TCR and uses thereof
The present invention relates to a TCR or functional variant thereof having antigenic specificity for CD1c molecules associated with a self-lipid, preferably (mLPA) or derivative thereof, to relative polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population of cells, antibody and pharmaceutical composition. The present invention also relates to the uses of said TCR and relative products, in particular for use in the treatment and/or prevention of an hematological disorder.
1. An isolated or purified T-cell receptor (TCR) having antigenic specificity for a self-lipid associated to CDIc molecule, wherein the self-lipid is a methyl-lysophosphatidic acid or derivative thereof wherein the TCR is in monomeric form and comprises:
a complementary determining region (CDRa1) amino acid sequence of SEQ. ID NO: 25; and
a complementary determining region (CDRa2) amino acid sequence of SEQ. ID NO: 26; and
a complementary determining region (CDRa3) amino acid sequence of SEQ. ID NO: 27; and
a complementary determining region (CDRb1) amino acid sequence of SEQ. ID NO: 28; and
a complementary determining regions (CDRb2) amino acid sequence of SEQ. ID NO: 29; and
complementary determining regions (CDRb3) amino acid sequence of SEQ. ID NO: 30.
2. The isolated or purified T-cell receptor (TCR) according to claim 1 wherein the methyl-lysophosphatidic acid is selected from the group consisting of: methyl-lysophosphatidic acid (mLPA), C16-methyl-lysophosphatidic acid (C16-mLPA) or C18-methyl-lysophosphatidic acid (C18-mLPA) or a derivative thereof.
3. An isolated or purified nucleic acid comprising a nucleotide sequence encoding the TCR as defined in claim 1 .
4. The isolated or purified nucleic acid according to claim 3 , wherein the nucleotide sequence comprises a) a nucleotide sequence of SEQ ID NOs: 15 and b) a nucleotide sequence of SEQ ID NOs: 16.
5. A recombinant expression vector comprising the nucleic acid according to claim 3 .
6. An isolated host cell comprising the recombinant expression vector of claim 5 .
7. A pharmaceutical composition comprising
a T cell comprising a recombinant expression vector including a nucleic acid encoding for a TCR
and a pharmaceutically acceptable carrier;
wherein the TCR has antigenic specificity for a self-lipid associated to CDIc molecule, wherein the self-lipid is a methyl-lysophosphatidic acid or derivative thereof;
wherein the TCR is in monomeric form and comprises;
a complementary determining region (CDRa1) amino acid sequence of SEQ. ID NO: 25; and
a complementary determining region (CDRa2) amino acid sequence of SEQ. ID NO: 26; and
a complementary determining region (CDRa3) amino acid sequence of SEQ. ID NO: 27; and
a complementary determining region (CDRb1) amino acid sequence of SEQ. ID NO: 28; and
a complementary determining regions (CDRb2) amino acid sequence of SEQ. ID NO: 29; and
complementary determining regions (CDRb3) amino acid sequence of SEQ. ID NO: 30.
8. The pharmaceutical composition according to claim 7 further comprising methyl lysophosphatidic acid (mLPA).
9. A method of treating a hematological disorder in a subject, the method comprising administering the pharmaceutical composition of claim 7 , wherein the hematological disorder is characterized by mLPA+ CD1c+ cancer cells.
10. The method of claim 9 wherein the hematological disorder is characterized by blood and bone marrow accumulation of immature and abnormal cells derived from hematopoietic precursors.
11. The method of claim 9 , wherein the hematological disorder is acute leukemia.
12. The method of claim 9 , further comprising administering at least one of asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, and/or azacytidine.
13. The method of claim 9 , wherein the method further comprises preventing hematological disorder relapse following hematopoietic stem cell transplantation (HSCT).
14. The method of claim 9 , wherein the pharmaceutical composition further comprises methyl lysophosphatidic acid (mLPA).
15. A method for the production of a host cell as defined in claim 6 comprising the step of transducing said host cell with a nucleic acid encoding for a TCR in monomeric form, wherein the TCR comprises:
a complementary determining region (CDRa1) amino acid sequence of SEQ. ID NO: 25; and
a complementary determining region (CDRa2) amino acid sequence of SEQ. ID NO: 26; and
a complementary determining region (CDRa3) amino acid sequence of SEQ. ID NO: 27; and
a complementary determining region (CDRb1) amino acid sequence of SEQ. ID NO: 28; and
a complementary determining regions (CDRb2) amino acid sequence of SEQ. ID NO: 29; and
complementary determining regions (CDRb3) amino acid sequence of SEQ. ID NO: 30.
16. The method according to claim 15 further comprising expanding said host cell.
17. The isolated or purified nucleic acid according to claim 3 , wherein the nucleotide sequence is codon optimized.
18. The isolated or purified T-cell receptor (TCR) according to claim 1 , wherein the TCR further comprises a murine, a human or a humanized amino acid sequence of a constant region.
19. The isolated host cell according to claim 6 , wherein the host cell is a T cell.
20. An isolated or purified T-cell receptor (TCR) having antigenic specificity for a self-lipid associated to CDIc molecule, wherein the self-lipid is a methyl-lysophosphatidic acid or derivative thereof, wherein the TCR is in monomeric form and comprises:
the amino acid sequence of SEQ ID NO: 1; and
the amino acid sequence of SEQ ID NO: 2.
21. An isolated or purified T-cell receptor (TCR) having antigenic specificity for a self-lipid associated to CD1c molecule, wherein the self-lipid is a methyl-lysophosphatidic acid or derivative thereof, wherein the TCR is in monomeric form and comprises:
the amino acid sequence of SEQ ID NO: 1; and
the amino acid sequence of SEQ ID No: 2, and
wherein the TCR further comprises a murine, a human or a humanized amino acid sequence of a constant region.
22. The method of claim 11 wherein the acute leukemia is primary acute myeloid leukemia or B-cell acute leukemia.
23. The method according to claim 16 wherein said host cell is expanded in the presence of methyl lysophosphatidic acid (mLPA).
24. The isolated or purified T-cell receptor (TCR) according to claim 18 , wherein the murine, human or humanized amino acid sequence of the constant region comprises:
the amino acid sequence of SEQ ID NO: 11;
the amino acid sequence of SEQ ID NO: 12; or
the amino acid sequence of SEQ ID NO: 13; or
the amino acid sequence of SEQ ID NO: 14.
25. The isolated or purified T-cell receptor (TCR) according to claim 21 , wherein the murine, human or humanized amino acid sequence of the constant region comprises:
the amino acid sequence of SEQ ID NO: 11;
the amino acid sequence of SEQ ID NO: 12; or
the amino acid sequence of SEQ ID NO: 13; or
the amino acid sequence of SEQ ID NO: 14.