MAGE-A4 T-cell receptor and method of use

Abstract

To provide a MAGE-A4 T cell receptor and a method for using the same.SOLUTION: Provided are an isolated T cell receptor (TCR) that specifically binds to an HLA-presenting cancer testis antigen melanoma-related target antigen A4 (MAGE-A4) peptide, and a method of treatment and diagnosis using the isolated TCR. The T cell receptor (TCR) is a membrane-binding heterodimer including α chain and β chain which resemble an immunoglobulin variable (V) region and a constant (C) region.SELECTED DRAWING: None

Claims

1. A T cell receptor (TCR) that specifically binds to the HLA-A2-presenting cancer testicular antigen melanoma-associated antigen 4 (MAGE-A4) peptide, wherein the TCR comprises a TCR alpha chain and a TCR beta chain, the TCR alpha chain comprises alpha chain variable domains including complementarity-determining regions (CDRs) 1, 2, and 3, respectively, containing the amino acid sequences of SEQ ID NOs. 662, 663, and 664, and the TCR beta chain comprises beta chain variable domains including CDR1, 2, and 3, respectively, containing the amino acid sequences of SEQ ID NOs. 670, 671, and 672.

2. The TCR according to claim 1, wherein the TCR alpha-chain variable domains CDR1, CDR2, and CDR3 and the TCR beta-chain variable domains CDR1, CDR2, and CDR3 are included in the TCR alpha-chain variable domain / TCR beta-chain variable domain amino acid sequence pair of Sequence ID No. 668 / 676.

3. The TCR according to claim 1 or 2, comprising the alpha-chain variable domain / beta-chain variable domain amino acid sequence pair of SEQ ID NO: 668 / 676.

4. The TCR according to claim 1 or 2, further comprising a detectable portion.

5. The TCR according to claim 1 or 2, wherein the TCR has on-target binding / off-target binding values ​​greater than 5, greater than 10, greater than 15, greater than 20, greater than 50, greater than 100, greater than 200, greater than 300, greater than 400, greater than 500, greater than 600, greater than 700, greater than 800, greater than 900, or greater than 1000.

6. The TCR according to claim 5, wherein the TCR has more than 10 on-target binding / off-target binding values.

7. The TCR according to claim 5, wherein the TCR has an on-target binding / off-target binding value greater than 500.

8. A pharmaceutical composition comprising a TCR according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.

9. Isolated cells exhibiting the TCR described in any one of claims 1 to 7.

10. A polynucleotide molecule comprising a polynucleotide sequence encoding the alpha-chain variable domain and the beta-chain variable domain of the TCR according to any one of claims 1 to 7.

11. A polynucleotide molecule according to claim 10, comprising the nucleotide sequence of sequence number 669.

12. A polynucleotide molecule according to claim 10, comprising the nucleotide sequence of sequence number 677.

13. A combination comprising a polynucleotide molecule containing a polynucleotide sequence encoding the alpha-chain variable domain of a TCR according to any one of claims 1 to 7, and a polynucleotide molecule containing a polynucleotide sequence encoding the beta-chain variable domain of a TCR according to any one of claims 1 to 7.

14. The combination according to claim 13, comprising the nucleotide sequence of sequence number 669.

15. The combination according to claim 13, comprising the nucleotide sequence of sequence number 677.

16. A vector comprising the polynucleotide molecule described in claim 10 or the combination described in claim 13.

17. Isolated cells comprising the vector according to claim 16.

18. The isolated cell according to claim 17, which is a T cell.

19. A pharmaceutical composition comprising isolated cells according to one of the claims 17, and a pharmaceutically acceptable carrier or diluent.

20. A combination comprising a vector containing a polynucleotide molecule comprising a polynucleotide sequence encoding the alpha-chain variable domain of a TCR according to any one of claims 1 to 7, and a vector containing a polynucleotide molecule comprising a polynucleotide sequence encoding the beta-chain variable domain of a TCR according to any one of claims 1 to 7.

21. Isolated cells comprising the combination described in claim 20.

22. The isolated cell according to claim 21, which is a T cell.

23. A pharmaceutical composition comprising isolated cells according to one of the claims 21 and a pharmaceutically acceptable carrier or diluent.

24. A composition comprising a TCR according to any one of claims 1 to 7 or isolated cells according to any one of claims 9, 17, and 21, or a pharmaceutical composition according to any one of claims 8, 19, and 23, for treating a subject having MAGE-A4-related disease or disorder.

25. The composition or pharmaceutical composition according to claim 24, wherein the MAGE-A4-related disease or disorder is MAGE-A4-related cancer.

26. The composition or pharmaceutical composition according to claim 25, wherein the MAGE-A4-related cancer is liposarcoma, neuroblastoma, myeloma, melanoma, metastatic melanoma, synovial sarcoma, bladder cancer, esophageal cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, head and neck cancer, non-small cell lung cancer, ovarian cancer, ovarian epithelial carcinoma, prostate cancer, breast cancer, astrocytic tumor, glioblastoma multiforme, undifferentiated astrocytoma, brain tumor, fallopian tube cancer, primary abdominal cancer, progressive solid tumor, soft tissue sarcoma, sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, metastatic solid tumor, colon cancer, stomach cancer, gastric cancer, rhabdomyosarcoma, myxoid round cell liposarcoma, or recurrent non-small cell lung cancer.

27. The composition or pharmaceutical composition according to any one of claims 24 to 26, wherein the composition or pharmaceutical composition is administered to the subject in combination with a second therapeutic agent.

28. The composition or pharmaceutical composition according to any one of claims 24 to 26, wherein the composition or pharmaceutical composition is administered parenterally.

29. (a) The property of not binding to cells expressing the predicted off-target peptide when determined by a luminescence assay, (b) The property of not binding to cells expressing the predicted off-target peptide when determined by flow cytometry assay, (c) The property of activating the T cell response twice as much as patient-derived MAGE-A4-specific TCRs, as determined by a TCR-mediated T cell signaling luminescence bioassay, (d) The property of activating the T cell response twice as much as affinity-matured (e.g., by phage display) MAGE-A4-specific TCRs, as determined by a TCR-mediated T cell signaling luminescence bioassay, A TCR according to claim 1 or 2, having characteristics selected from the group consisting of the following.

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