Combined T cell receptor gene therapy of cancer against MHC I and MHC II-restricted epitopes of the tumor antigen NY-ESO-1
The present invention relates to the field of immunotherapy, in particular adoptive T cell therapy or T cell receptor (TCR) gene therapy of cancer. The invention provides a nucleic acid encoding at least one T cell receptor alpha chain construct and/or TCR beta chain construct of a TCR construct capable of specifically binding to an epitope from NY-ESO-1 (also designated CTAG-1) in complex with a human MHC, wherein the TCR alpha chain construct and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid selected from SEQ ID NO: 1-20. The invention provides TCR constructs restricted to an epitope from NY-ESO-1 presented on MHC I, and, for the first time, TCR constructs restricted to an epitope from NY-ESO-1 presented on MHC II molecules, and thus enables a combined adoptive T cell therapy with both recombinant CD4+ and re-combinant CD8+ T cells. The invention also provides proteins and host cells corresponding to said TCR constructs, as well as the medical use of such constructs, in particular, in the diagnosis, prevention, and/or treatment of a proliferative or viral disease, wherein, preferably, both TCR constructs restricted to MHC I and MHC II molecules are provided in a kit. The invention also relates to a mouse transgenic for the human TCR loci and human HLA-DR4, ABabDR4 mouse.
1. A nucleic acid encoding at least one T cell receptor (TCR) alpha chain construct and/or TCR beta chain construct of a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MEW, wherein the TCR alpha chain construct and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) as set forth in SEQ ID NO: 1 or having at least 90% sequence identity to an amino acid selected from SEQ ID NOs: 2 and 4-19 .
2. The nucleic acid of claim 1 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID:21 in complex with HLA-DR4, wherein the TCR alpha chain construct comprises a CDR3 as set forth in SEQ ID NO: 1 or having at least 90% sequence identity to an amino acid selected from SEQ ID NOs: 2 and 4-9 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid selected from SEQ ID NOs: 10-18.
3. The nucleic acid of claim 2 ,
a) wherein the TCR alpha chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NOs: 22-30, which is optionally encoded by a sequence selected from SEQ ID NOs: 31-39, wherein the TCR alpha chain construct preferably comprises a sequence having at least 80% sequence identity to any of SEQ ID NOs: 40-48 and is optionally encoded by any of SEQ ID NOs: 49-57,
b) and/or wherein the TCR beta chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NOs: 58-66, which is optionally encoded by a sequence selected from SEQ ID NOs: 67-75, wherein the TCR beta chain construct preferably comprises a sequence having at least 80% sequence identity to any of SEQ ID NOs: 76-84 and is optionally encoded by any of SEQ ID NOs: 85-93,
c) wherein the TCR construct is preferably encoded by any of SEQ ID NOs: 94-102;
d) wherein the TCR alpha chain construct and/or TCR/beta chain construct or TCR construct preferably is an expression vector suitable for expression is a host cell selected from the group comprising a human T cell.
4. The nucleic acid of claim 1 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID:103 in complex with HLA-A2, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to SEQ ID NO: 19 and the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to SEQ ID NO: 20.
5. The nucleic acid of claim 4 ,
a) wherein the TCR alpha chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NO: 104, which is optionally encoded by SEQ ID NO: 105, wherein the TCR alpha chain construct preferably comprises a sequence having at least 80% sequence identity to SEQ ID NO: 106 and is optionally encoded by SEQ ID NO: 107,
b) and/or wherein the TCR beta chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NO: 108, which is optionally encoded by SEQ ID NO: 109, wherein the TCR beta chain construct preferably comprises a sequence having at least 80% sequence identity to SEQ ID NO: 110 and is optionally encoded by SEQ ID NO: 111,
c) wherein the TCR construct is preferably encoded by SEQ ID NO: 112,
d) wherein the TCR alpha chain construct and/or TCR/beta chain construct or TCR construct preferably is an expression vector suitable for expression is a host cell selected from the group comprising a human T cell.
