# US 12,180,261 B2 · T cell receptors

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- Number: US 12,180,261 B2
- Document ID: US12180261B2
- Status: Granted
- Kind: B2
- Application number: 18/363,672
- Filed: 2023-08-01
- Published: 2024-01-11
- Granted: 2024-12-31
- Earliest claimed: 2016-04-08
- Assignees: Adaptimmune Limited
- Applicants: Adaptimmune Limited
- Inventors: Nicholas Tribble; William Lawrance; Eleanor Bagg
- Web page: https://patentgrep.com/patent/US12180261B2

## CPC

- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- 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 40/32: T-cell receptors [TCR]
- A61K 40/4268: {MAGE}
- A61P 35/00: Antineoplastic agents
- C07K 14/4748: {Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE}
- 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)
- 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

The present invention relates to T cell receptors (TCRs) which bind the HLA-A*0201 restricted peptide GVYDGEEHSV (SEQ ID NO: 1) derived from the MAGE-B2 protein. The TCRs of the invention demonstrate excellent specificity profiles for this MAGE epitope. Also provided are nucleic acids encoding the TCRs, cells engineered to present the TCRs, cells harbouring expression vectors encoding the TCRs and pharmaceutical compositions comprising the TCRs, nucleic acids or cells of the invention.

## Claims

### Claim 1

A T cell receptor (TCR) that comprises a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein:
(A) the TCR alpha chain variable domain is comprised in a sequence in which:
(i) amino acid residues 1-27 has (a) at least 90% identity to the sequence of amino acid residues 1-27 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 1-27 of SEQ ID No: 3;
(ii) amino acid residues 28-33 is amino acid residues 28-33 of SEQ ID NO: 3;
(iii) amino acid residues 34-47 has (a) at least 90% identity to the sequence of amino acid residues 34-47 of SEQ ID NO: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 34-47 of SEQ ID No: 3;
(iv) amino acid residues 48-53 is amino acid residues 48-53 of any of SEQ ID NOs: 3 or 7;
(v) amino acid residues 54-90 has (a) at least 90% identity to the sequence of amino acid residues 54-90 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 54-90 of SEQ ID No: 3; and
(vi) amino acid residues 91-105 is amino acid residues 91-105 of SEQ ID NO: 3; and
(B) the TCR beta chain variable domain is comprised in a sequence in which:
(i) amino acid residues 1-45 has (a) at least 90% identity to the amino acid sequence of residues 1-45 of SEQ ID No: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 1-45 of SEQ ID No: 4;
(ii) amino acid residues 46-50 is amino acid residues 46-50 of SEQ ID NO: 4;
(iii) amino acid residues 51-67 has (a) at least 90% identity to the sequence of amino acid residues 51-67 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 51-67 of SEQ ID No: 4;
(iv) amino acid residues 68-72 is amino acid residues 68-72 of SEQ ID NO: 4 or 11;
(v) amino acid residues 73-109 has (a) at least 90% identity to the sequence of amino acid residues 73-109 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 73-109 of SEQ ID No: 4; and
(vi) amino acid residues 110-123 is amino acid residues 110-123 of any one of SEQ ID NOs: 10, 11 or 12, or amino acid residues 110-123 of SEQ ID NO: 4 provided that amino acid residues 48-53 of the TCR alpha chain variable domain is amino acid residues 48-53 of SEQ ID NO: 7.

### Claim 2 (depends on 1)

The TCR of claim 1, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3 or 7.

### Claim 3 (depends on 1)

The TCR of claim 1, wherein the TCR beta chain variable domain is comprised in the amino acid sequence of any one of SEQ ID NOs: 4, 10, 11 or 12.

### Claim 4 (depends on 1)

The TCR of claim 1, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3 or 7, and the TCR beta chain variable domain is comprised in the amino acid sequence of any one of SEQ ID NOs: 4, 10, 11 or 12.

### Claim 5 (depends on 1)

The TCR of claim 1, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 7, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 4.

### Claim 6 (depends on 1)

The TCR of claim 1, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 10.

### Claim 7 (depends on 1)

The TCR of claim 1, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 11.

### Claim 8 (depends on 1)

The TCR of claim 1, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 12.

