T cell receptors specific for mesothelin and their use in immunotherapy

Patent metadata

Field	Value
Publication number	US-12595290-B2
Application number	US-201917291985-A
Country	US
Kind code	B2
Filing date	Nov 8, 2019
Priority date	Nov 9, 2018
Publication date	Apr 7, 2026
Grant date	Apr 7, 2026

Abstract

Binding proteins specific for Msln20-28 or Msln530-538 peptides are provided herein. Polynucleotides encoding the binding proteins, as well as compositions and recombinant host cells comprising the binding proteins or polynucleotides are also provided. The compositions and recombinant host cells may be used to treat a subject having mesothelioma, pancreatic cancer, ovarian cancer, lung cancer, a cancer wherein an Msln20-28 peptide is expressed on a tumor cell of the cancer, or a cancer wherein an Msln530-538 peptide is expressed on a tumor cell of the cancer.

First claim

The invention claimed is:

1 . A binding protein comprising a T cell receptor (TCR) α-chain variable domain (Vα) and a TCR β-chain variable domain (Vβ), wherein:
(a) the Vα comprises the complementarity determining region (CDR)1α, CDR2α, and CDR3α amino acid sequences set forth in SEQ ID NOs: 93, 94, and 39, respectively and the Vβ comprises the CDR1β, CDR2β, and CDR3β amino acid sequences set forth in SEQ ID NOs: 91, 92, and 40, respectively; or
(b) the Vα comprises the CDR1α, CDR2α, and CDR3α amino acid sequences set forth in SEQ ID NOs: 89, 90, and 37, respectively and the Vβ comprises the CDR1β, CDR2β, and CDR3β amino acid sequences set forth in SEQ ID NOs: 87, 88, and 38, respectively
wherein the binding protein is capable of specifically binding to a SEQ ID NO:32:HLA-A: 0201 complex,
wherein the binding protein comprises:
(i) a TCR α-chain constant domain and a TCR β-chain constant domain, wherein the TCR α-chain constant domain, the TCR β-chain constant domain, or both comprise a non-native cysteine residue; and/or
(ii) a single chain TCR (scTCR) or a CAR.

2 . The binding protein of claim 1 , comprising:
(a) the CDR1α amino acid sequence set forth in SEQ ID NO: 93; (b) the CDR2α amino acid sequence set forth in SEQ ID NO: 94; (c) the CDR3α amino acid sequence set forth in SEQ ID NO: 39; (d) the CDR1β amino acid sequence set forth in SEQ ID NO: 91; (e) the CDR2β amino acid sequence set forth in SEQ ID NO: 92; and (f) the CDR3β amino acid sequence set forth in SEQ ID NO: 40.

3 . The binding protein of claim 2 , wherein the Vα comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 102, and wherein the Vβ comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 101.

4 . The binding protein of claim 2 , comprising a TCR α chain (TCRα) and a TCR β chain (TCRβ), wherein the TCRα comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 110 or 29, and/or wherein the TCRβ comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 109 or 28.

5 . The binding protein of claim 1 , comprising:
(a) the CDR1α amino acid sequence set forth in SEQ ID NO: 89; (b) the CDR2α amino acid sequence set forth in SEQ ID NO: 90; (c) the CDR3α amino acid sequence set forth in SEQ ID NO: 37; (d) the CDR1β amino acid sequence as set forth in SEQ ID NO: 87; (e) the CDR2β amino acid sequence set forth in SEQ ID NO: 88; and (f) the CDR3β amino acid sequence set forth in SEQ ID NO: 38.

6 . The binding protein of claim 5 , wherein the Vα comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO:100 and the Vβ comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO:99.

7 . The binding protein of claim 5 , comprising a TCR α chain (TCRα) and a TCR β chain (TCRβ), wherein the TCRα comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 108 or 23, and/or wherein the TCRβ comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 107 or 22.

8 . The binding protein of claim 1 , wherein:
the Vα comprises or consists of the amino acid sequence set forth in SEQ ID NO: 102 and the Vβ comprises or consists of the amino acid sequence set forth in SEQ ID NO: 101; or the Vα comprises or consists of the amino acid sequence set forth in SEQ ID NO: 100 and the Vβ comprises or consists of the amino acid sequence set forth in SEQ ID NO: 99.

