# US 10,370,446 B2 · Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway

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- Number: US 10,370,446 B2
- Document ID: US10370446B2
- Status: Granted
- Kind: B2
- Application number: 15/252,133
- Filed: 2016-08-30
- Published: 2016-12-15
- Granted: 2019-08-06
- Earliest claimed: 2005-06-08
- Assignees: Emory University; Dana-Farber Cancer Institute, Inc.; The Brigham and Women's Hospital, Inc.; President and Fellows of Harvard College
- Applicants: Emory University; Dana-Farber Cancer Institute, Inc.; Brigham and Women's Hospital; President and Fellows of Harvard College
- Inventors: Gordon Freeman; Arlene Sharpe; David M. Dorfman; Rafi Ahmed; Daniel Barber; E. John Wherry
- Web page: https://patentgrep.com/patent/US10370446B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/1709: {from mammals}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C12N 15/1138: {against receptors or cell surface proteins}
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 33/505: {involving T-cells}
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/55516: {Proteins; Peptides}
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- A61K 2039/572: {cytotoxic response}
- C07K 2317/70: characterized by effect upon binding to a cell or to an antigen
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/74: Inducing cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2310/14: interfering nucleic acids [NA]
- G01N 2800/26: Infectious diseases, e.g. generalised sepsis
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO 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

### Claim 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

The method of claim 2, wherein the cytokine is interferon γ, tumor necrosis factor α or interleukin -2.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 4)

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.

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 6)

The method of claim 6, wherein the cytokine is interferon γ, tumor necrosis factor α or interleukin -2.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 9)

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.

### Claim 12 (depends on 11)

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

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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

### Claim 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.

### Claim 18 (depends on 17)

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

### Claim 19 (depends on 17)

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

### Claim 20 (depends on 17)

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.

### Claim 21 (depends on 17)

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.