### Claim 9 (depends on 1)

The TCR of claim 1, which is an alpha-beta heterodimer, having an alpha chain TRAV10+TRAC constant domain sequence and a beta chain TRBV24-1+TRBC-2 constant domain sequence.

### Claim 10 (depends on 1)

The TCR of claim 1, which is in single chain format of the type Vα-L-Vβ, Vβ-L-Vα, Vα-Cα-L-Vβ, or Vα-L-Vβ-Cβ, wherein Vα and Vβ are TCR α and β variable regions respectively, Cα and Cβ are TCR α and β constant regions respectively, and L is a linker sequence.

### Claim 11 (depends on 1)

One or more polynucleotides encoding the TCR of claim 1.

### Claim 12 (depends on 11)

A cell comprising the one or more polynucleotides of claim 11.

### Claim 13 (depends on 1)

A cell presenting the TCR of claim 1, optionally wherein the cell is isolated or non-naturally occurring.

### Claim 14 (depends on 13)

The cell of claim 13, wherein the cell is a T-cell.

### Claim 15 (depends on 14)

A method for treating cancer in a subject, comprising administering to the subject the T cell of claim 14, wherein the subject has a cancer cell that expresses a melanoma-associated antigen (MAGE) A4 protein and/or a MAGE B2 protein.

### Claim 16 (depends on 13)

A pharmaceutical composition comprising the cell of claim 13, together with one or more pharmaceutically acceptable carriers or excipients.

### Claim 17

An isolated or non-naturally occurring cell presenting a TCR encoded by a nucleic acid, wherein the nucleic acid encodes a TCR that comprises:
(A) a TCR alpha chain variable domain in which:
(i) amino acid residues 1-27 has (a) at least 90% identity to the sequence of amino acid residues 1-27 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 1-27 of SEQ ID No: 3;
(ii) amino acid residues 28-33 is amino acid residues 28-33 of SEQ ID NO: 3;
(iii) amino acid residues 34-47 has (a) at least 90% identity to the sequence of amino acid residues 34-47 of SEQ ID NO: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 34-47 of SEQ ID No: 3;
(iv) amino acid residues 48-53 is amino acid residues 48-53 of any of SEQ ID NOs: 3 or 7;
(v) amino acid residues 54-90 has (a) at least 90% identity to the sequence of amino acid residues 54-90 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 54-90 of SEQ ID No: 3; and
(vi) amino acid residues 91-105 is amino acid residues 91-105 of SEQ ID NO: 3; and
(B) the TCR beta chain variable domain is comprised in a sequence in which:
(i) amino acid residues 1-45 has (a) at least 90% identity to the amino acid sequence of residues 1-45 of SEQ ID No: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 1-45 of SEQ ID No: 4;
(ii) amino acid residues 46-50 is amino acid residues 46-50 of SEQ ID NO: 4;
(iii) amino acid residues 51-67 has (a) at least 90% identity to the sequence of amino acid residues 51-67 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 51-67 of SEQ ID No: 4;
(iv) amino acid residues 68-72 is amino acid residues 68-72 of SEQ ID NO: 4 or 11;
(v) amino acid residues 73-109 has (a) at least 90% identity to the sequence of amino acid residues 73-109 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to amino acid residues 73-109 of SEQ ID No: 4; and
(vi) amino acid residues 110-123 is amino acid residues 110-123 of any one of SEQ ID NOs: 10, 11 or 12, or amino acid residues 110-123 of SEQ ID NO: 4, provided that amino acid residues 48-53 of the TCR alpha chain variable domain is amino acid residues 48-53 of SEQ ID NO: 7.

### Claim 18 (depends on 17)

The cell of claim 17, wherein the cell is a T-cell.

### Claim 19 (depends on 18)

A method for treating cancer in a subject, comprising administering to the subject the T cell of claim 18, wherein the subject has a cancer cell that expresses a melanoma-associated antigen (MAGE) A4 protein and/or a MAGE B2 protein.

### Claim 20 (depends on 17)

A pharmaceutical composition comprising the cell of claim 17, together with one or more pharmaceutically acceptable carriers or excipients.