T cell receptors that bind to mixed lineage leukemia (MLL)-specific phosphopeptides and methods of use thereof
Provided are TCRs (e.g., TCRs that bind to MLL, e.g., TCRs that bind to an MLL phosphopeptide, e.g., TCRs that bind to an MLL phosphopeptide/MHC complex), cells and pharmaceutical compositions comprising these TCRs, nucleic acids encoding these TCRs, expression vectors and host cells for making these TCRs, and methods of treating a subject using these TCRs.
1. A method of treating cancer in a subject, the method comprising administering to the subject an engineered cell comprising a T cell receptor (TCR) that comprises:
(a) a CDR1α comprising the amino acid sequence of SEQ ID NO: 11, a CDR2α comprising the amino acid sequence of SEQ ID NO: 16, a CDR3α comprising the amino acid sequence of SEQ ID NO: 21, a CDR1β comprising the amino acid sequence of SEQ ID NO: 26, a CDR2β comprising the amino acid sequence of SEQ ID NO: 31, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 36;
(b) a CDR1α comprising the amino acid sequence of SEQ ID NO: 12, a CDR2α comprising the amino acid sequence of SEQ ID NO: 17, a CDR3α comprising the amino acid sequence of SEQ ID NO: 22, a CDR1β comprising the amino acid sequence of SEQ ID NO: 27, a CDR2β comprising the amino acid sequence of SEQ ID NO: 32, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 37;
(c) a CDR1α comprising the amino acid sequence of SEQ ID NO: 13, a CDR2α comprising the amino acid sequence of SEQ ID NO: 18, a CDR3α comprising the amino acid sequence of SEQ ID NO: 23, a CDR1β comprising the amino acid sequence of SEQ ID NO: 28, a CDR2β comprising the amino acid sequence of SEQ ID NO: 33, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 38;
(d) a CDR1α comprising the amino acid sequence of SEQ ID NO: 13, a CDR2α comprising the amino acid sequence of SEQ ID NO: 109, a CDR3α comprising the amino acid sequence of SEQ ID NO: 23, a CDR1β comprising the amino acid sequence of SEQ ID NO: 28, a CDR2β comprising the amino acid sequence of SEQ ID NO: 33, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 38;
(e) a CDR1α comprising the amino acid sequence of SEQ ID NO: 14, a CDR2α comprising the amino acid sequence of SEQ ID NO: 19, a CDR3α comprising the amino acid sequence of SEQ ID NO: 24, a CDR1β comprising the amino acid sequence of SEQ ID NO: 29, a CDR2β comprising the amino acid sequence of SEQ ID NO: 34, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 39; or
(f) a CDR1α comprising the amino acid sequence of SEQ ID NO: 15, a CDR2α comprising the amino acid sequence of SEQ ID NO: 20, a CDR3α comprising the amino acid sequence of SEQ ID NO: 25, a CDR1β comprising the amino acid sequence of SEQ ID NO: 30, a CDR2β comprising the amino acid sequence of SEQ ID NO: 35, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 40.
2. The method of claim 1 , wherein the TCR comprises a CDR1α comprising the amino acid sequence of SEQ ID NO: 11, a CDR2α comprising the amino acid sequence of SEQ ID NO: 16, a CDR3α comprising the amino acid sequence of SEQ ID NO: 21, a CDR1β comprising the amino acid sequence of SEQ ID NO: 26, a CDR2β comprising the amino acid sequence of SEQ ID NO: 31, and a CDR3β comprising the amino acid sequence of SEQ ID NO: 36.
3. The method of claim 1 , wherein the TCR is a human TCR.
4. The method of claim 1 , wherein the TCR comprises:
(a) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 1, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 2;
(b) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 86, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 87;
(c) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 3, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 4;
(d) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 88, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 89;
(e) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 5, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 6;
(f) an α chain variable region (Vα) comprising the amino 5 acid sequence of SEQ ID NO: 106, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 107;
(g) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 7, and a β chain variable 10 region (Vβ) comprising the amino acid sequence of SEQ ID NO: 8;
(h) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 7, and a β chain variable region (Vβ) comprising the amino acid sequence of 15 SEQ ID NO: 108; or
(i) an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 9, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 10.
