a subject comprising administering to the subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds specifically to human programmed death ligand 1 (PD-L1) wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) comprising an amino acid sequence of SEQ ID NO: 82; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR) comprising an amino acid sequence of SEQ ID NO: 90.

2. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
(a) a HCDR1 domain having an amino acid sequence of SEQ ID NO: 84;
(b) a HCDR2 domain having an amino acid sequence of SEQ ID NO: 86;
(c) a HCDR3 domain having an amino acid sequence of SEQ ID NO: 88;
(d) a LCDR1 domain having an amino acid sequence of SEQ ID NO: 92;
(e) a LCDR2 domain having an amino acid sequence of SEQ ID NO: 94; and
(f) a LCDR3 domain having an amino acid sequence of SEQ ID NO: 96.

3. The method of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 82/90.

4. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof has one or more of the following properties:
(a) binds monomeric PD-L1 with a binding dissociation equilibrium constant (K D ) of less than about 310 pM as measured in a surface plasmon resonance assay at 37° C.;
(b) binds monomeric human PD-L1 with a K D less than about 180 pM in a surface plasmon resonance assay at 25° C.;
(c) binds dimeric human PD-L1 with a K D of less than about 15 pM as measured in a surface plasmon resonance assay at 37° C.; and
(d) binds dimeric human PD-L1 with a K D less than about 8 pM in a surface plasmon resonance assay at 25° C.

5. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof blocks binding of PD-L1 to programmed death 1 (PD-1) receptor.

6. The method of claim 1 , wherein the subject has primary or recurrent cancer.

7. The method of claim 1 , wherein the tumor is selected from the group consisting of brain cancer, renal cell carcinoma, ovarian cancer, gastric cancer, bladder cancer, breast cancer, prostate cancer, colon cancer, ovarian cancer, non-small-cell lung cancer, squamous cell carcinoma of head and neck, colorectal cancer, myeloma, and melanoma.

8. The method of claim 1 , wherein the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered to the subject in combination with a second therapeutic agent.

9. The method of claim 8 , wherein the second therapeutic agent is selected from the group consisting of radiation therapy, a chemotherapeutic agent, a cytotoxic agent, surgery, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin 2 (Ang-2) inhibitor, a cancer vaccine, an anti-PD-1 antibody, a transforming growth factor beta (TGFbeta) inhibitor, an epithelial growth factor receptor (EGFR) inhibitor, an antibody to a T-cell co-inhibitor, an antibody to a tumor specific antigen, a CD20 inhibitor, a corticosteroid, and a dietary supplement.

10. The method of claim 9 , wherein the pharmaceutical composition is administered in combination with a VEGF antagonist.

11. The method of claim 10 , wherein the VEGF antagonist is selected from the group consisting of an anti-VEGF antibody, a small molecule kinase inhibitor of VEGF receptor, and a VEGF-inhibiting fusion protein.

12. The method of claim 1 , wherein the pharmaceutical composition is administered subcutaneously, intravenously, intradermally, intraperitoneally, orally, intramuscularly or intracranially.

13. The method of claim 1 , wherein the antibody or antigen-binding fragment is administered at a dose of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight of the subject.

14. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR of SEQ ID NO: 82 and a LCVR of SEQ ID NO: 90.

15. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises a HCDR1 of SEQ ID NO: 84, a HCDR2 of SEQ ID NO: 86, a HCDR3 of SEQ ID NO: 88, a LCDR1 of SEQ ID NO: 92, a LCDR2 of SEQ ID NO: 94, and a LCDR3 of SEQ ID NO: 96.

Assignees

• Regeneran Pharmaceuticals Inc
• Regeneron Pharma

Inventors

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

Classifications

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• C07K16/22

  against growth factors {; against growth regulators} · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title

• A61K39/3955 Primary

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K45/06

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