SIMULTANEOUS INHIBITION OF PD-L1/PD-L2

• US 20130017199A1
• Filed: 11/24/2010
• Published: 01/17/2013
• Est. Priority Date: 11/24/2009
• Status: Abandoned Application

• Current Assignee: Amplimmune, Inc. (Astrazeneca PLC)
• Original Assignee: Amplimmune Incorporated A Corporation
• Inventors: Langermann, Solomon
• Application Number:
  US13/511,879
• Publication Number:
  US 20130017199A1
• Time in Patent Office: Days
• US Class Current: 424/134.1
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• 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 31/14 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 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Methods and compositions for treating an infection or disease that results from (1) failure to elicit rapid T cell mediated responses, (2) induction of T cell exhaustion, T cell anergy or both, or (3) failure to activate monocytes, macrophages, dendritic cells and/or other APCs, for example, as required to kill intracellular pathogens. The method and compositions solve the problem of undesired T cell inhibition by simultaneously inhibiting the PD-1 ligands, PD-L1 and PD-L2. The immune response can be modulated by providing antagonists which bind with different affinity, by varying the dosage of agent which is administered, by intermittent dosing over a regime, and combinations thereof, that provides for dissociation of agent from the molecule to which it is bound prior to being administered again. In some cases it may be particularly desirable to stimulate the immune system, then remove the stimulation.

Claims

1. A method of modulating an immune response comprising administering to a subject an effective amount of an immunomodulatory agent to increase IFNγ

producing cells and decrease Treg cells at a tumor site or a pathogen infected area of the subject.

4. The method of claim 1, wherein the immunomodulatory agent simultaneously blocks the binding of endogenous PD-L1 and PD-L2 to PD-1.

5. The method of claim 1, wherein the immunomodulatory agent binds to PD-1.

6. The method of claim 1, wherein the immunomodulatory agent is selected from the group consisting of PD-1, PD-L1, PD-L2, B7.1, fusion proteins thereof and bispecific antibodies that specifically bind to both PD-L1 and PD-L2.

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

8. The method of claim 1, wherein more than one immunomodulatory agent is administered.

9. The method of claim 1, wherein the infection is a chronic viral infection, a bacterial infection, a fungal infection, a mycoplasm infection, a parasitic infection, elicits disease mediated by a toxin during the acute phase of infection or where the infection is characterized by reduced T cell response.

10. The method of claim 9, wherein the viral infection is an infection with a hepatitis virus, a human immunodeficiency virus, a human T-lymphotrophic virus, a herpes virus, an Epstein-Barr virus, filovirus, a human papilloma virus, an Epstein Barr virus, an influenza virus, a respiratory synticial virus, an encephalitis virus, a dengue fever virus, and a papilloma virus.

11. The method of claim 9, wherein the parasitic infection is malaria or Leishmania.

12. The method of claim 9, wherein the bacterial infection is caused by a bacterium selected from the group consisting of Mycobacterium tuberculosis, Bacillus anthracis, Staphylococcus, Listeria, and Clamydia trachomatis.

13. The method of claim 1, further comprising administering a disease antigen in combination with the immunomodulatory agent to enhance an immune response against the disease.

14. The method of claim 1, wherein the immunomodulatory agent is a fusion protein of a PD-1 ligand.

15. The method of claim 14, wherein the PD-1 ligand is a variant PD-1 ligand that has increased affinity for PD-1 as compared to a wild-type PD-1 ligand.

16. The method of claim 14, wherein the fusion protein comprises the extracellular domain of PD-L2 or a fragment thereof capable of binding to PD-1.

17. The method of claim 16, wherein the fusion protein has an amino acid sequence according to SEQ ID NO:

60.

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

19. The method of claim 18, wherein the additional active agent is an agent that depletes or inhibits the function of CD4+CD25+ Tregs.

20. The method of claim 18, wherein the agent that depletes or inhibits the function of CD4+CD25+ Tregs is cyclophosphamide.

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

22. The method of claim 1, wherein the tumor is selected from the group consisting of sarcoma, melanoma, lymphoma, neuroblastoma, and carcinoma.

2. A method of modulating an immune response comprising administering to a subject an effective amount of an immunomodulatory agent to increase the number of Th17 cells or the level of IL-17 production at a tumor site or a pathogen infected area of the subject.

3. A method of modulating an immune response comprising administering to a subject an effective amount of an immunomodulatory agent to reduce the number of PD-1 positive cells at a tumor site or a pathogen infected area of the subject.

23. A composition comprising an immunomodulatory agent that increases IFNγ

producing cells and decreases Treg cells at a tumor site or a pathogen infected area of a subject in combination with one or more disease antigens.

24. A composition comprising an immunomodulatory agent that increases IFNγ

producing cells and decreases Treg cells at a tumor site or a pathogen infected area of a subject in combination with a vaccine.