5. The method of claim 1 , wherein the TCR comprises an α chain variable region (Vα) comprising the amino acid sequence of SEQ ID NO: 86, and a β chain variable region (Vβ) comprising the amino acid sequence of SEQ ID NO: 87.
6. The method of claim 1 , wherein the TCR comprises:
(a) an α chain comprising the amino acid sequence of SEQ ID NO: 249, and a β chain comprising the amino acid sequence of SEQ ID NO: 250;
(b) an α chain comprising the amino acid sequence of any one of SEQ ID NOs: 58, 236, 259, 260, 272, 261, or 249, and a β chain comprising the amino acid sequence of any one of SEQ ID NOs: 59, 237, 262, 263, 264, 273, 60, and 250;
(c) an α chain comprising the amino acid sequence of SEQ ID NO: 251, and a β chain comprising the amino acid sequence of SEQ ID NO: 252;
(d) an α chain comprising the amino acid sequence of SEQ ID NO: 61, and a β chain comprising the amino acid sequence of SEQ ID NOs: 62 or 63;
(e) an α chain comprising the amino acid sequence of SEQ ID NO: 64, and a β chain comprising the amino acid sequence of SEQ ID NOs: 65 or 66;
(f) an α chain comprising the amino acid sequence of SEQ ID NO: 255, and a β chain comprising the amino acid sequence of SEQ ID NO: 256;
(g) an α chain comprising the amino acid sequence of SEQ ID NO: 67, and a β chain comprising the amino acid sequence of SEQ ID NOs: 68 or 69;
(h) an α chain comprising the amino acid sequence of SEQ ID NO: 257, and a β chain comprising the amino acid sequence of SEQ ID NO: 258; or
(i) an α chain comprising the amino acid sequence of SEQ ID NO: 70, and a β chain comprising the amino acid sequence of SEQ ID NOs: 71 or 72.
7. The method of claim 1 , wherein the TCR comprises an α chain comprising the amino acid sequence of SEQ ID NO: 58, and a β chain comprising the amino acid sequence of SEQ ID NO: 59.
8. The method of claim 1 , wherein the engineered cell is administered intravenously.
9. The method of claim 1 , further comprising administering an additional therapeutic agent to the subject.
10. The method of claim 9 , wherein the additional therapeutic agent is a chemotherapeutic, a radiotherapeutic, or a checkpoint targeting agent.
11. The method of claim 10 , wherein the checkpoint targeting agent is an antagonist anti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonist anti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonist VISTA antibody, an antagonist CD96 antibody, an antagonist anti-CEACAM1 antibody, an antagonist anti-TIGIT antibody, an agonist anti-CD137 antibody, an agonist anti-GITR antibody, or an agonist anti-OX40 antibody.
12. The method of claim 9 , wherein the additional therapeutic agent is a vaccine.
13. The method of claim 12 , wherein the vaccine comprises a heat shock protein peptide complex (HSPPC) comprising a heat shock protein complexed with an antigenic peptide.
14. The method of claim 13 , wherein the heat shock protein is hsc70 or gp96, and is complexed with a tumor-associated antigenic peptide.
15. The method of claim 1 , wherein the cancer is a MLL positive cancer.
16. The method of claim 15 , wherein the cancer is leukemia, myeloma, or sarcoma.
17. The method of claim 16 , wherein the leukemia is mixed lineage leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.
18. The method of claim 16 , wherein the myeloma is chronic myeloid cancer.
19. The method of claim 16 , wherein the sarcoma is synovial sarcoma or liposarcoma.
20. The method of claim 1 , wherein the engineered cell is a T cell, a natural killer T (NKT) cell, an invariant natural killer T (iNKT) cell, a mucosal-associated invariant T (MaiT) cell, or a natural killer (NK) cell.