ANTI PD-1 ANTIBODIES

• US 20170267762A1
• Filed: 07/22/2015
• Published: 09/21/2017
• Est. Priority Date: 07/22/2014
• Status: Active Grant

• Current Assignee: Apollomics Inc.
• Original Assignee: CB Therapeutics Inc.
• Inventors: QIU, Junzhuan, SUN, Ziyong, ZHA, Jiping
• Granted Patent: US 10,428,146 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/12 Schistosomicides
• 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: C07K 16/2818 against CD28 or CD152
• 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• 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 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/32 : fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: C12N 2501/599 : with CD designations not provided for elsewhere
• CPC Class Codes: C12N 5/0636 : T lymphocytes
• 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 relates to antibodies and antigen-binding fragments thereof that bind to PD-1, and to methods of using such antibodies and antigen-binding fragments. For example, the present invention provides humanized anti-PD-1 antibodies and methods of use thereof.

Claims

1. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain CDR1 sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs:

24, 34, 45, 55, 65, 75, 85, 95, 105, and 115;

a light chain CDR2 sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs;

25, 35, 46, 56, 66, 76, 86, 96, 106, and 116;

a light chain CDR3 sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs;

26, 36, 47, 57, 67, 77, 87, 97, 107, and 117;

a heavy chain CDR1 sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs;

19, 29, 40, 50, 60, 70, 80, 90, 100, and 110;

a heavy chain CDR2 sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs;

20, 30, 41, 51, 61, 71, 81, 91, 101, and 111; and

a heavy chain CDR3 sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs;

21, 31, 42, 52, 62, 72, 82, 92, 102, and 112.

2. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

24, 34, 45, 55, 65, 75, 85, 95, 105, and 115;

a light chain CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs;

25, 35, 46, 66, 76, 86, 96, 106, and 116;

a light chain CDR3 consisting of an amino acid sequences selected from the group consisting of SEQ ID NOs;

26, 36, 47, 57, 67, 77, 87, 97, 107, and 117;

a heavy chain CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs;

19, 29, 40, 50, 60, 70, 80, 90, 100, and 110;

a heavy chain CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs;

20, 30, 41, 51, 61, 71, 81, 91, 101, and 111;

and a heavy chain CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs;

21, 31, 42, 52, 62, 72, 82, 92, 102, and 112.

3. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

24, 25, and 26, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

19, 20, and 21, respectively.

4. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

34, 35, and 36, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

29, 30, and 31, respectively.

5. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

45, 46, and 47, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

40, 41, and 42, respectively.

6. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

55, 56, and 57, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

50, 51, and 52, respectively.

7. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

65, 66, and 67, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

60, 61, and 62, respectively.

8. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

75, 76, and 77, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

70, 71, and 72, respectively.

9. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

85, 86, and 87, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

80, 81, and 82, respectively.

10. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

95, 96, and 97, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

90, 91, and 92, respectively.

11. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

105, 106, and 107, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

100, 101, and 102, respectively.

12. The antibody or fragment of claim 1, wherein the antibody or fragment thereof comprises a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs:

115, 116, and 117, respectively; and

a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence having at least 80% homology to an amino acid sequence according to SEQ ID NOs;

110, 111, and 112, respectively.

13. The isolated antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is chimeric or humanized.

22. An isolated antibody or fragment thereof, wherein the antibody or fragment thereof binds to the same epitope as an antibody or fragment thereof according to claim 1.

23. An isolated antibody or fragment thereof, wherein the antibody or fragment thereof competes for binding to PD-1 with an antibody or fragment thereof of claim 1, wherein the competition is measured by ELISA, flow cytometry, or surface plasmon resonance (SPR) assay.

24. The isolated antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is selected from the group consisting of a monoclonal antibody, an scFv, a Fab fragment, an Fab′

fragment, and an F(ab)′

fragment.

25. An antibody or fragment thereof according to claim 1, wherein the antibody or fragment thereof is linked or conjugated to a therapeutic agent.

26. The antibody or fragment thereof according to claim 25, wherein the therapeutic agent is a cytotoxic drug, a radioactive isotope, an immunomodulator, or an antibody.

36. A composition comprising the antibody or fragment thereof according to claim 1 and a pharmaceutically acceptable carrier.

