# US 12,109,235 B2 · TGF-beta receptors and methods of use

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- Number: US 12,109,235 B2
- Document ID: US12109235B2
- Status: Granted
- Kind: B2
- Application number: 16/946,388
- Filed: 2020-06-19
- Published: 2020-12-24
- Granted: 2024-10-08
- Earliest claimed: 2019-06-21
- Assignees: Kite Pharma, Inc.
- Applicants: Kite Pharma, Inc.
- Inventors: Sarah Wyman; Peter Emtage; Gabrielle Romain
- Web page: https://patentgrep.com/patent/US12109235B2

## CPC

- C07K 14/495: Transforming growth factor [TGF]
- C07K 14/71: for growth factors; for growth regulators
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/4211: {CD19 or B4}
- A61K 40/4261: {Proteoglycans, e.g. glypican, brevican or CSPG4}
- A61K 40/4276: {Prostate specific membrane antigen [PSMA]}
- A61P 35/00: Antineoplastic agents
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C12N 5/0636: {T lymphocytes}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2239/28: Expressing multiple CARs, TCRs or antigens
- A61K 2239/31: characterized by the route of administration
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/53: Liver
- 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

Provided herein are engineered receptors involved in cytokine signaling. Also provided herein are engineered receptors for modulating TGF-β signaling, methods of modulating TGF-β signaling and treating cancer using chimeric antigen receptors.

## Claims

### Claim 1

A recombinant polypeptide consisting of an extracellular domain (ECD) from a Transforming Growth Factor-beta (TGF-β) receptor, a transmembrane domain (TMD), and an intracellular domain (ICD) consisting of an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6, wherein the recombinant polypeptide binds to TGF-β1 and functions as a dominant negative inhibitor of TGF-β receptor.

### Claim 2 (depends on 1)

The recombinant polypeptide according to claim 1, wherein the ECD is selected from TGF-βRI or TGF-βRII.

### Claim 3 (depends on 1)

The recombinant polypeptide according to claim 1, wherein the TMD is selected from the group consisting of Transforming Growth Factor-beta receptor I (TGF-βRI), Transforming Growth Factor-beta receptor II (TGF-βRII), Platelet-derived growth factor receptor (PDGFR), Cluster of differentiation 4 (CD4), Cluster of differentiation 8 (CD8), Cluster of differentiation 28 (CD28), Cluster of differentiation 127 CD127), Cluster of differentiation 132 (CD132), Cluster of differentiation 3-zeta (CD3ζ), Tumor necrosis factor ligand superfamily 9 (4-IBB), Tumor necrosis factor ligand superfamily 4 (OX40), Inducible T-cell costimulatory (ICOS), Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Programmed cell death protein 1 (PD-1), Lymphocyte activation gene 3 (LAG-3), Natural Killer cell receptor 2B4 (2B4), Interleukin-5 (IL-5), Interleukin-7 (IL-7), Interleukin-7 subunit alpha (IL-7Ra), B- and T-lymphocyte attenuator (BTLA) and mutants thereof.

### Claim 4 (depends on 1)

The recombinant polypeptide according to claim 1, wherein the intracellular domain (ICD) lacks amino acid residues responsible for signaling and phosphorylation present in wild-type TGF-β receptor.

### Claim 5 (depends on 1)

The recombinant polypeptide according claim 1, wherein the ECD comprises the amino acid sequence having at least 75% sequence identity to SEQ ID NO: 15 and the TMD comprises the amino acid sequence having at least 75% sequence identity to SEQ ID NO: 16.

### Claim 6 (depends on 1)

The recombinant polypeptide according to claim 1, wherein the polypeptide consists of the amino acid sequence having at least 75% sequence identity to SEQ ID NO: 14.

### Claim 7 (depends on 1)

An expression vector comprising a nucleic acid encoding the polypeptide according to claim 1.

### Claim 8 (depends on 7)

The expression vector according to claim 7, further comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR).

### Claim 9 (depends on 8)

The expression vector according to claim 8, wherein the CAR binds to a tumor antigen comprising Cluster of differentiation 19 (CD19), Cluster of differentiation 20 (CD20), Prostate-specific membrane antigen (PSMA), Prostrate-cancer membrane antigen (PCMA), C-type lectin-like molecule 1 (CLL-1), or Glypican 3 (GPC3).

### Claim 10 (depends on 9)

The expression vector according to claim 9, wherein the CAR binds to a tumor antigen comprising GPC3.

### Claim 11 (depends on 7)

A T cell transduced with the expression vector according to claim 7.