# US 12,636,344 B2 · Preferentially expressed antigen in melanoma (PRAME) T cell receptors and methods of use thereof

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- Number: US 12,636,344 B2
- Document ID: US12636344B2
- Status: Granted
- Kind: B2
- Application number: 17/793,952
- Filed: 2021-01-22
- Published: 2023-02-23
- Granted: 2026-05-26
- Earliest claimed: 2020-01-24
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Natalie Bowerman; Johanna Hansen
- Web page: https://patentgrep.com/patent/US12636344B2

## CPC

- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- C07K 14/4748: {Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE}
- 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 39/001189: {PRAME}
- A61P 35/00: Antineoplastic agents
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 16/30: from tumour cells
- C07K 16/32: against translation products of oncogenes
- C12N 5/0636: {T lymphocytes}
- C12N 15/625: {containing a sequence coding for a signal sequence}
- C12N 15/86: Viral vectors
- A61K 2039/5156: {expressing foreign proteins}
- C07K 2317/32: specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12N 2740/10043: viral genome or elements thereof as genetic vector
- 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)
- 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)
- 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

The present invention provides isolated T cell receptors (TCRs) that specifically bind to an HLA-displayed cancer testis antigen preferentially expressed antigen in melanoma (FRAME) peptide, as well as therapeutic and diagnostic methods of using those isolated TCRs.

## Claims

### Claim 1

A T cell receptor (TCR) that binds specifically to an HLA-A2 presented preferentially expressed antigen in melanoma (PRAME) peptide,
wherein the TCR comprises a TCR alpha chain and a TCR beta chain, and
wherein the TCR alpha chain comprises an alpha chain variable domain comprising a complementarity determining region (CDR) 1, a CDR2, and a CDR3 comprising the amino acid sequences of SEQ ID NOs: 493, 494, and 495, respectively, and the TCR beta chain comprises a beta chain variable domain comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences of SEQ ID NOs: 496, 497, and 498, respectively.

### Claim 2 (depends on 1)

The TCR of claim 1.

### Claim 3 (depends on 1)

A polynucleotide molecule comprising
a) a polynucleotide sequence that encodes the alpha chain variable domain of the TCR as set forth in claim 1; and/or
b) a polynucleotide sequence that encodes the beta chain variable domain of the TCR as set forth in claim 1.

### Claim 4 (depends on 3)

A vector comprising the polynucleotide molecule of claim 3.

### Claim 5 (depends on 4)

An cell expressing the vector of claim 4.

### Claim 6 (depends on 5)

A pharmaceutical composition comprising the isolated cell of claim 5 and a pharmaceutically acceptable carrier or diluent.

### Claim 7 (depends on 3)

The polynucleotide molecule of claim 3, wherein the polynucleotide sequence that encodes the alpha chain variable domain comprises the nucleotide sequence of SEQ ID NO: 906.

### Claim 8 (depends on 3)

The polynucleotide molecule of claim 3, wherein the polynucleotide sequence that encodes the beta chain variable domain comprises the nucleotide sequence of SEQ ID NO: 908.

### Claim 9 (depends on 3)

A cell expressing the polynucleotide molecule of claim 3.

### Claim 10 (depends on 1)

A method of treating a subject having a PRAME-associated disease or disorder, comprising administering to the subject a therapeutically effective amount of the TCR as set forth in claim 1, thereby treating the subject.

### Claim 11 (depends on 10)

The method of claim 10, wherein the PRAME-associated disease or disorder is PRAME-associated cancer.

### Claim 12 (depends on 11)

The method of claim 11, wherein the PRAME-associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a melanoma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, an esophageal squamous cell carcinoma, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, an ovarian epithelial cancer, a prostate cancer, a breast cancer, an astrocytic tumor, a glioblastoma multiforme, an anaplastic astrocytoma, a brain tumor, a fallopian tube cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, a sarcoma, a myelodysplastic syndrome, an acute myeloid leukemia, a Hodgkin lymphoma, a non-Hodgkin lymphoma, a Hodgkin disease, a multiple myeloma, a metastatic solid tumors, a colorectal carcinoma, a stomach cancer, a gastric cancer, a rhabdomyosarcoma, a myxoid round cell liposarcoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, testicular germ cell tumor, uveal melanoma, kidney renal papillary cell carcinoma, kidney renal clear cell carcinoma, thymoma, colon adenocarcinoma, cervical squamous cell carcinoma, cervical tumor, pancreatic adenocarcinoma, liver cancer, hepatocellular carcinoma, mesothelioma, or a recurrent non-small cell lung cancer.