6. A protein encoded by the nucleic acid of claim 1 .
7. A host cell comprising a nucleic acid of claim 1 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO::21 in complex with HLA-DR4, wherein the TCR alpha chain construct comprises a CDR3 as set forth in SEQ ID NO: 1 or having at least 90% sequence identity to an amino acid selected from SEQ ID NOs: 2 and 4-9 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid selected from SEQ ID NOs: 10-18, and wherein the host cell preferably is a CD4+T cell.
8. A pharmaceutical composition comprising
a) a nucleic acid of claim 1 encoding a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MHC.
9. The pharmaceutical composition of claim 8 , comprising a nucleic acid wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID:21 in complex with HLA-DR4, wherein the TCR alpha chain construct comprises a CDR3 as set forth in SEQ ID NO: 1 or having at least 90% sequence identity, preferably, 100% sequence identity, to an amino acid selected from SEQ ID NO: 2-9 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity, preferably, 100% sequence identity, to an amino acid selected from SEQ ID NO: 10-18, a protein encoded by said nucleic acid, or a host cell comprising said nucleic acid.
10. The pharmaceutical composition of claim 8 , comprising a nucleic acid wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID:103 in complex with HLA-A2, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity, preferably, 100% sequence identity, to SEQ ID NO: 19 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity, preferably, 100% sequence identity, to SEQ ID NO: 20, a protein encoded by said nucleic acid, or a host cell comprising said nucleic acid.
11. A kit for use in medicine, comprising, as a first component
a) a nucleic acid encoding a TCR alpha chain construct and/or TCR beta chain construct capable of specifically binding to an epitope from a NY-ESO-1 in complex with a human MHC II wherein the TCR alpha chain construct and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) as set forth in SEQ ID NO: 1 or having at least 90% sequence identity to an amino acid selected from SEQ ID NOs: 2 and 4-19; or
b) a protein encoded by said nucleic acid of part a comprising a TCR construct capable of specifically binding to NY-ESO-1 in complex with a human MHC II; or
c) a host cell comprising the nucleic acid of part a,
and/or
i) a nucleic acid encoding at least one T cell receptor (TCR) alpha chain construct and/or TCR beta chain construct of a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MHC I, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid as set forth in SEQ ID NO: 3 and wherein the TCR alpha chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NO: 24 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid as set forth in SEQ ID NO: 20 and wherein the TCR beta chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NO: 108; or
ii) a protein encoded by said nucleic acid of part i comprising a TCR construct capable of specifically binding to an epitope from said defined antigen in complex with a human MHC I; or
iii) a host cell comprising the nucleic acid of part i,
wherein said defined antigen preferably is a tumor-associated or tumor-specific antigen selected from the group comprising cancer-testis-antigens such as NY-ESO-1.
12. A kit of claim 11 , wherein the nucleic acid of part a encodes a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MHC, wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID: 21 in complex with HLA-DR4, wherein the TCR alpha chain construct comprises a CDR3 as set forth in SEQ ID NO: 1 or having 100% sequence identity to an amino acid selected from SEQ ID NO: 2, 4-9 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to an amino acid selected from SEQ ID NO: 10-18.
13. The pharmaceutical composition of claim 8 for use in the diagnosis, prevention and/or treatment of a proliferative or viral disease,
preferably a benign or malignant tumor disease, wherein the proliferating cells or the tumor expresses NY-ESO-1.
14. The pharmaceutical composition of claim 13 for use in immune therapy, preferably, in adoptive T cell therapy or TCR gene therapy.
15. A host cell comprising a nucleic acid of claim 1 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO:103 in complex with HLA-A2, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to SEQ ID NO: 19 and the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to SEQ ID NO: 20, and wherein the host cell preferably is a CD8+T cell.
16. A pharmaceutical composition comprising a protein of claim 6 comprising a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MHC.
