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 method of treating an HLA-A*02-positive patient who has acute myeloid leukemia, comprising administering to the patient a population of transformed CD8+cells expressing at least one vector encoding a T cell receptor (TCR),
wherein the TCR comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9,
wherein the TCR is capable of binding to a peptide consisting of the amino acid sequence of ALSVLRLAL (SEQ ID NO: 133) in a complex with an MHC class I molecule.
2. The method of claim 1 , wherein the population of transformed cells are produced by a method comprising
isolating a cell from a subject,
transforming the cell with at least one vector encoding the TCR to produce a transformed cell, and
expanding the transformed cell to produce the population of transformed cells.
3. The method of claim 2 , wherein the subject is the patient.
4. The method of claim 2 , wherein the subject is a healthy donor.
5. The method of claim 1 , wherein the TCR comprises an α chain comprising the amino acid sequence of SEQ ID NO: 6 and a β chain comprising the amino acid sequence of SEQ ID NO: 12.
6. The method of claim 1 , wherein the population of transformed cells are administered in the form of a pharmaceutical composition.
7. The method of claim 6 , wherein the pharmaceutical composition comprises a chemotherapeutic agent selected from the group consisting of asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, and vincristine.
8. The method of claim 1 , wherein the TCR comprises:
a CDR1α chain comprising the amino acid sequence of SEQ ID NO: 1,
a CDR2α chain comprising the amino acid sequence of SEQ ID NO: 2,
a CDR3α chain comprising the amino acid sequence of SEQ ID NO: 3,
a CDR1β chain comprising the amino acid sequences of SEQ ID NO: 7,
a CDR2β chain comprising the amino acid sequence of SEQ ID NO: 8, and
a CDR3β chain comprising the amino acid sequence of SEQ ID NO: 9.
9. The method of claim 1 , wherein the TCR comprises
a CDR1α chain consisting of the amino acid sequence of SEQ ID NO: 1,
a CDR2α chain comprising the amino acid sequence of SEQ ID NO: 2,
a CDR3α chain consisting of the amino acid sequence of SEQ ID NO: 3,
a CDR1β chain consisting of the amino acid sequence of SEQ ID NO: 7,
a CDR2β chain comprising the amino acid sequence of SEQ ID NO: 8, and
a CDR3β chain consisting of the amino acid sequence of SEQ ID NO: 9.
10. The method of claim 1 , wherein the TCR comprises
a CDR1α chain comprising the amino acid sequence of SEQ ID NO: 1,
a CDR2α chain comprising the amino acid sequence of SEQ ID NO: 2,
a CDR3α chain consisting of the amino acid sequence of SEQ ID NO: 3,
a CDR1β chain comprising the amino acid sequence of SEQ ID NO: 7,
a CDR2β chain comprising the amino acid sequence of SEQ ID NO: 8, and
a CDR3β chain consisting of the amino acid sequence of SEQ ID NO: 9.
11. The method of claim 1 , wherein the TCR comprises
a CDR1α chain comprising the amino acid sequence of SEQ ID NO: 1,
a CDR2α chain consisting of the amino acid sequence of SEQ ID NO: 2,
a CDR3α chain comprising the amino acid sequence of SEQ ID NO: 3,
a CDR1β chain comprising the amino acid sequence of SEQ ID NO: 7,
a CDR2β chain consisting of the amino acid sequence of SEQ ID NO: 8, and
a CDR3β chain comprising the amino acid sequence of SEQ ID NO: 9.
12. The method of claim 1 , wherein the TCR comprises
a CDR1α chain consisting of the amino acid sequence of SEQ ID NO: 1,
a CDR2α chain comprising the amino acid sequence of SEQ ID NO: 2,
a CDR3α chain comprising the amino acid sequence of SEQ ID NO: 3,
a CDR1β chain consisting of the amino acid sequence of SEQ ID NO: 7,
a CDR2β chain comprising the amino acid sequence of SEQ ID NO: 8, and
a CDR3β chain comprising the amino acid sequence of SEQ ID NO: 9.
13. The method of claim 1 , wherein the TCR comprises
a CDR1α chain consisting of the amino acid sequence of SEQ ID NO: 1,
a CDR2α chain consisting of the amino acid sequence of SEQ ID NO: 2,
a CDR3α chain consisting of the amino acid sequence of SEQ ID NO: 3,
a CDR1β chain consisting of the amino acid sequence of SEQ ID NO: 7,
a CDR2β chain consisting of the amino acid sequence of SEQ ID NO: 8, and
a CDR3β chain consisting of the amino acid sequence of SEQ ID NO: 9.
14. The method of claim 1 , wherein the TCR comprises an α chain variable region having 80% sequence identity to the amino acid sequence of SEQ ID NO: 4 and a β chain variable region having 80% sequence identity to the amino acid sequence SEQ ID NO: 10.
15. The method of claim 1 , wherein the TCR comprises an α chain variable region having 95% sequence identity to the amino acid sequence of SEQ ID NO: 4 and a β chain variable region having 95% sequence identity to the amino acid sequence SEQ ID NO: 10.
16. The method of claim 14 , wherein in α chain variable region or the β chain variable region comprises an amino acid at position 44 according to the IMGT numbering substituted with another suitable amino acid thereby improving stability and/or pairing of said chains.
17. The method of claim 1 , wherein the TCR comprises an α chain constant region having 80% sequence identity to the amino acid sequence of SEQ ID NO: 5 and a β chain constant region having 80% sequence identity to the amino acid sequence SEQ ID NO: 11.
18. The method of claim 1 , wherein the TCR comprises an α chain constant region having 95% sequence identity to the amino acid sequence of SEQ ID NO: 5 and a β chain constant region having 95% sequence identity to the amino acid sequence SEQ ID NO: 11.
19. The method of claim 1 , wherein the TCR comprises an α chain having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 6 and a β chain having at least 80% sequence identity to the amino acid sequence SEQ ID NO: 12.
20. The method of claim 1 , wherein the TCR comprises an α chain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 6 and a β chain having at least 95% sequence identity to the amino acid sequence SEQ ID NO: 12.