# US 11,028,364 B2 · Compositions and methods for modulating an immune response

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,028,364 B2
- Document ID: US11028364B2
- Status: Granted
- Kind: B2
- Application number: 15/778,524
- Filed: 2016-11-23
- Published: 2018-11-29
- Granted: 2021-06-08
- Earliest claimed: 2015-11-23
- Assignees: President and Fellows of Harvard College
- Applicants: President and Fellows of Harvard College
- Inventors: Peter T. Sage; Arlene H. Sharpe
- Web page: https://patentgrep.com/patent/US11028364B2

## CPC

- C12N 5/0637: {Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg}
- A61K 35/26: Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/22: Immunosuppressive or immunotolerising
- A61K 40/42: Cancer antigens
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- A61K 2039/515: {Animal cells}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55522: {Cytokines; Lymphokines; Interferons}
- A61K 2039/55527: {Interleukins}
- C07K 16/248: {IL-6}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C12N 2501/2302: Interleukin-2 (IL-2)
- C12N 2501/2306: Interleukin-6 (IL-6)
- C12N 2501/2321: Interleukin-21 (IL-21)
- C12N 2501/515: CD3, T-cell receptor complex
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention provides methods of modulating follicular regulatory T (TFR) cell-mediated immune responses and the use of those methods in the treatment of diseases or conditions such as viral, bacterial, pathogenic, or fungal infections or cancer. Such methods provide for boosting of antibody production through the use of IL-21 to overcome TFR cell suppression of antibody production.

## Claims

### Claim 1

A composition comprising T follicular regulatory (TFR) cells and a cytokine, wherein said composition has reduced immune suppressive activity,
wherein the reduced immune suppressive activity results in a protective antibody response, and
wherein the cytokine is IL-21 or IL-6.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the reduced immune suppressive activity is characterized by a boost in antibody production in vitro and in vivo as compared to native TFR cells.

### Claim 3 (depends on 1)

A method of upregulating an immune response in a subject comprising administering to the subject, an effective amount of the composition of claim 1.

### Claim 4 (depends on 1)

A vaccine comprising the composition of claim 1.

### Claim 5

A method of preparing a composition comprising TFR cells having reduced immune suppressive activity comprising the steps of:
a) obtaining an initial population of cells comprising TFR cells, T regulatory (Treg) progenitor cells, or both;
b) contacting the cells ex vivo in the presence of a cytokine; and
c) isolating the TFR cells from the population wherein the isolated TFR cells have reduced immune suppressive activity,
wherein the reduced immune suppressive activity results in a protective antibody response, and
wherein the cytokine is IL-21 or IL-6.

### Claim 6 (depends on 5)

The method of claim 5, wherein the reduced immune activity results in a boost in antibody production.

### Claim 7 (depends on 5)

The method of claim 5, wherein the initial population of cells is isolated from the peripheral blood, tissues or organs of one or more subjects.

### Claim 8 (depends on 5)

The method of claim 5, further comprising sorting TFR cells and Treg progenitor cells from the cell population prior to contacting the cell with the cytokine.

### Claim 9 (depends on 5)

The method of claim 5, further comprising the step of expanding the cell population.

### Claim 10

A method of modulating an immune response in a subject in need thereof comprising:
administering to the subject a) an effective amount of a composition comprising T follicular regulatory (TFR) cells and a cytokine, wherein the cytokine is IL-21 or IL-6.

### Claim 11 (depends on 10)

The method of claim 10, wherein the TFR cells are administered conjointly or in combination with the cytokine.

### Claim 12 (depends on 10)

The method of claim 10, wherein the TFR cells are contacted with the cytokine prior to administering to the subject.

### Claim 13 (depends on 10)

The method of claim 10, wherein the TFR cells are isolated from the peripheral blood of a subject.

### Claim 14 (depends on 10)

The method of claim 10, wherein the TFR cell modulation results in boosted antibody production.

### Claim 15 (depends on 10)

The method of claim 10, wherein the method further comprises administering a vaccine to the subject.

### Claim 16 (depends on 10)

The method of claim 10, comprising co-administering a composition comprising TFH cells and a vaccine.

### Claim 17 (depends on 10)

The method of claim 10, wherein the composition is administered intravenously.

### Claim 18 (depends on 10)

The method of claim 10, wherein the subject is afflicted with a disease or condition selected from the group consisting viral infection, bacterial infection, pathogenic infection, fungal infection, and cancer.

### Claim 19

An adjuvant comprising a composition of TFH cells and a cytokine, wherein the adjuvant has an increased protective antibody response, wherein the cytokine is IL-21 or IL-6.

### Claim 20 (depends on 19)

The adjuvant of claim 19, wherein the TFH cells are purified from the peripheral blood of a subject.

### Claim 21 (depends on 19)

A method of boosting antibody production in a subject in need thereof comprising administering to the subject the adjuvant of claim 19.