T cell receptor and uses thereof
View Patent ↗A method has been developed to efficiently proliferate and culture a CTL specific to WT1 peptides under limiting dilution conditions. Utilizing this method, CTLs capable of recognizing both a state where a wildtype WT1 specific peptide is presented by HLA-A*24:02 and a state where a mutant WT1 specific peptide is presented by HLA-A*24:02 have been successfully obtained.
1. A nucleic acid comprising: (1) a cDNA sequence encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3; and (2) a cDNA sequence encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7.
2. A cDNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7.
3. A vector comprising (a) or (b) below:
(a) a DNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7; or
(b) a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7.
4. A transformed cell comprising (a) or (b) below:
(a) a DNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7; or
(b) a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7.
5. A transformed cell comprising a DNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3 and a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7, the transformed cell being detectable by a molecule multimerized by binding a wildtype WT1 peptide restricted to HLA-A*24:02 and a molecule multimerized by binding a mutant WT1 peptide restricted to HLA-A*24:02.
6. The transformed cell according to claim 4 , which is a lymphocyte.
7. A pharmaceutical composition for treating a WT1 positive cancer, the pharmaceutical composition comprising the transformed cell according to claim 6 as an active ingredient.
8. A kit for detecting any one of a wildtype WT1 peptide restricted to HLA-A*24:02 and a mutant WT1 peptide restricted to HLA-A*24:02, the kit comprising at least one of (d) to (f) below and instructions for using the kit:
(d) a cDNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3, and a cDNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7;
(e) a vector comprising a DNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7; or
(f) a transformed cell comprising a DNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7; or
(f)(2) a transformed cell comprising a DNA encoding a T cell receptor α-chain protein having the amino acid sequences of SEQ ID NOs: 1 to 3 and a DNA encoding a T cell receptor β-chain protein having the amino acid sequences of SEQ ID NOs: 5 to 7, the transformed cell being detectable by a molecule multimerized by binding a wildtype WT1 peptide restricted to HLA-A*24:02 and a molecule multimerized by binding a mutant WT1 peptide restricted to HLA-A*24:02; and
(f)(3) the transformed cell according to (f)(1), which is a lymphocyte.
9. A nucleic acid comprising: (1) a cDNA sequence encoding a T cell receptor α-chain protein having the amino acid sequence of SEQ ID NO: 4; and (2) a cDNA sequence encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 8.
10. A nucleic acid comprising: (1) a cDNA sequence encoding a T cell receptor α-chain protein having the amino acid sequence of SEQ ID NO: 14; and (2) a cDNA sequence encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 15.
11. A cDNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 8.
12. A cDNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 15.
13. A vector comprising one of (a) to (d) below:
(a) a DNA encoding a T cell receptor α-chain protein having the amino acid sequence of SEQ ID NO: 4, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 8;
(b) a DNA encoding a T cell receptor α-chain protein having the amino acid sequence of SEQ ID NO: 14, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 15;
(c) a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 8; or
(d) a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 15.
14. A transformed cell comprising one of (a) to (d) below:
(a) a DNA encoding a T cell receptor α-chain protein having the amino acid sequence of SEQ ID NO: 4, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 8;
(b) a DNA encoding a T cell receptor α-chain protein having the amino acid sequence of SEQ ID NO: 14, and a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 15;
(c) a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 8; or
(d) a DNA encoding a T cell receptor β-chain protein having the amino acid sequence of SEQ ID NO: 15.
15. A transformed cell comprising a DNA encoding a T cell receptor α-chain protein having any one of the amino acid sequences of SEQ ID NOs: 4 and 14, and a DNA encoding a T cell receptor β-chain protein having any one of the amino acid sequences of SEQ ID NOs: 8 and 15, the transformed cell being detectable by a molecule multimerized by binding a wildtype WT1 peptide restricted to HLA-A*24:02 and a molecule multimerized by binding a mutant WT1 peptide restricted to HLA-A*24:02.
16. The transformed cell according to claim 15 , which is a lymphocyte.
17. A pharmaceutical composition for treating a WT1 positive cancer, the pharmaceutical composition comprising the transformed cell according to claim 15 as an active ingredient.
18. A kit for detecting any one of a wildtype WT1 peptide restricted to HLA-A*24:02 and a mutant WT1 peptide restricted to HLA-A*24:02, the kit comprising at least one of (a) to (c) below and instructions for using the kit:
(a) a cDNA encoding a T cell receptor α-chain protein having any one of the amino acid sequences of SEQ ID NOs: 4 and 14, and a cDNA encoding a T cell receptor β-chain protein having any one of the amino acid sequences of SEQ ID NOs: 8 and 15;
(b) a vector comprising a DNA encoding a T cell receptor α-chain protein having any one of the amino acid sequences of SEQ ID NOs: 4 and 14, and a DNA encoding a T cell receptor β-chain protein having any one of the amino acid sequences of SEQ ID NOs: 8 and 15; or
(c)(1) a transformed cell comprising a DNA encoding a T cell receptor α-chain protein having any one of the amino acid sequences of SEQ ID NOs: 4 and 14, and a DNA encoding a T cell receptor β-chain protein having any one of the amino acid sequences of SEQ ID NOs: 8 and 15; or
(c)(2) a transformed cell comprising a DNA encoding a T cell receptor α-chain protein having any one of the amino acid sequences of SEQ ID NOs: 4 and 14 and a DNA encoding a T cell receptor β-chain protein having any one of the amino acid sequences of SEQ ID NOs: 8 and 15, the transformed cell being detectable by a molecule multimerized by binding a wildtype WT1 peptide restricted to HLA-A*24:02 and a molecule multimerized by binding a mutant WT1 peptide restricted to HLA-A*24:02; and
(c)(3) the transformed cell according to (c)(1), which is a lymphocyte.