T-cell receptor
Provided is a T cell receptor capable of binding to a peptide having the amino acid sequence shown in SEQ ID NO: 27 or a complex of the peptide and HLA-A24. A T cell receptor capable of binding to a peptide having the amino acid sequence shown in SEQ ID NO: 28 or a complex of the peptide and HLA-A02. Disclosed T cell receptors are useful in treating or avoiding cancers which are associated with expression of glypican-3.
1. A T cell receptor (TCR) comprising,
as complementarity determining regions of the α chain,
the amino acid sequence shown in SEQ ID NO: 1,
the amino acid sequence shown in SEQ ID NO: 2, and
the amino acid sequence shown in SEQ ID NO: 3; or
the amino acid sequence shown in SEQ ID NO: 4,
the amino acid sequence shown in SEQ ID NO: 5, and
the amino acid sequence shown in SEQ ID NO: 6, and
as complementarity determining regions of the β chain,
the amino acid sequence shown in SEQ ID NO: 7,
the amino acid sequence shown in SEQ ID NO: 8, and
the amino acid sequence shown in SEQ ID NO: 9; or
the amino acid sequence shown in SEQ ID NO: 10,
the amino acid sequence shown in SEQ ID NO: 11, and
the amino acid sequence shown in SEQ ID NO: 12.
2. The T cell receptor (TCR) according to claim 1 comprising,
as an α chain variable region,
the amino acid sequence shown in SEQ ID NO: 19,
the amino acid sequence shown in SEQ ID NO: 19 wherein one or several amino acids are
deleted, substituted or added, or
an amino acid sequence having 90% or more identity with the amino acid sequence shown
in SEQ ID NO: 19; or
the amino acid sequence shown in SEQ ID NO: 20,
the amino acid sequence shown in SEQ ID NO: 20 wherein one or several amino acids are
deleted, substituted or added, or
an amino acid sequence having 90% or more identity with the amino acid sequence shown
in SEQ ID NO: 20, and
as a β chain variable region,
the amino acid sequence shown in SEQ ID NO: 21,
the amino acid sequence shown in SEQ ID NO: 21 wherein one or several amino acids are
deleted, substituted or added, or
an amino acid sequence having 90% or more identity with the amino acid sequence shown
in SEQ ID NO: 21; or
the amino acid sequence shown in SEQ ID NO: 22,
the amino acid sequence shown in SEQ ID NO: 22 wherein one or several amino acids are
deleted, substituted or added, or
an amino acid sequence having 90% or more identity with the amino acid sequence shown
in SEQ ID NO: 22.
3. The T cell receptor according to claim 1 , comprising
as an α chain constant region,
the amino acid sequence shown in SEQ ID NO: 25,
the amino acid sequence shown in SEQ ID NO: 25 wherein one or several amino acids are
deleted, substituted or added, or
an amino acid sequence having 90% or more identity with the amino acid sequence shown
in SEQ ID NO: 25, and
as a β chain constant region,
the amino acid sequence shown in SEQ ID NO: 26,
the amino acid sequence shown in SEQ ID NO: 26 wherein one or several amino acids are
deleted, substituted or added, or
an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 26.
4. A nucleic acid encoding the T cell receptor according to claim 1 .
5. An expression vector comprising the nucleic acid according to claim 4 .
6. An isolated cell comprising the nucleic acid according to claim 4 .
7. The isolated cell according to claim 6 , wherein said cell is a lymphocyte or a pluripotent stem cell.
8. The isolated cell according to claim 6 , wherein said cell is a cytotoxic T lymphocyte.
9. A method of producing an isolated cell comprising the nucleic acid according to claim 4 , comprising a step of introducing the nucleic acid into the cell.
10. A T cell induced from a pluripotent stem cell comprising the nucleic acid according to claim 4 .
11. A method of producing a T cell, comprising the following steps:
(1) a step of differentiating a pluripotent stem cell comprising the nucleic acid according to claim 4 into a hematopoietic progenitor cell, and
(2) a step of differentiating the hematopoietic progenitor cell into a T cell.
12. The method according to claim 11 , wherein said T cell is a cytotoxic T cell, in particular a CD8 positive cytotoxic T cell.
13. A medicament comprising an isolated cell,
wherein the isolated cell comprises a nucleic acid encoding the T cell receptor, wherein the T cell receptor comprises,
as complementarity determining regions of the α chain,
the amino acid sequence shown in SEQ ID NO: 1,
the amino acid sequence shown in SEQ ID NO: 2, and
the amino acid sequence shown in SEQ ID NO: 3; or
the amino acid sequence shown in SEQ ID NO: 4,
the amino acid sequence shown in SEQ ID NO: 5, and
the amino acid sequence shown in SEQ ID NO: 6, and
as complementarity determining regions of the β chain,
the amino acid sequence shown in SEQ ID NO: 7,
the amino acid sequence shown in SEQ ID NO: 8, and
the amino acid sequence shown in SEQ ID NO: 9: or
the amino acid sequence shown in SEQ ID NO: 10,
the amino acid sequence shown in SEQ ID NO: 11, and
the amino acid sequence shown in SEQ ID NO: 12.
14. A method of treating cancer, comprising administering to a subject the medicament according to claim 13 in which the isolated cell is a lymphocyte or a T cell induced from a pluripotent stem cell comprising a nucleic acid encoding the T cell receptor, wherein the cancerous cells express glypican-3.
15. A method for killing a cell expressing glypican-3, comprising administering the isolated cell according to claim 6 to the cell expressing glypican-3, wherein the isolated cell is a lymphocyte or a T cell induced from a pluripotent stem cell.
16. A method of treating cancer, comprising administering to a subject an isolated cell comprising a nucleic acid encoding the T cell receptor according to claim 1 , wherein the cancerous cells express glypican-3, and the isolated cell is a lymphocyte or a T cell induced from a pluripotent stem cell.
17. A method of making a therapeutic agent for treating a disease expressing glypican-3, comprising inducing a T cell from a pluripotent stem cell comprising a nucleic acid encoding the T cell receptor of claim 1 .