37. An isolated polynucleotide encoding the antibody or fragment thereof according to claim 1.

38. An expression vector comprising the isolated polynucleotide according to claim 37.

39. A host cell comprising the expression vector according to claim 38.

41. A method for increasing T cell activation, the method comprising contacting T cells with an antibody or fragment thereof according to claim 1.

42. A method for reducing tumors or inhibiting the growth of tumor cells in a subject, the method comprising administering to the subject a therapeutically effective amount of the isolated antibody or fragment thereof according to claim 1.

43. A method for treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the isolated antibody or fragment thereof according to claim 1 to the subject.

44. The method according to claim 43, wherein the cancer is selected from the group consisting of lymphoma, leukemia, melanoma, glioma, breast cancer, lung cancer, colon cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, liver cancer, stomach cancer, rectal cancer, testicular cancer, salivary cancer, thyroid cancer, thymic cancer, epithelial cancer, head or neck cancer, gastric cancer, pancreatic cancer, or a combination thereof.

45. A method for treating an infectious disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of the isolated antibody or fragment thereof according to claim 1 to the subject.

46. The method according to claim 45, wherein the infectious disease is selected from the group consisting of candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal conditions, gram negative sepsis, tuberculosis, mononucleosis, influenza, respiratory illness caused by Respiratory Syncytial Virus, malaria, schistosomiasis, and trypanosomiasis.

14. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain variable region comprising an amino acid sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs:

23, 33, 44, 54, 64, 74, 84, 94, 104, 114, 133, and 143;

and a heavy chain variable region comprising an amino acid sequence having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs;

18, 28, 39, 49, 59, 69, 79, 89, 99, 109, 131, and 141.

15. The isolated antibody or fragment thereof of claim 14, wherein the antibody or fragment thereof comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

23, 33, 44, 54, 64, 74, 84, 94, 104, 114, 133, and 143; and

a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs;

18, 28, 39, 49, 59, 69, 79, 89, 99, 109, 131, and 141.

16. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain variable region according to SEQ ID NO:

133 or 152 and a heavy chain variable region according to SEQ ID NO;

131.

17. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain variable region according to SEQ ID NO:

143 and a heavy chain variable region according to SEQ ID NO;

141.

18. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain according to SEQ ID NO:

139 or 153 and a heavy chain according to SEQ ID NO;

135.

19. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain according to SEQ ID NO:

139 or 153 and a heavy chain according to SEQ ID NO;

137.

20. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain according to SEQ ID NO:

149 and a heavy chain according to SEQ ID NO;

145.

21. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof comprises a light chain according to SEQ ID NO:

149 and a heavy chain according to SEQ ID NO;

147.

27. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof has an affinity for PD-1 of about 1 nM to about 0.01 nM.

28. The isolated antibody or fragment thereof according to claim 27, wherein the antibody or fragment thereof as an affinity for PD-1 of about 1 nM or less.

29. The isolated antibody or fragment thereof according to claim 27, wherein the antibody or fragment thereof as an affinity for PD-1 of about 0.1 nM or less.

34. The isolated antibody or fragment thereof according to claim 28, wherein the antibody or fragment thereof increases T cell production of IL-2 and IFNγ

.

30. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody has a binding EC50 of about 5 ng/mL to about 1000 ng/mL.

31. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody blocks binding of PD-1 to PD-L1.

32. An isolated antibody or fragment thereof of claim 31, wherein the antibody or fragment thereof blocks the binding of PD-1 to PD-L1 or PD-L2 at an IC50 of about 5 ng/mL to about 1000 ng/mL.

33. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment increases T cell activation as measured by inflammatory cytokine production.

35. An isolated antibody or fragment thereof that binds to PD-1, wherein the antibody or fragment thereof is produced by a hybridoma selected from the group consisting of 10D1, 4C10, 7D3, 13F1, 15H5, 14A6, 22A5, 6E1, 5A8, 7A4, and/or 7A4D.

40. An isolated hybridoma cell line selected from the group consisting of 10D1, 4C10, 7D3, 13F1, 15H5, 14A6, 22A5, 6E1, 5A8, 7A4 and 7A4D.