METHODS AND COMPOSITIONS FOR THE TREATMENT OF PERSISTENT INFECTIONS AND CANCER BY INHIBITING THE PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY

• US 20160362492A1
• Filed: 08/30/2016
• Published: 12/15/2016
• Est. Priority Date: 06/08/2005
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Emory University, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Brigham and Women's Hospital Incorporated, Dana-Farber Cancer Institute, Emory University, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Freeman, Gordon, Sharpe, Arlene, Dorfman, David M., Ahmed, Rafi, Barber, Daniel, Wherry, E. John
• Granted Patent: US 10,370,446 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/1709 from mammals
• 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: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 31/18 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 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 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/70 : characterized by effect upon binding to a cell or to an antigen
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 15/1138 : against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: G01N 2800/26 : Infectious diseases, e.g. generalised sepsis
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/505 : involving T-cells
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
• CPC Class Codes: G01N 33/57492 : involving compounds localized on the membrane of tumor or cancer cells
• 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

The present invention provides methods and compositions for the treatment, prevention, or reduction of persistent infections, such as chronic infections, latent infections, and slow infections and cancer. The methods and compositions of the invention are also useful for the alleviation of one or more symptoms associated with such infections and cancer.

Claims

1. A method of increasing cytotoxic activity of anergic T cells in a subject having a lymphoproliferative cancer, comprising

administering to the subject having the lymphoproliferative cancer an effective amount of an agent that reduces the activity of a Programmed Cell Death (PD)-1 polypeptide, wherein the agent is an anti-PD-1 antibody,

thereby increasing the cytotoxic activity of anergic T cells in the subject with the lymphoproliferative cancer, wherein the lymphoproliferative cancer is a Hodgkin'"'"'s lymphoma.

2. The method of claim 1, wherein increasing the cytotoxic activity of allergic T cells comprises increasing cytokine production or T cell proliferation.

4. The method of claim 1, further comprising measuring cytotoxic T cell activity in a biological sample from the subject.

5. The method of claim 4, wherein measuring cytotoxic T cell activity comprises measuring the cytotoxic activity of anergic CD8+ T cells in the biological sample from the subject.

6. The method of claim 4, wherein measuring cytotoxic T cell activity comprises measuring the production of a cytokine by T cells in the biological sample from the subject.

7. The method of claim 6, wherein the cytokine is interferon γ

, tumor necrosis factor α

or interleukin-2.

8. The method of claim 1, wherein the Hodgkin'"'"'s lymphoma is a nodular lymphocyte predominant Hodgkin'"'"'s lymphoma.

9. The method of claim 1, wherein the method further comprises administering to the subject an effective amount of a second compound that induces an immune response.

10. The compound of claim 9, wherein the second compound is an anti-inflammatory compound, an antineoplastic compound or an analgesic.

11. The method of claim 9, wherein the second compound is an anti-CTLA-4 antibody, an anti-BTLA antibody, or an anti-B7-H4 antibody.

12. The method of claim 11, wherein the second compound reduces cancer cell volume.

13. The method of claim 1, wherein the antibody is a monoclonal antibody, a humanized antibody, a deimmunized antibody, or an immunoglobulin (Ig) fusion protein.

14. The method of claim 1, wherein the subject is human.

15. The method of claim 1, wherein the method decreases a symptom of the lymphoproliferative cancer in the subject.

16. The method of claim 1, wherein the method decreases the size of the tumor or the prevalence of cancer cells.

3. The method of claim 3, wherein the cytokine is interferon γ

, tumor necrosis factor α

or interleukin-2.

17. A method of increasing cytotoxic activity of anergic T cells in a subject having a lymphoproliferative cancer, comprising

administering to the subject having the lymphoproliferative cancer an effective amount of (a) an agent that reduces the activity of a Programmed Cell Death (PD)-1 polypeptide, wherein the agent is an anti-PD-1 antibody or an anti-Programmed Cell Death Ligand (PD-L1) antibody, and (b) an anti-CTLA-4 antibody,

thereby increasing the cytotoxic activity of anergic T cells in the subject with the lymphoproliferative cancer, wherein the lymphoproliferative cancer is a Hodgkin'"'"'s lymphoma or angioimmunoblastic T cell lymphoma.

18. The method of claim 17, wherein the Hodgkin'"'"'s lymphoma is a nodular lymphocyte predominant Hodgkin'"'"'s lymphoma.

19. The method of claim 17, wherein the subject is human.

20. The method of claim 17, wherein the anti-PD-L1 antibody is a monoclonal antibody, a humanized antibody, a deimmunized antibody, or an immunoglobulin (Ig) fusion protein.

21. The method of claim 17, wherein the anti-PD-1 antibody is a monoclonal antibody, a humanized antibody, a deimmunized antibody, or an immunoglobulin (Ig) fusion protein.