PD-1 ANTAGONISTS AND METHODS OF USE THEREOF

• US 20110195068A1
• Filed: 08/25/2009
• Published: 08/11/2011
• Est. Priority Date: 08/25/2008
• Status: Abandoned Application

• Current Assignee: Medimmune LLC (Astrazeneca PLC)
• Original Assignee: Medimmune LLC (Astrazeneca PLC)
• Inventors: Liu, Linda, Langermann, Solomon
• Application Number:
  US13/060,998
• Publication Number:
  US 20110195068A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• 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 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/06 Antimalarials
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/4748 : Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
• CPC Class Codes: C07K 14/521 : Chemokines
• CPC Class Codes: C07K 14/70532 : B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 14/7158 : for chemokines
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C12N 15/62 : DNA sequences coding for fusion proteins
• 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

Compositions and methods for enhancing and/or prolonging the activation of T cells (i.e., increasing antigen-specific proliferation of T cells, enhancing cytokine production by T cells, stimulating differentiation ad effector functions of T cells and/or promoting T cell survival) or overcoming T cell exhaustion and/or anergy are provided. Suitable compositions include PD-1 receptor antagonists that bind to and block the endogenous PD-1 receptor without triggering inhibitory signals from PD-1, or bind to and block PD-1 receptor ligands and preventing them from interacting with PD-1 receptors. Methods for using the PD-1 receptor antagonists to enhance immune responses in subjects in need thereof are provided.

Claims

1. A method of modulating an immune response comprising administering an effective amount a PD-1 antagonist to induce, augment, or enhance an immune response against a tumor, wherein the dose of the molecule, the timing of administration of the molecule and/or the affinity of the molecule allows for intermittent access of a ligand to the PD-1 receptor.

2. The method of claim 1 wherein the PD-1 antagonist inhibits or reduces binding of endogenous PD-L1 to PD-1.

3. The method of claim 1 wherein the PD-1 antagonist inhibits or reduces binding of endogenous PD-L2 to PD-1.

4. The method of claim 1 wherein the PD-1 antagonist binds to PD-1.

5. The method of claim 1 wherein the PD-1 antagonist is selected from the group consisting of PD-1, PD-L1, PD-L2, B7.1, and fragments thereof.

6. The method of claim 1 wherein the molecule binds to PD-1 or a ligand thereof for three months or less after in vivo administration.

7. The method of claim 1 wherein more than one PD-1 antagonist is administered.

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

bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, uterine, ovarian, testicular and hematologic.

9. The method of claim 1 further comprising administering a tumor antigen in combination with the PD-1 antagonist to enhance an immune response against the tumor.

10. The method of claim 1, wherein the PD-1 antagonist is a fusion protein of a PD-1 ligand.

11. The method of claim 10, wherein the fusion protein comprises the extracellular domain of PD-L2 or a fragment thereof capable of binding to PD-1.

12. The method of claim 11 wherein the fusion protein has an amino acid sequence according to SEQ ID NO:

57.

13. The method of claim 1, further comprising administering with the PD-1 antagonist an additional active agent selected from the group consisting of immunomodulators, agents that deplete or inhibit the function of Tregs, and costimulatory molecules.

16. The method of claim 1 for enhancing antigen presenting cell function comprising contacting APCs with a PD-1 antagonist in an amount effective to inhibit, reduce, or block PD-1 signal transduction in the APCs or enhance clearance of diseased.

17. A composition comprising an effective amount of a PD-1 receptor antagonist to bind to a ligand of a PD-1 receptor in vivo and reduce or inhibit PD-1 receptor signal transduction.

14. The method of claim 17, wherein the additional active agent is an agent that depletes or inhibits the function of CD4+CD25+ Tregs.

15. The method of claim 17, wherein the agent that depletes or inhibits the function of CD4+CD25+ Tregs is cyclophosphamide.

18. The composition of claim 17 wherein the PD-1 antagonist comprises a B7-DC polypeptide or fragment thereof that binds B7-H1 polypeptide and inhibits or reduces binding of the B7-H1 polypeptide to the PD-1 receptor.

19. The composition of claim 18 wherein the fragment comprises the extracellular domain of B7-DC or fragment thereof that binds B7-H1 or the extracellular domain of B7-H1 or fragment thereof that binds B7-DC.

20. The composition of claim 17 wherein the PD-1 antagonist comprises a fusion protein.

21. The composition of claim 20 wherein the fusion proteins binds the PD-1 receptor without triggering signal transduction through the PD-1 receptor.

22. The composition of claim 17 wherein the PD-1 receptor antagonist comprises a B7-H1 polypeptide that binds to B7-DC polypeptide and inhibits or reduces binding of the B7-DC polypeptide to PD-1 receptors.

23. The composition of claim 22 wherein the PD-1 receptor antagonist comprises a fusion protein.

24. A composition comprising an effective amount of a polypeptide to bind PD-1 in vivo without triggering signal transduction through PD-1.

25. The composition of claim 24 wherein the polypeptide comprises a B7-DC or B7-H1 polypeptide modified so that it binds to PD-1 without triggering signal transduction.

26. The composition of claim 24 wherein the polypeptide comprises a variant extracellular domain of B7-DC or B7-H1 modified so that the polypeptide binds to PD-1 without triggering signal transduction through PD-1.

27. A fusion polypeptide comprising:

a) a first fusion partner, and

b) a second fusion partner,

wherein the first fusion partner comprises a variant extracellular domain or fragment thereof of a ligand of PD-1 modified to bind PD-1 without triggering signal transduction through PD-1 and wherein the first fusion partner is fused directly to the second fusion partner, or optionally, is fused to a linker sequence that is fused to the second fusion partner.

28. The fusion polypeptide of claim 27 wherein the second fusion partner comprises one or more domains of an Ig heavy chain constant region.

29. The fusion polypeptide of claim 28 wherein the second polypeptide comprises an amino acid sequence corresponding to the hinge, C_H2 and C_H3 regions of a human immunoglobulin Cγ

1 chain.

30. The fusion polypeptide of claim 27, wherein the first polypeptide comprises the extracellular domain of B7-DC or B7-H1 modified to bind PD-1 without triggering signal transduction through PD-1.