T cell receptors and immune therapy using the same
The present invention pertains to antigen recognizing constructs against tumor associated antigens (TAA), in particular the TAA Serine protease inhibitor Kazal-type 2 (SPINK2). The invention in particular provides novel T cell receptor (TCR) based molecules which are selective and specific for the tumor expressed antigen of the invention. The TCR of the invention, and SPINK2 binding fragments derived therefrom, are of use for the diagnosis, treatment and prevention of SPINK2 expressing cancerous diseases. Further provided are nucleic acids encoding the antigen recognizing constructs of the invention, vectors comprising these nucleic acids, recombinant cells expressing the antigen recognizing constructs and pharmaceutical compositions comprising the compounds of the invention.
1. A single chain TCR comprising an alpha chain and a beta chain,
wherein the alpha chain comprises
SEQ ID NO: 97,
SEQ ID NO: 98, and
SEQ ID NO: 99, and
the beta chain comprises
SEQ ID NO: 103,
SEQ ID NO: 104, and
SEQ ID NO: 105.
2. The single chain TCR according to claim 1 , wherein said single chain TCR binds specifically and/or selectively to a SPINK2-001 antigenic peptide consisting of the amino acid sequence of SEQ ID NO: 133 in complex with an WIC class I molecule.
3. The single chain TCR according to claim 1 , comprising an alpha TCR variable chain region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 100 and a beta TCR variable chain region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 106.
4. The single chain TCR according to claim 1 , wherein in the variable domain of the α or β chain, an amino acid at position 44 according to the IMGT numbering is substituted with another suitable amino acid thereby improving stability and/or pairing of said chains.
5. A nucleic acid encoding for the single chain TCR according to claim 1 .
6. A vector comprising the nucleic acid according to claim 5 .
7. A host cell comprising the single chain TCR according to claim 1 , or a nucleic acid encoding said single chain TCR, or a vector comprising said nucleic acid, optionally the host cell is a lymphocyte, optionally a T lymphocyte or T lymphocyte progenitor, optionally a CD4 or CD8 positive T-cell.
8. A pharmaceutical composition comprising the single chain TCR according to claim 1 , or a nucleic acid encoding said single chain TCR, or a vector comprising said nucleic acid, or the host cell comprising said single chain TCR, and a pharmaceutical acceptable carrier, stabilizer and/or excipient.
9. The single chain TCR according to claim 1 , comprising an alpha TCR variable chain region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 100 and a beta TCR variable chain region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 106.
10. The single chain TCR according to claim 1 , comprising an alpha chain constant region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 101 and a beta chain constant region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 107.
11. The single chain TCR according to claim 1 , comprising an alpha chain constant region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 101 and a beta chain constant region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 107.
12. The single chain TCR according to claim 1 , wherein the alpha chain comprises at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 102 and the beta chain comprises at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 108.
13. The single chain TCR according to claim 1 , wherein
the CDR1 alpha chain comprises SEQ ID NO: 97,
the CDR2 alpha chain comprises SEQ ID NO: 98,
the CDR3 alpha chain comprises SEQ ID NO: 99,
the CDR1 beta chain comprises SEQ ID NO: 103,
the CDR2 beta chain comprises SEQ ID NO: 104, and
the CDR3 beta chain comprises SEQ ID NO: 105.
14. The single chain TCR according to claim 1 , wherein
the CDR1 alpha chain consists of SEQ ID NO: 97,
the CDR2 alpha chain comprises SEQ ID NO: 98,
the CDR3 alpha chain comprises SEQ ID NO: 99,
the CDR1 beta chain consists of SEQ ID NO: 103,
the CDR2 beta chain comprises SEQ ID NO: 104, and
the CDR3 beta chain comprises SEQ ID NO: 105.
15. The single chain TCR according to claim 1 , wherein
the CDR1 alpha chain consists of SEQ ID NO: 97,
the CDR2 alpha chain consists of SEQ ID NO: 98,
the CDR3 alpha chain consists of SEQ ID NO: 99,
the CDR1 beta chain consists of SEQ ID NO: 103,
the CDR2 beta chain consists of SEQ ID NO: 104, and
the CDR3 beta chain consists of SEQ ID NO: 105.
16. The single chain TCR of claim 1 , wherein said TCR is a soluble TCR.
17. The single chain TCR of claim 15 , wherein said TCR is a soluble TCR.