ANTI-PD-1 ANTIBODIES AND METHODS OF USE THEREOF

• US 20160159905A1
• Filed: 12/03/2015
• Published: 06/09/2016
• Est. Priority Date: 12/09/2014
• Status: Active Grant

• Current Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Original Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Inventors: Abdiche, Yasmina Noubia, Cho, Helen Kim, HO, Weihsien, JOOSS, Karen Ute, Rajpal, Arvind, Youssef, Sawsan
• Granted Patent: US 10,155,037 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• 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: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention provides antagonizing antibodies that bind to programmed cell death protein 1 (PD-1) and methods of using same. The anti-PD-1 antibodies can be used therapeutically alone or in combination with other therapeutics to treat cancer and other diseases.

Claims

1. An isolated antagonist antibody that specifically binds to PD-1 and comprises:

a heavy chain variable region (VH) comprising a VH complementarity determining region one (CDR1), VH CDR2, and VH CDR3 of the VH having an amino acid sequence selected group the group consisting of SEQ ID NO;

3, SEQ ID NO;

4;

SEQ ID NO;

5; and

SEQ ID NO;

6; and

a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3 of the VL having an amino acid sequence selected from the group consisting of SEQ ID NO;

2;

SEQ ID NO;

7;

SEQ ID NO;

8; and

SEQ ID NO;

9.

2. The isolated antagonist antibody of claim 1, wherein the antibody comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO:

13, 14, or 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO;

16, 17, 24, 25, 27, 28, 35, or 36, a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO;

18, 23, 26, or 37, a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO;

10, 22, 30, or 32, a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO;

11, 20, or 33 and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO;

12, 21, 31, or 34.

3. The isolated antagonist antibody of claim 1, wherein the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO:

3, 4, 5, or 6, or a variant thereof with one or several conservative amino acid substitutions in residues that are not within a CDR.

4. The isolated antagonist antibody of claim 3, wherein the antibody comprises a VL comprising the amino acid sequence shown in SEQ ID NO:

2, 7, 8, or 9, or a variant thereof with one or several amino acid substitutions in amino acids that are not within a CDR.

5. The isolated antagonist antibody of claim 1, wherein the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO:

3, 4, 5, or 6, and a VL comprising the amino acid sequence shown in SEQ ID NO;

2, 7, 8, or 9.

6. The isolated antagonist antibody of claim 1, wherein the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO:

29 or 38 and a light chain comprising the amino acid sequence shown in SEQ ID NO;

39.

7. The isolated antagonist antibody of claim 1, wherein the antibody comprises a constant region.

8. The isolated antagonist antibody of claim 7, wherein the antibody has an isotype that is selected from the group consisting of IgG₂, IgG_2Δ

a, IgG₄, IgG<sub>4Δ

b</sub>, IgG<sub>4Δ

c</sub>, IgG₄ S228P, IgG<sub>4Δ

b</sub> S228P and IgG<sub>4Δ

c</sub> S228P.

9. The isolated antagonist antibody of claim 7, wherein the constant region is IgG₄ S228P.

10. The isolated antagonist antibody of claim 1, wherein each CDR of the antibody is defined in accordance with the Kabat definition, the Chothia definition, the combination of the Kabat definition and the Chothia definition, the AbM definition, or the contact definition of CDR.

11. An isolated antagonist antibody that specifically binds to PD-1 and competes for binding to PD-1 with, and/or binds to an epitope that is the same as or overlaps with the epitope on PD-1 recognized by, the antibody of claim 1.

13. The isolated antibody of claim 1, wherein the antibody promotes IFNγ

and/or TNF secretion from T cells.

14. The isolated antibody of claim 1, wherein the antibody promotes proliferation of T cells.

15. The isolated antibody of claim 1, wherein the antibody inhibits tumor growth.

16. The isolated antibody of claim 1, wherein the antibody binds human PD-1 and mouse PD-1.

17. The isolated antibody of claim 16, wherein the antibody binds human PD-1 with an affinity of about 0.73 nM at 25°

C. as measured by surface plasmon resonance.

18. An isolated cell line that produces the antibody of claim 1.

19. An isolated nucleic acid encoding the antibody of claim 1.

20. A recombinant expression vector comprising the nucleic acid of claim 19.

21. A host cell comprising the expression vector of claim 20.

22. A hybridoma capable of producing the antibody of claim 1.

23. A method of producing an anti-PD-1 antagonist antibody, the method comprising:

culturing a cell line that recombinantly produces the antibody of claim 1 under conditions wherein the antibody is produced; and

recovering the antibody.