### Claim 13 (depends on 10)

The method of claim 10, wherein the TCR is administered to the subject in combination with a second therapeutic agent.

### Claim 14 (depends on 10)

The method of claim 10, wherein the TCR administered subcutaneously, intravenously, intradermally, intraperitoneally, orally, intramuscularly or intracranially to the subject.

### Claim 15 (depends on 1)

The TCR of claim 1, further comprising a detectable moiety.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the TCR of claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 17 (depends on 1)

A cell presenting the TCR of claim 1.

### Claim 18 (depends on 17)

A pharmaceutical composition comprising the cell of claim 17.

### Claim 19 (depends on 1)

A cell comprising
a first polynucleotide molecule, wherein the first polynucleotide molecule comprises a polynucleotide sequence that encodes the alpha chain variable domain of the TCR as set forth in claim 1; and
a second polynucleotide molecule, wherein the second polynucleotide molecule comprises a polynucleotide sequence that encodes the beta chain variable domain of the TCR as set forth in claim 1.

### Claim 20 (depends on 19)

The cell of claim 19, wherein the polynucleotide sequence that encodes the alpha chain variable domain of the TCR comprises the nucleotide sequence of SEQ ID NO: 906, and wherein the polynucleotide sequence that encodes the beta chain variable domain of the TCR comprises the nucleotide sequence of SEQ ID NO: 908.

### Claim 21 (depends on 19)

The cell of claim 19, wherein the first polynucleotide molecule is contained within a vector.

### Claim 22 (depends on 19)

The cell of claim 19, wherein the second polynucleotide molecule is contained within a vector.

### Claim 23 (depends on 19)

The cell of claim 19, wherein the first polynucleotide molecule and the second polynucleotide molecule are contained within a vector.

### Claim 24 (depends on 19)

A pharmaceutical composition comprising the cell of claim 19.

### Claim 25 (depends on 19, 20, 21, 22, 23)

A pharmaceutical composition comprising the cell of any one of claims 19-23.

### Claim 26 (depends on 5, 17)

A method of treating a subject having an PRAME-associated disease or disorder, comprising administering to the subject a plurality of the cells of any one of claims 5, 17, and 19-23, thereby treating the subject.

### Claim 27 (depends on 26)

The method of claim 26, wherein the PRAME-associated disease or disorder is PRAME-associated cancer.

### Claim 28 (depends on 27)

The method of claim 27, wherein the PRAME-associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a melanoma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, an esophageal squamous cell carcinoma, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, an ovarian epithelial cancer, a prostate cancer, a breast cancer, an astrocytic tumor, a glioblastoma multiforme, an anaplastic astrocytoma, a brain tumor, a fallopian tube cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, a sarcoma, a myelodysplastic syndrome, an acute myeloid leukemia, a Hodgkin lymphoma, a non-Hodgkin lymphoma, a Hodgkin disease, a multiple myeloma, a metastatic solid tumors, a colorectal carcinoma, a stomach cancer, a gastric cancer, a rhabdomyosarcoma, a myxoid round cell liposarcoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, testicular germ cell tumor, uveal melanoma, kidney renal papillary cell carcinoma, kidney renal clear cell carcinoma, thymoma, colon adenocarcinoma, cervical squamous cell carcinoma, cervical tumor, pancreatic adenocarcinoma, liver cancer, hepatocellular carcinoma, mesothelioma, or a recurrent non-small cell lung cancer.

### Claim 29 (depends on 26)

The method of claim 26, wherein the plurality of cells is administered to the subject in combination with a second therapeutic agent.

### Claim 30 (depends on 26)

The method of claim 26, wherein the plurality of cells is administered subcutaneously, intravenously, intradermally, intraperitoneally, orally, intramuscularly or intracranially to the subject.