Human anti-PD-1 antibodies and uses therefor

• US 9,102,727 B2
• Filed: 03/13/2013
• Issued: 08/11/2015
• Est. Priority Date: 09/26/2008
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, Emory University
• Original Assignee: Dana-Farber Cancer Institute, Emory University
• Inventors: Freeman, Gordon J., Ahmed, Rafi, Jones, Timothy D., Carr, Francis J., Gregson, James P.
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US13/802,172
• Publication Number:
  US 20130291136A1
• Time in Patent Office: 881 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 33/10 : Anthelmintics
• CPC Class Codes: A61P 33/12 : Schistosomicides
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is based, in part, on the identification of novel human anti-PD-1, PD-L1, and PD-L2 antibodies. Accordingly, the invention relates to compositions and methods for diagnosing, prognosing, and treating conditions that would benefit from modulating PD-1, PD-L1, and/or PD-L2 activity (e.g., persistent infectious diseases, autoimmune diseases, asthma, transplant rejection, inflammatory disorders and tumors) using the novel human anti-PD-1, PD-L1, and PD-L2 antibodies described herein.

Claims

1. An isolated antibody or antigen-binding fragment thereof, comprising:

a) a heavy chain variable region sequence comprising the three CDR sequences of SEQ ID NOs;

7-9;

or

b) a light chain variable region sequence comprising the three CDR sequences of SEQ ID NOs;

10-12,

wherein the isolated antibody, or antigen-binding fragment thereof, binds to a PD-1 protein having the amino acid sequence of SEQ ID NO;

2, and the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, or human.

2. The isolated antibody or antigen-binding fragment of claim 1, comprising:

a) a heavy chain variable region sequence selected from the group consisting of SEQ ID NOs;

25-29, or a sequence with at least about 95% homology to a heavy chain sequence selected from the group consisting of SEQ ID NOs;

25-29;

or

b) a light chain variable region sequence selected from the group consisting of SEQ ID NOs;

30-33, or a sequence with at least about 95% homology to a light chain sequence selected from the group consisting of SEQ ID NOs;

30-33.

3. The isolated antibody or antigen-binding fragment of claim 2, comprising:

a) a heavy chain variable region sequence comprising SEQ ID NO;

27 or 28, or a sequence with at least about 95% homology to a heavy chain sequence comprising SEQ ID NO;

27 or 28; and

b) a light chain variable region sequence comprising SEQ ID NO;

32 or 33, or a sequence with at least about 95% homology to a light chain sequence comprising SEQ ID NO;

32 or 33.

4. The isolated antibody or antigen-binding fragment of claim 1, wherein the isolated antibody or antigen-binding fragment inhibits the binding of an antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:

76 and a light chain variable region comprising the sequence of SEQ ID NO;

77 to Fc-PD-1.

5. The isolated antibody or antigen-binding fragment of claim 1, wherein the isolated antibody or antigen-binding fragment inhibits a PD-1-mediated signal.

7. An isolated nucleic acid encoding the antibody or antigen-binding fragment of claim 1.

8. A vector comprising the isolated nucleic acid of claim 7.

9. An isolated host cell comprising the nucleic acid of claim 7.

10. The host cell of claim 9 that produces the antibody or antigen-binding fragment encoded by the nucleic acid.

11. A pharmaceutical composition, comprising the isolated antibody or antigen-binding fragment of claim 1 and a pharmaceutically-acceptable carrier.

12. A method of reactivating exhausted T cells, comprising contacting a population of T cells, wherein at least some T cells express PD-1, with an effective amount of a composition comprising an antibody, or an antigen-binding fragment thereof, of claim 1.

13. The method of claim 12, wherein the step of contacting is performed in vitro, ex vivo, or in vivo.

14. A method of treating a subject suffering from cancer, comprising administering to the subject a composition comprising an effective amount of an isolated antibody, or an antigen-binding fragment thereof, of claim 1.

15. The method of claim 14, wherein the cancer is selected from the group consisting of a solid tumor, a hematologic cancer, bladder cancer, brain cancer, breast cancer, colon cancer, gastric cancer, glioma, head cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, neck cancer, ovarian cancer, melanoma, pancreatic cancer, renal cancer, salivary cancer, stomach cancer, thymic epithelial cancer, and thyroid cancer.

16. A method of producing the antibody or antigen-binding fragment of claim 1, comprising culturing a cell that produces the antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment from the cell culture.

17. The isolated antibody or antigen-binding fragment of claim 1, comprising:

a) a heavy chain variable region sequence comprising the three CDR sequences of SEQ ID NOs;

7-9; and

b) a light chain variable region sequence comprising the three CDR sequences of SEQ ID NOs;

10-12.

18. The isolated antibody or antigen-binding fragment of claim 17, comprising:

a) a heavy chain variable region sequence selected from the group consisting of SEQ ID NOs;

25-29, or a sequence with at least about 95% homology to a heavy chain sequence selected from the group consisting of SEQ ID NOs;

25-29; and

b) a light chain variable region sequence selected from the group consisting of SEQ ID NOs;

30-33, or a sequence with at least about 95% homology to a light chain sequence selected from the group consisting of SEQ ID NOs;

30-33.

19. The isolated antibody or antigen-binding fragment of claim 2, comprising:

a) a heavy chain variable region sequence selected from the group consisting of SEQ ID NOs;

25-29;

or

b) a light chain variable region sequence selected from the group consisting of SEQ ID NOs;

30-33.

20. The isolated antibody or antigen-binding fragment of claim 19, comprising:

a) a heavy chain variable region sequence selected from the group consisting of SEQ ID NOs;

25-29; and

b) a light chain variable region sequence selected from the group consisting of SEQ ID NOs;

30-33.

21. The isolated antibody or antigen-binding fragment of claim 20, comprising:

a) a heavy chain variable region sequence comprising SEQ ID NO;

27 or 28; and

b) a light chain variable region sequence comprising SEQ ID NO;

32 or 33.

6. An isolated nucleic acid encoding a polypeptide, wherein the polypeptide comprises a sequence selected from the group consisting of SEQ ID NOs:

25-33, or a sequence with at least about 95% homology to a sequence selected from the group consisting of SEQ ID NOs;

25-33.