25. The method of claim 21, wherein the heavy and light chains of the antibody are encoded on separate vectors.

26. The method of claim 21, wherein the heavy and light chains of the antibody are encoded on the same vector.

27. A pharmaceutical composition comprising the antibody of claim 1, and a pharmaceutically acceptable carrier.

28. A kit for the treatment of cancer comprising the pharmaceutical composition of claim 27.

29. A method for treating cancer in a subject in need thereof, the method comprising administering to the individual an effective amount of the anti-PD-1 antibody of claim 1 such that one or more symptoms associated with the cancer is ameliorated in the individual.

30. The method of claim 29, wherein the cancer is selected from the group consisting of gastric cancer, sarcoma, lymphoma, Hodgkin'"'"'s lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

31. The method of claim 29 wherein the individual is a previously treated adult patient with locally advanced or metastatic melanoma, squamous cell head and neck cancer (SCHNC), ovarian carcinoma, sarcoma, or relapsed or refractory classic Hodgkin'"'"'s Lymphoma (cHL).

32. The method of claim 29, wherein the anti-PD-1 antibody is administered at a dosage of about 0.5 mg/kg, about 1.0 mg/kg, about 3.0 mg/kg, or about 10 mg/kg.

33. The method of claim 29, wherein the anti-PD-1 antibody is administered once every 7, 14, 21, or 28 days.

34. The method of claim 29, wherein the anti-PD-1 antibody is administered intravenously or subcutaneously.

35. The method of claim 29, wherein the method further comprises administering an effective amount of a second therapeutic agent.

36. The method of claim 35, wherein the second therapeutic agent is selected from the group consisting of an anti-CTLA4 antibody, an anti-4-1 BB antibody, a second PD-1 antagonist, an anti-PD-L1 antibody, an anti-TIM3 antibody, an anti-LAG3 antibody, an anti-TIGIT antibody, an anti-OX40 antibody, an anti-GITR antibody, a tyrosine kinase inhibitor, and an ALK inhibitor.

37. The method of claim 36, wherein the tyrosine kinase inhibitor is axitinib or palbociclib.

38. The method of claim 36, wherein the ALK inhibitor is sunitinib or crizotinib.

39. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject (1) an effective amount of the anti-PD-1 antibody of claim 1, and (2) an effective amount of a vaccine capable of eliciting an immune response against cells of the cancer.

40. A method for enhancing the immunogenicity or therapeutic effect of a vaccine administered to a subject for the treatment of cancer, the method comprising administering to the subject receiving the vaccine an effective amount of the anti-PD-1 antibody of claim 1.

41. The method of claim 39, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and colorectal cancer.

42. The method of claim 40, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and colorectal cancer.

43. The method of claim 39, further comprising administering to the subject an effective amount of one or more other immune modulators.

44. The method of claim 40, further comprising administering to the subject an effective amount of one or more other immune modulators.

45. The method of claim 43, wherein the other immune modulators are selected from the group consisting of protein kinase receptor inhibitor, a CTLA-4 antagonist, a CD40 agonist, and a TLR9 agonist.

46. The method of claim 44, wherein the other immune modulators are selected from the group consisting of protein kinase receptor inhibitor, a CTLA-4 antagonist, a CD40 agonist, and a TLR9 agonist.

12. An isolated anti-PD-1 antibody, wherein the antibody comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO:

13, a VH CDR2 comprising the amino acid sequence of SEQ ID NO;

17, a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO;

23, a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO;

10, a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO;

20, and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO;

21.

24. A method of producing an anti-PD-1 antagonist antibody, the method comprising:

culturing a cell line comprising nucleic acid encoding an antibody comprising a heavy chain comprising the amino acid sequence shown in SEQ ID NO;

29 or 38 and a light chain comprising the amino acid sequence shown in SEQ ID NO;

39 under conditions wherein the antibody is produced; and

recovering the antibody.