Methods of upmodulating adaptive immune response using anti-PD-1 antibodies

• US 7,521,051 B2
• Filed: 12/22/2003
• Issued: 04/21/2009
• 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: Andrews, John, Valge-Archer, Viia, Collins, Mary, Wood, Clive R., Carreno, Beatriz M., Russell, Caroline, Luxenberg, Deborah, Carter, Laura L., Bennett, Frances K., Jussif, Jason
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US10/540,084
• Publication Number:
  US 20060210567A1
• Time in Patent Office: 1,947 Days
• Field of Search: None
• US Class Current: 424/144.1
• 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. A method of upmodulating adaptive immune response comprising:

contacting a lymphocyte with an isolated anti-PD-1 antibody, wherein the antibody comprises;

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 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.

2. The method of claim 1, wherein the antibody comprises a VH domain selected from the group consisting of SEQ ID NO:

6, SEQ ID NO;

10 and SEQ ID NO;

14;

or a VL domain selected from the group consisting of SEQ ID NO;

8, SEQ ID NO;

12 and SEQ ID NO;

16.

3. The method of claim 1, wherein the antibody specifically binds to the extracellular domain of PD-1 with an affinity constant greater than 10⁷ M⁻

1.

4. The method of claim 1, wherein the antibody inhibits the binding of PD-L1 or PD-L2 to PD-1 with an IC₅₀ of less than 10 nM.

5. The method of claim 1, wherein the antibody is a human antibody.

6. The method of claim 1, wherein the antibody is IgG₁ or IgG₄.

7. The method of claim 6, wherein the antibody is IgG_1λ

or IgG_1k.

8. The method of claim 1, wherein the antibody is selected from the group consisting of:

an antibody comprising a VH domain of SEQ ID NO;

6 and a VL domain of SEQ ID NO;

8;

an antibody comprising a VH domain of SEQ ID NO;

10 and a VL domain of SEQ ID NO;

12; and

an antibody comprising a VH domain of SEQ ID NO;

14 and a VL domain of SEQ ID NO;

16.

9. The method of claim 1, wherein the lymphocyte is a T cell, B cell or monocyte.

10. The method of claim 1, wherein the antibody is immobilized on a support matrix or crosslinked.

11. The method of claim 1, wherein the support matrix comprises one or more material chosen from agarose, dextran, cellulose, PVDF, silica, nylon, dacron, polystyrene, polyacrylates, polyvinyls, teflons, polyglycolic acid, polyhydroxyalkanoate, collagen and gelatin.

12. The method of claim 1, wherein the anti-PD-1 antibody modulates immune cell response mediated by an antigen receptor.

13. The method of claim 12, wherein the antigen receptor signal is co-presented with the anti-PD-1 antibody.

14. The method of claim 12, wherein the antigen receptor signal and anti-PD-1 antibody are spaced by no more than 100 μ

m.

15. The method of claim 12, wherein the antigen receptor signal is delivered by an anti-CD3 antibody.