9 . The binding protein of claim 1 , wherein the binding protein comprises a TCR Cβ and a TCR Cα, wherein the TCR Cβ comprises a cysteine amino acid in place of a native serine at amino acid position 57 and the TCR Cα comprises a cysteine amino acid in place of a native threonine at amino acid position 48.

10 . A binding protein comprising a T cell receptor (TCR) α-chain variable domain (Vα) and a TCR β-chain variable domain (Vβ), wherein:
(a) the Vα comprises the CDR1α amino acid sequence set forth in SEQ ID NO: 80, the CDR2α amino acid sequence set forth in SEQ ID NO: 81 or 118, and CDR3α amino acid sequence set forth in SEQ ID NO: 33 and the Vβ comprises the CDR1β, CDR2β, and CDR3β amino acid sequences set forth in SEQ ID NOs: 78, 79, and 34, respectively; or
(b) the Vα comprises the CDR1α amino acid sequence set forth in SEQ ID NO: 85, the CDR2α amino acid sequence set forth in SEQ ID NO: 86 or 119, and CDR3α amino acid sequence set forth in SEQ ID NO: 35 and the Vβ comprises the CDR1β, CDR2β, and CDR3β amino acid sequences set forth in SEQ ID NOs: 82, 79, and 36, respectively,
wherein the binding protein is capable of specifically binding to a SEQ ID NO:31:HLA-A: 0201 complex,
wherein the binding protein comprises:
(i) a TCR α-chain constant domain and a TCR β-chain constant domain, wherein the TCR α-chain constant domain, the TCR β-chain constant domain, or both comprise a non-native cysteine residue; and/or
(ii) a scTCR or a CAR.

11 . The binding protein of claim 10 , comprising:
(a) the CDR1α amino acid sequence set forth in SEQ ID NO: 80; (b) the CDR2α amino acid sequence set forth in SEQ ID NO: 81 or 118; (c) the CDR3α amino acid sequence set forth in SEQ ID NO: 33; (d) the CDR1β amino acid sequence as set forth in SEQ ID NO: 78; (e) the CDR2β amino acid sequence set forth in SEQ ID NO: 79; and (f) the CDR3β amino acid sequence set forth in SEQ ID NO: 34.

12 . The binding protein of claim 11 , wherein the Vα comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 96, and wherein the Vβ comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 95.

13 . The binding protein of claim 11 , comprising a TCR α chain (TCRα) and a TCR β chain (TCRβ), wherein the TCRα comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 104 or 7, and/or wherein the TCRβ comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 103 or 6; or (ii) wherein the TCRα comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 106 or 15, and/or wherein the TCR β comprises or consists of an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO: 105 or 14.

14 . The binding protein of claim 10 , comprising:
(a) the CDR1α amino acid sequence set forth in SEQ ID NO: 85; (b) the CDR2α amino acid sequence set forth in SEQ ID NO: 86 or 119; (c) the CDR3α amino acid sequence set forth in SEQ ID NO: 35; (d) the CDR1β amino acid sequence set forth in SEQ ID NO: 82; (e) the CDR2β amino acid sequence set forth in SEQ ID NO: 79; and (f) the CDR3β amino acid sequence set forth in SEQ ID NO: 36.

15 . The binding protein of claim 10 , wherein:
the Vα comprises or consists of the amino acid sequence set forth in SEQ ID NO: 96 and the Vβ comprises or consists of the amino acid sequence set forth in SEQ ID NO: 95; or the Vα comprises or consists of the amino acid sequence set forth in SEQ ID NO: 98 and the Vβ comprises or consists of the amino acid

Assignees

• Fred Hutchinson Cancer Center
• Juno Therapeutics Inc

Inventors

• Schmitt Thomas M
• Chapuis Aude G
• Greenberg Philip D

Classifications

• A61K40/4255

  Mesothelin [MSLN] · CPC title

• A61K40/32

  T-cell receptors [TCR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• C12N5/0636

  T lymphocytes · CPC title

• A61K2239/49

  Breast · CPC title