Antibodies against PD-1

• US 7,488,802 B2
• Filed: 12/22/2003
• Issued: 02/10/2009
• Est. Priority Date: 12/23/2002
• Status: Expired due to Fees

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC), Wyeth (Pfizer Inc.)
• Original Assignee: MedImmune Ltd. (Astrazeneca PLC), Wyeth (Pfizer Inc.)
• Inventors: Valge-Archer, Vila, Collins, Mary, Wood, Clive R., Andrews, John, Carreno, Beatriz M., Russell, Caroline, Luxenberg, Deborah, Carter, Laura L., Bennett, Frances K., Jussif, Jason
• Primary Examiner(s): Ouspenski; Ilia
• Application Number:
  US10/741,481
• Publication Number:
  US 20040213795A1
• Time in Patent Office: 1,877 Days
• Field of Search: None
• US Class Current: 530/387.1
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• 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

Abstract

This disclosure provides antibodies and antigen-binding fragments that can act as agonists and/or antagonists of PD-1 (Programmed Death 1), thereby modulating immune responses in general, and those mediated by TcR and CD28, in particular. The disclosed compositions and methods may be used for example, in treating autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer, and other immune system disorders.

Claims

1. An isolated antibody comprising:

a VH domain comprising SEQ ID NO;

6, SEQ ID NO;

10 , SEQ ID NO;

14 or SEQ ID NO;

47,

wherein the antibody specifically binds an epitope within the extracellular domain of human or mouse PD-1.

5. The isolated antibody of claim 1, wherein the antibody comprises:

a VH domain comprising SEQ ID NO;

6; and

a VL domain comprising SEQ ID NO;

8.

6. The isolated antibody of claim 1, wherein the antibody comprises:

a VH domain comprising SEQ ID NO;

10; and

a VL domain comprising SEQ ID NO;

12.

7. The isolated antibody of claim 1, wherein the antibody comprises:

a VH domain comprising SEQ ID NO;

14; and

a VL domain comprising SEQ ID NO;

16.

8. The isolated antibody of claim 1, wherein the antibody comprises:

a VH domain comprising SEQ ID NO;

47; and

a VL domain comprising SEQ ID NO;

49.

9. The isolated antibody of claim 1, wherein the antibody comprises a VL domain comprising SEQ ID NO:

8.

10. The isolated antibody of claim 1, wherein the antibody comprises a VL domain comprising SEQ ID NO:

12.

11. The isolated antibody of claim 1, wherein the antibody comprises a VL domain comprising SEQ ID NO:

16.

12. The isolated antibody of claim 1, wherein the antibody comprises a VL domain comprising SEQ ID NO:

49.

13. The isolated antibody of any one of claims 1-3, wherein the antibody is an antigen binding fragment Fab, F(ab′

)₂, Fv, scFv, Fd or dAb.

14. The isolated antibody of any one of claims 1-3,

wherein the antibody specifically binds to the extracellular domain of PD-1 with an affinity constant greater than 10⁷ M⁻

1.

15. The isolated antibody of any one of claims 1-3,

where the antibody inhibits the binding of PD-L1 or PD-L2 to PD-1 with an IC₅₀ of less than 10nM.

16. The isolated antibody of any one of claims 1-3,

wherein the antibody is a human antibody.

17. The isolated antibody of any one of claims 1-3,

wherein the antibody is IgG₁ or IgG₄.

18. The isolated antibody of any one of claims 1-3,

wherein the antibody is IgG_1λ

or IgG_1κ

.

19. A pharmaceutical composition comprising the isolated antibody of any one of claims 1-3, 4-12.

2. An isolated antibody comprising:

a VL domain comprising SEQ ID NO;

8, SEQ ID NO;

12, SEQ ID NO;

16 or SEQ ID NO;

49,

wherein the antibody specifically binds an epitope within the extracellular domain of human or mouse PD-1.

20. The isolated antibody of claim 2, wherein the antibody comprises a VL domain comprising SEQ ID NO:

8.

21. The isolated antibody of claim 2, wherein the antibody comprises a VL domain comprising SEQ ID NO:

12.

22. The isolated antibody of claim 2, wherein the antibody comprises a VL domain comprising SEQ ID NO:

16.

23. The isolated antibody of claim 2, wherein the antibody comprises a VL domain comprising SEQ ID NO:

49.

3. An isolated antibody comprising:

a VH domain or an antigen-binding fragment thereof that comprises 3 CDRs; and

a VL domain or an antigen-binding fragment thereof that comprises 3 CDRs;

wherein the antibody comprises at least 3 VH domain CDRs having sequences of;

SEQ ID NO;

23, SEQ ID NO;

24 and SEQ ID NO;

25;

or

SEQ ID NO;

29, SEQ ID NO;

30 and SEQ ID NO;

31;

or

SEQ ID NO;

35, SEQ ID NO;

36 and SEQ ID NO;

37;

or

SEQ ID NO;

50, SEQ ID NO;

51 and SEQ ID NO;

52;

or at least 3 VL domain CDRs having sequences of;

SEQ ID NO;

26, SEQ ID NO;

27 and SEQ ID NO;

28;

or

SEQ ID NO;

32, SEQ ID NO;

33 and SEQ ID NO;

34;

or

SEQ ID NO;

38, SEQ ID NO;

39 and SEQ ID NO;

40;

or

SEQ ID NO;

53, SEQ ID NO;

54, and SEQ ID NO;

55; and

wherein the antibody specifically binds an epitope within the extracellular domain of human or mouse PD-1.

4. An antibody produced by steps comprising:

(a) providing a nucleic acid encoding 3 VL domain CDRs having sequences of;

SEQ ID NO;

26, SEQ ID NO;

27 and SEQ ID NO;

28;

or SEQ ID NO;

32, SEQ ID NO;

33 and SEQ ID NO;

34;

or SEQ ID NO;

38, SEQ ID NO;

39 and SEQ ID NO;

40;

or SEQ ID NO;

53, SEQ ID NO;

54, and SEQ ID NO;

55;

(b) combining a repertoire of nucleic acids encoding 3 VH domain CDRs with the nucleic acid encoding the 3 VL domain CDRs, so as to provide a product repertoire of nucleic acids encoding the 3 VL domain CDRs and the repertoire of 3 VH domain CDRs

(c) expressing the nucleic acids of the product repertoire;

(d) selecting an antigen-binding fragment comprising a variable domain that specifically binds to PD-1 and that is expressed from the nucleic acids of the product repertoire; and

(e) producing an antibody comprising the antigen-binding fragment.