17. A pharmaceutical composition comprising a host cell of claim 7 expressing a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MHC.
18. The kit of claim 11 for use in the diagnosis, prevention and/or treatment of a proliferative or viral disease, preferably a benign or malignant tumor disease, wherein the proliferating cells or the tumor expresses NY-ESO-1.
19. The kit for use of claim 18 for use in immune therapy, preferably, in adoptive T cell therapy or TCR gene therapy.
20. The nucleic acid of claim 2 , wherein the TCR alpha chain construct comprises a CDR3 having 100% sequence identity to an amino acid selected from SEQ ID NOs: 2 and 4-9 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to an amino acid selected from SEQ ID NO: 10-18.
21. The nucleic acid of claim 4 , wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity-to SEQ ID NO: 19 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to SEQ ID NO: 20.
22. The host cell of claim 7 , wherein the TCR alpha chain construct comprises a CDR3 having 100% sequence identity to an amino acid selected from SEQ ID NOs: 2 and 4-9 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to an amino acid selected from SEQ ID NOs: 10-18.
23. The host cell of claim 15 , wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to SEQ ID NO: 19 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to SEQ ID NO: 20.
24. A nucleic acid encoding at least one T cell receptor (TCR) alpha chain construct and/or TCR beta chain construct of a TCR construct capable of specifically binding to an epitope from NY-ESO-1 in complex with a human MHC, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid as set forth in SEQ ID NO: 3 and wherein the TCR alpha chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NO: 24 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to an amino acid as set forth in SEQ ID NO: 20 and wherein the TCR beta chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to SEQ ID NO: 108.
25. The nucleic acid of claim 24 , wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity-to SEQ ID NO: 3 and/or the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to SEQ ID NO: 20.
26. The nucleic acid of claim 24 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID:21 in complex with HLA-DR4.
27. The nucleic acid of claim 24 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO:103 in complex with HLA-A2.
28. A host cell comprising a nucleic acid of claim 24 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO:21 in complex with HLA-DR4.
29. A host cell comprising a nucleic acid of claim 24 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO:103 in complex with HLA-A2.
30. The nucleic acid of claim 1 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID:103 in complex with HLA-A2, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to SEQ ID NO: 19.
31. The nucleic acid of claim 30 , wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to SEQ ID NO: 19.
32. A host cell comprising a nucleic acid of claim 1 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO:103 in complex with HLA-A2, wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having at least 90% sequence identity to SEQ ID NO: 19, and wherein the host cell preferably is a CD8+T cell.
33. The host cell of claim 32 , wherein the TCR alpha chain construct comprises a complementarity determining region 3 (CDR3) having 100% sequence identity to SEQ ID NO: 19.
34. The host cell of claim 7 , wherein the host cell is a human T cell.
35. The host cell of claim 15 , wherein the host cell is a human T cell.
36. The host cell of claim 28 , wherein the host cell is a human T cell.
37. The host cell of claim 29 , wherein the host cell is a human T cell.
38. The host cell of claim 32 , wherein the host cell is a human T cell.
39. The nucleic acid of claim 2 , wherein the TCR alpha chain construct comprises a CDR3 having SEQ ID NO: 2, and/or the TCR beta chain construct comprises a CDR3 having SEQ ID NO: 11.
40. The nucleic acid of claim 39 , wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to SEQ ID NO: 23, and/or the TCR beta chain construct comprises a variable region having at least 80% sequence identity to SEQ ID NO: 59.
41. The nucleic acid of claim 40 , wherein the TCR alpha chain construct comprises a variable region having SEQ ID NO: 23, and/or the TCR beta chain construct comprises a variable region having SEQ ID NO: 59.
42. A host cell comprising a nucleic acid of claim 39 , wherein the TCR construct is capable of specifically binding to the epitope consisting of SEQ ID NO:21 in complex with HLA-DR4.
43. The host cell of claim 42 , wherein the host cell is a human T cell.