T cell receptors specific for mesothelin and their use in immunotherapy
AssigneesFred Hutchinson Cancer Center, Juno Therapeutics, Inc.
InventorsThomas M. Schmitt, Aude G. Chapuis, Philip D. Greenberg
Life of this patent
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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.
Claims38
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.
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.
An isolated polynucleotide that encodes a binding protein that is capable of specifically binding to a SEQ ID NO:32:HLA-A:
- 02*01 complex, wherein the polynucleotide comprises or consists of the polynucleotide sequence set forth in SEQ ID NO:
- 120.
A T cell receptor (TCR) comprising an alpha-chain (TCRα) and a beta-chain (TCRβ), wherein the TCRα and the TCRβ comprise the amino acid sequences set forth in SEQ ID NOs:
- (i) 110 and 109, respectively;
- (ii) 108 and 107, respectively;
- (iii) 104 and 103, respectively;
- or
- (v) 106 and 105, respectively.
A polynucleotide encoding a T cell receptor (TCR),
- wherein the encoded TCR comprises an alpha-chain (TCRα) and a beta-chain (TCRβ), wherein the TCRα and the TCRβ comprise the CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences set forth in:
- (i) 93, 94, 39, 91, 92, and 40, respectively, wherein the binding protein is capable of specifically binding to a SEQ ID NO:32:HLA-A:
- 0201 complex;
- (ii) 89, 90, 37, 87, 88, and 38, respectively, wherein the binding protein is capable of specifically binding to a SEQ ID NO:32:HLA-A:
- 0201 complex;
- (iii) 80, 81 or 118, 33, 78, 79, and 34, respectively, wherein the binding protein is capable of specifically binding to a SEQ ID NO:31:HLA-A:
- 0201 complex;
- or
- (iv) 85, 86 or 119, 35, 82, 79, and 36, respectively, wherein the binding protein is capable of specifically binding to a SEQ ID NO:31:HLA-A:
- 0201 complex;
- and wherein:
- (1) the polynucleotide comprises a sequence encoding a viral 2A peptide, an internal ribosome entry site (IRES), a furin cleavage site, or any combination thereof, disposed between a sequence encoding the TCRβ and a sequence encoding the TCRα;
- and/or
- (2) the polynucleotide further encodes a CD8 co-receptor α-chain and a CD8 co-receptor β-chain;
- and/or
- (3) the polynucleotide is comprised in a viral vector.
A method of treating a cancer associated with mesothelin expression and/or activity in a subject, the method comprising administering to the subject an effective amount of T cells comprising CD8+ T cells, wherein
- (1) cells of the cancer express a SEQ ID NO:32:HLA-A:
- 0201 complex, and the T cells express an αβ T cell receptor (TCR) comprising the CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences set forth in SEQ ID NOs:
- 93, 94, 39, 91, 92, and 40, respectively, or set forth in SEQ ID NOs:
- 89, 90, 37, 87, 88, and 38, respectively;
- or
- (2) cells of the cancer express a SEQ ID NO:31:HLA-A:
- 0201 complex, and the T cells express an αβ T cell receptor (TCR) comprising the CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences set forth in 80, 81 or 118, 33, 78, 79, and 34, respectively, or set forth in SEQ ID NOs:
- 85, 86 or 119, 35, 82, 79, and 36, respectively.
Dependencies are inferred from the claim text.