Anti-PD1 antibodies and their use as therapeutics and diagnostics

• US 8,735,553 B1
• Filed: 11/10/2013
• Issued: 05/27/2014
• Est. Priority Date: 09/13/2013
• Status: Active Grant

• Current Assignee: Beigene Switzerland Gmbh (BeiGene Ltd.)
• Original Assignee: BeiGene Ltd.
• Inventors: Li, Kang, Zhang, Tong, Liu, Qi, Song, Jing, Xu, Lanlan, Peng, Hao
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US14/076,214
• Time in Patent Office: 198 Days
• US Class Current: 530/388.22
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• 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 2317/34 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 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/53 Hinge
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/569 Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/70 characterized by effect upon binding to a cell or to an antigen
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of 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

Provided are antibodies that specifically bind to Programmed Death-1 (PD1, Pdcd-1, or CD279) and inhibit PD1-mediated cellular signaling and activities in immune cells, antibodies binding to a set of amino acid residues required for its ligand binding, and uses of these antibodies to treat or diagnose cancer, infectious diseases or other pathological disorders modulated by PD1-mediated functions.

Claims

1. An antibody antigen binding domain which specifically binds human PD-1, and comprises complementarity determining region (CDR) 1, CDR2 and CDR3, in a combination selected from (a)-(r) as follows, wherein the antibody (Ab), heavy chain (HC) or light chain (LC) and CDR nomenclature system (Kabat, IMGT or composite) from which the CDR combinations derive are shown in the first column, and residues in bold text are Kabat system, and residues underlined are IMGT system:

2. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

3. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

4. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

5. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

6. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

7. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

8. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

9. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

10. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

11. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

12. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

13. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

14. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

15. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

16. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

17. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

18. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

19. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

20. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) comprising a CDR1, CDR2 and CDR3 combination selected from (g), (h) and (i), and a light chain variable region (Vk) comprising a CDR1, CDR2 and CDR3 combination selected from (j), (k) and (l).

21. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in a combination select from (c), (f), (i), (l), (o) and (r), as follows:

22. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) or a light chain variable region (Vk), comprising a sequence selected from the group consisting of:

23. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) and a light chain variable region (Vk) comprising a sequence selected from the group consisting of:

24. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) or a light chain variable region (Vk) comprising:

317-4B6 H (SEQ ID NOS;

24) or 317-4B6 L (SEQ NOS;

26).

25. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) and a light chain variable region (Vk) comprising:

317-4136 H (SEQ ID NOS;

24) and 317-4B6 L (SEQ NOS;

26).

26. An antibody antigen binding domain according to claim 1 which specifically binds PD1 residues:

K45 and I93 (equivalent to K58 and I106 in SEQ ID NO

     2).

27. An antibody antigen binding domain according to claim 1 which induces IL-2 release in PD-1-transformed cells co-cultured with OS8/PD-L1 or OS8/PD-L2 cotransformed cells, and/or inhibits of IL-2 secretion in P3Z-transformed cells co-cultured with PD-L1- or PD-L2-transformed cells, wherein:

OS8 (SEQ ID NO;

89) is a membrane-anchored chimeric Ab constructed by fusing the single chain variable fragment (scFv) of an anti-human CD3 mAb OKT3 to the C-terminal domain (113-220) of mouse CD8α

; and

P3Z (SEQ ID NO;

90) is a chimeric PD-1 receptor, constructed by fusing the extracellular and transmembrane domains of human PD-1 to the cytoplasmic domain of human CD3ζ

chain.

28. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 1.

29. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 20.

30. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 25.

31. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 1 and an IgG4 heavy chain effector or constant domain comprising any of SEQ ID NO:

83-88.

32. An IgG antibody comprising an antibody antigen binding domain according to claim 1 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

33. An IgG antibody comprising an antibody antigen binding domain according to claim 20 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

34. An IgG antibody comprising an antibody antigen binding domain according to claim 25 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

35. A method of using an antibody antigen binding domain according to claim 1 comprising the step of administering the domain to a person determined to have cancer or a viral infection or to otherwise be in need of PD-I antagonism.