Compositions of PD-1 antagonists and methods of use

• US 8,709,416 B2
• Filed: 12/20/2011
• Issued: 04/29/2014
• Est. Priority Date: 08/25/2008
• Status: Expired due to Fees

• Current Assignee: Medimmune LLC (Astrazeneca PLC)
• Original Assignee: Amplimmune, Inc. (Astrazeneca PLC)
• Inventors: Langermann, Solomon, Liu, Linda
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US13/332,164
• Publication Number:
  US 20120114649A1
• Time in Patent Office: 861 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 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 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/70532 : B7 molecules, e.g. CD80, CD86
• 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: 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

Methods of treating cancer and infectious diseases utilizing a treatment regimen comprising administering a compound that reduces inhibitory signal transduction in T cells, in combination with a potentiating agent, such as cyclophosphamide, to produce potent T cell mediated responses, are described. Compositions comprising the PD-1 antagonists and potentiating agents useful in the methods of the invention are also disclosed.

Claims

1. A method of increasing a T cell response in a human comprising administering to the subject an anti-PD-1 antibody or an antigen binding fragment thereof in combination with a potentiating agent selected from the group consisting of cyclophosphamide and an analog of cyclophosphamide,

wherein administration of the anti-PD-1 antibody or antigen binding fragment thereof in combination with the potentiating agent increases a T cell response,

wherein the dose of the potentiating agent is less than 200 mg/kg,

wherein the dose of the potentiating agent is not effective to have direct anti-tumor activity,

and wherein the T cell response achieved by the combination of anti-PD-1 antibody and the potentiating agent is greater than the T cell response achieved by administering either the anti-PD-1 antibody alone or the potentiating agent alone.

2. The method of claim 1 wherein the anti-PD-1 antibody or antigen binding fragment thereof inhibits, reduces, modulates or abolishes signal transduction mediated by PD-1.

3. The method of claim 1 wherein the anti-PD-1 antibody is a human anti-PD-1 antibody or antigen binding fragment thereof.

4. The method of claim 1 wherein the antigen binding fragment is a Fab, F(ab′

)₂, or Fv fragment.

5. The method of claim 1 wherein the anti-PD-1 antibody or antigen binding fragment thereof is a humanized, chimeric, or single-chain antibody or fragment thereof.

6. The method of claim 1 wherein the potentiating agent reduces the activity of regulatory T lymphocytes (Tregs).

7. The method of claim 1 wherein the amount of potentiating agent is sub-therapeutic in the absence of the anti-PD-1 antibody or an antigen binding fragment thereof.

8. The method of claim 1 wherein the dose of the potentiating agent is 8 mg/kg of cyclophosphamide or an analog of cyclophosphamide.

9. The method of claim 1 further comprising administering an additional immunomodulatory agent.

10. The method of claim 1 further comprising administering an additional agent selected from the group consisting of an anti-CTLA4 antibody, a mitosis inhibitor, an aromatase inhibitor, an A2a adenosine receptor (A2AR) antagonist, and an angiogenesis inhibitor.

11. The method of claim 10 wherein the angiogenesis inhibitor is a VEGF inhibitor.

12. The method of claim 11 wherein the VEGF inhibitor is bevacizumab or VEGF-Trap.

13. The method of claim 1 wherein the potentiating agent is administered before the anti-PD-1 antibody or antigen binding fragment thereof.

14. The method of claim 13 wherein the potentiating agent is administered at least 1, 2, 3, 5, 10, 15, 20, 24, or 30 hours before the anti-PD-1 antibody or antigen binding fragment thereof.

15. The method of claim 1 wherein the anti-PD-1 antibody or antigen binding fragment thereof and the potentiating agent are administered to a subject having cancer or an infection.

16. The method of claim 15 wherein the cancer is selected from the group consisting of a bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, uterine, ovarian, testicular, and hematologic cancer.

17. The method of claim 15 wherein the cancer is selected from the group consisting of gastric cancer, glioma, leukemia, melanoma, multiple myeloma, renal cell carcinoma, and urothelial cancer.

18. The method of claim 15 wherein the cancer is melanoma.

19. The method of claim 15 wherein the infection is a viral infection.

20. The method of claim 19 wherein the viral infection is selected from the group consisting of, papilloma, herpes, encephalitis, influenza, hepatitis, and the common cold.

21. The method of claim 19 wherein the viral infection is caused by a virus selected from the group consisting of, human papilloma virus (HPV), herpes simplex virus (HSV), human influenza virus A, hepatitis C virus (HCV), hepatitis B virus (HBV), and human rhinovirus.

22. The method of claim 15 wherein the infection is a non-viral infection.

23. The method of claim 22 wherein the non-viral infection is caused by a microorganism selected from the group consisting of Actinomyces, Anabaena, Bacillus, Bacteroides, Bdellovibrio, Bordetella, Borrelia, Campylobacter, Caulobacter, Chlamydia, Chlorobium, Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus, Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus, Hemophilus influenza type B (HIB), Hyphomicrobium, Legionella, Leptspirosis, Listeria, Meningococcus A, B and C, Methanobacterium, Micrococcus, Myobacterium, Mycoplasma, Myxococcus, Neisseria, Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas, Phodospirillum, Rickettsia, Salmonella, Shigella, Spirillum, Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus, Thermoplasma, Thiobacillus, Treponema, Vibrio, Yersinia, Cryptococcus neoformans, Histoplasma sp. (such as Histoplasma capsulatum), Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Leishmania, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium sp. (such as Plasmodium falciparum), Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis and Schistosoma mansoni.

27. The method of claim 15 wherein the T cell response against the cancer achieved by the combination of the anti-PD1 antibody and the potentiating agent is greater than the T cell response against the cancer achieved by administering either the anti-PD 1 antibody alone or the potentiating agent alone.

28. The method of claim 1 wherein the dosage of potentiating agent is 5 mg/kg.

24. A pharmaceutical dosage unit comprising an anti-PD-1 antibody or an antigen binding fragment thereof and a potentiating agent selected from the group consisting of cyclophosphamide and an analog of cyclophosphamide,

wherein administration of the dosage unit to a subject increases a T cell response in the subject,

wherein the dose of the potentiating agent is less than 200 mg/kg,

wherein the dose of potentiating agent is not effective to have direct anti-tumor activity,

and wherein the T cell response achieved by the dosage unit is greater than the T cell response achieved by administering either the anti-PD-1 antibody alone or the potentiating agent alone.

25. A method of increasing T cell response in a human comprising administering to a human the pharmaceutical dosage unit of claim 24.

26. The pharmaceutical dosage unit of claim 24 further comprising an antigen.