# US 8,772,026 B2 · Enhancement of immune responses by 4-1 BB-binding agents

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- Number: US 8,772,026 B2
- Document ID: US8772026B2
- Status: Granted
- Kind: B2
- Application number: 13/426,151
- Filed: 2012-03-21
- Published: 2012-09-06
- Granted: 2014-07-08
- Earliest claimed: 2001-10-09
- Assignees: Mayo Foundation for Medical Education and Research
- Applicants: Lieping Chen; Scott E. Strome
- Inventors: Lieping Chen; Scott E. Strome
- Web page: https://patentgrep.com/patent/US8772026B2

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/12: Viral antigens
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/19: Dendritic cells
- A61K 40/24: Antigen-presenting cells [APC]
- A61K 40/428: {Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/55516: {Proteins; Peptides}
- A61K 2039/55522: {Cytokines; Lymphokines; Interferons}
- A61K 2039/585: {wherein the target is cancer}
- A61K 2239/31: characterized by the route of administration
- C12N 2710/20034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

This invention features methods of enhancing immune responses in mammalian subjects and in vitro methods of enhancing the response of a T cell. Also embodied by the invention are methods of receiving and preventing the induction of energy in T cells.

## Claims

### Claim 1

A method of treating a subject that has, or is at high risk of developing, cancer, the method comprising administering to the subject a population of cells comprising an activated T cell obtained by a procedure comprising exposing in culture a cell sample comprising T cells to (i) an immunogenic stimulus, wherein the immunogenic stimulus comprises an immunogenic molecule produced by a tumor cell, or a peptide epitope of such a molecule, but does not comprise a tumor cell, and (ii) an agonistic antibody, or an antibody fragment, that binds to 4-1BB.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cells of the cell sample are from the subject.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The method of claim 1, wherein the procedure comprises multiple exposures.

### Claim 5 (depends on 4)

The method of claim 4, wherein the level of immune activity of exposed cells is tested after one or more exposures.

### Claim 6 (depends on 5)

The method of claim 5, wherein the immune activity is cytotoxic T lymphocyte (CTL) activity.

### Claim 7 (depends on 5)

The method of claim 5, wherein the immune activity is helper T cell activity.

### Claim 8 (depends on 1)

The method of claim 1, wherein, prior to the procedure, the T cells in the cell sample are anergic.

### Claim 9 (depends on 1)

The method of claim 1, wherein the cell sample comprises CD4+T cells, CD8+T cells, or CD4+T cells and CD8+T cells.

### Claim 10 (depends on 1)

The method of claim 1, wherein the activated T cell exerts a neutralizing effect or a cytotoxic effect on tumor cells in the subject.

### Claim 11 (depends on 1)

The method of claim 1, wherein the culture further comprises one or more cytokines or growth factors.

### Claim 12 (depends on 1)

The method of claim 1, wherein the immunogenic stimulus comprises, a tumor cell lysate, a tumor-associated antigen (TAA), a peptide epitope of a TAA, or a heat shock protein bound to a peptide epitope of a protein expressed by a tumor cell.

### Claim 13 (depends on 12)

The method of claim 12, wherein the TAA is a molecule produced by a cancer cell of a cancer selected from the group consisting of a leukemia, a lymphoma, a neurological cancer, a melanoma, a breast cancer, a lung cancer, a head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a prostate cancer, a renal cell cancer, a bone cancer, and a vascular cancer.

### Claim 14 (depends on 1)

The method of claim 1, wherein the immunogenic stimulus comprises
(i) an antigen presenting cell (APC) comprising a major histocompatibility complex (MHC) molecule with a peptide-epitope bound thereto, wherein the peptide-epitope is a fragment of a TAA,
(ii) an APC that has been incubated with tumor cells, a tumor cell lysate, a tumor-associated antigen (TAA), a peptide-epitope of a TAA, or a heat shock protein bound to a peptide-epitope expressed by a tumor cell, or
(iii) a hybrid cell formed by fusing a cancer cell and an APC.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cytokine is granulocyte macrophage-colony stimulating factor (GM-CSF).

### Claim 16 (depends on 14)

The method of claim 14, wherein the MHC molecule is a MHC class I molecule or a MHC class II molecule.

### Claim 17 (depends on 14)

The method of claim 14, wherein the APC of (i), (ii), or (iii) is a dendritic cell.

### Claim 18 (depends on 14)

The method of claim 14, wherein the cancer cell is of a cancer selected from the group consisting of a leukemia, a lymphoma, a neurological cancer, a melanoma, a breast cancer, a lung cancer, a head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a prostate cancer, a renal cell cancer, a bone cancer, and a vascular cancer.