# US 2023/0265205 A1 · Metabolism-based chimeric antigen receptors and methods of treatment

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- Number: US 2023/0265205 A1
- Document ID: US20230265205A1
- Status: Published application
- Kind: A1
- Application number: 18/041,123
- Filed: 2021-08-09
- Published: 2023-08-24
- Earliest claimed: 2020-08-10
- Assignees: Arizona Board of Regents on behalf of Arizona State University
- Applicants: Arizona Board of Regents on behalf of Arizona State University
- Inventors: Abhinav ACHARYA; Mamta WANKHEDE
- Web page: https://patentgrep.com/patent/US20230265205A1

## CPC

- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/5068: {Cell membranes or bacterial membranes enclosing drugs (liposomes with additional exogenous lipids A61K9/127)}
- A61K 9/5184: {Virus capsids or envelopes enclosing drugs (liposomes with additional exogenous lipids A61K9/127)}
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 40/10: characterised by the cell type used
- A61K 40/17: Monocytes; Macrophages
- A61K 40/20: characterised by the effect or the function of the cells
- A61K 40/24: Antigen-presenting cells [APC]
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/42: Cancer antigens
- A61K 40/4211: {CD19 or B4}
- A61P 35/00: Antineoplastic agents
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70535: {Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)}
- C07K 16/22: against growth factors {; against growth regulators}
- C07K 16/3092: {against tumour-associated mucins}
- C12N 5/0642: {Granulocytes, e.g. basopils, eosinophils, neutrophils, mast cells}
- C12N 5/0645: {Macrophages, e.g. Kuepfer cells in the liver; Monocytes}
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- A61K 2039/804: {Blood cells [leukemia, lymphoma]}
- A61K 2239/22: Intracellular domain
- A61K 2239/39: characterised by a specific adjuvant, e.g. cytokines or CpG
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/03: containing a transmembrane segment
- C12N 2510/00: Genetically modified cells
- 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)

## Abstract

Disclosed are compositions comprising chimeric antigen receptors (CARs) and related methods of use in cancer immunotherapy. Compositions include reprogrammed immune cells (e.g., macrophages, neutrophils, dendritic cells, and T cells) that are metabolically fit for tumor microenvironments. The engineered immune cells are reprogrammed to express one or more of recombinant CARs at their cell surfaces and are loaded with glycolysis accelerating metabolites (e.g., F16BP or succinate). Methods of treating a subject with a condition, such as cancer, are also disclosed and include administering an effective amount of a composition comprising an engineered immune cell to a subject in need thereof.

## Claims

### Claim 1

A composition comprising:
a chimeric antigen receptor (CAR) comprising an extracellular domain comprising a single chain variable fragment (scFv) that binds CD19, CD22, mesothelin, CA-125, or HER2;
a cytoplasmic domain comprising a costimulatory domain and a signaling domain; and
a glycolysis accelerating metabolite.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the extracellular domain comprising the scFv and/or the cytoplasmic domain comprising the costimulatory domain and the signaling domain are expressed in an immune cell by delivery of mRNA or plasmid DNA encoding the extracellular domain and/or the cytoplasmic domain.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the glycolysis accelerating metabolite is in particle form.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the glycolysis accelerating metabolite is in particle form that encapsulates and releases one or more adjuvants in a controlled manner.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the costimulatory domain comprises an intracellular p85-mediated PI3K recruiting domain or a CD3zeta domain.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the signaling domain comprises an FcRgamma, a 4-1BB, a CD28, and/or an ICOS signaling domain.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the glycolysis accelerating metabolite comprises F6P, G6P, PVP, F16BP, or succinate.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the composition is expressed in antigen presenting cells, macrophages, dendritic cells, or neutrophils

### Claim 9

(canceled)

### Claim 10 (depends on 1)

An isolated nucleic acid molecule encoding the CAR in the composition of claim 1.

### Claim 11 (depends on 10)

A vector comprising the nucleic acid molecule of claim 10.

### Claim 12 (depends on 10)

A cell comprising the nucleic acid molecule of claim 10.

### Claim 13 (depends on 11)

A cell comprising the vector of claim 11.

### Claim 14 (depends on 13)

The cell of claim 13, wherein the cell is a human antigen presenting cell, macrophage, human T cell, NK cell, or human neutrophil.

### Claim 15

(canceled)

### Claim 16

(canceled)

### Claim 17 (depends on 1)

An engineered cell comprising the composition of claim 1.

### Claim 18 (depends on 17)

The engineered cell of claim 17, wherein the engineered cell is an immune cell or an immune effector cell.

### Claim 19

(canceled)

### Claim 20 (depends on 18)

The engineered cell of claim 18, wherein the immune effector cell is a T cell, an NK cell, or a macrophage.

### Claim 21

(canceled)

### Claim 22 (depends on 17)

The engineered cell of claim 17 for use in the treatment of a solid tumor, lymphoma and/or leukemia tumors.

### Claim 23

(canceled)

### Claim 24

A pharmaceutical composition comprising:
a genetically-modified human macrophage comprising a chimeric antigen receptor (CAR) comprising an extracellular domain comprising a single chain variable fragment (scFv) that binds CD19, CD22, mesothelin, CA-125, or HER2, and a cytoplasmic domain comprising a costimulatory domain and a signaling domain; and
a glycolysis accelerating metabolite.

### Claim 25 (depends on 24)

A method for treating a subject suffering from a solid or diffused tumor, comprising introducing into the subject a therapeutically effective amount of the pharmaceutical composition of claim 24.

### Claim 26 (depends on 25)

The method of claim 25, wherein the solid or diffused tumor is a lymphoma and/or leukemia and/or melanoma and/or ovarian tumor.