Chimeric antigen receptors targeting B-cell maturation antigen
The invention provides an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA). The invention also provides host cells, such as T-cells or natural killer (NK) cells, expressing the CAR and methods for destroying multiple myeloma cells.
1. A chimeric antigen receptor (CAR) comprising:
(a) an antigen binding domain, wherein the antigen binding domain comprises an antigen-binding portion of a monoclonal antibody that binds B-Cell Maturation Antigen (BCMA) or a variable region of a monoclonal antibody that binds BCMA;
(b) a hinge domain;
(c) a transmembrane domain that comprises a CD28 transmembrane domain or a CD8α transmembrane domain;
(d) a 4-1BB intracellular T cell signaling domain; and
(e) a CD3 ζ intracellular T cell signaling domain.
2. The CAR of claim 1 , wherein the antigen binding domain comprises a single chain variable fragment (scFv) of a monoclonal antibody that binds BCMA.
3. The CAR of claim 1 , wherein the variable region comprises a heavy chain variable region of a monoclonal antibody that binds BCMA.
4. The CAR of claim 1 , wherein the hinge domain comprises a CD8α hinge domain.
5. The CAR of claim 1 , wherein the hinge domain comprises a CD28 hinge domain.
6. The CAR of claim 1 , wherein the transmembrane domain is a CD8α transmembrane domain.
7. The CAR of claim 1 , wherein the transmembrane domain is a CD28 transmembrane domain.
8. The CAR of claim 1 , wherein the antigen binding domain comprises an scFv that binds BCMA and the transmembrane domain comprises the CD28 transmembrane domain.
9. The CAR of claim 1 , wherein the antigen binding domain comprises a heavy chain variable region of a monoclonal antibody that binds BCMA, the hinge domain comprises a CD8α hinge domain, and the transmembrane domain comprises the CD8α transmembrane domain.
10. A CAR comprising:
(a) an scFv that binds BCMA;
(b) a hinge domain;
(c) a human CD28 transmembrane domain;
(d) a human 4-1BB intracellular T cell signaling domain; and
(e) a human CD3 ζ intracellular T cell signaling domain.
11. A CAR comprising:
(a) a variable region of a monoclonal antibody that binds BCMA;
(b) a human CD8α hinge domain;
(c) a human CD8α transmembrane domain;
(d) a human 4-1BB intracellular T cell signaling domain; and
(e) a human CD3 ζ intracellular T cell signaling domain.
12. A polynucleotide encoding the CAR of claim 1 .
13. A lentiviral vector comprising the polynucleotide of claim 12 .
14. A T cell that expresses the CAR of claim 1 .
15. A composition comprising the T cell of claim 14 .
16. A pharmaceutical composition comprising the T cell of claim 14 and a pharmaceutically acceptable carrier.
17. A method of treating a subject that has multiple myeloma comprising administering to the subject the pharmaceutical composition of claim 16 .
18. A polynucleotide encoding the CAR of claim 10 .
19. A lentiviral vector comprising the polynucleotide of claim 18 .
20. A T cell that expresses the CAR of claim 10 .
21. A composition comprising the T cell of claim 20 .
22. A pharmaceutical composition comprising the T cell of claim 20 and a pharmaceutically acceptable carrier.
23. A method of treating a subject that has multiple myeloma comprising administering to the subject the pharmaceutical composition of claim 22 .
24. A polynucleotide encoding the CAR of claim 11 .
25. A lentiviral vector comprising the polynucleotide of claim 24 .
26. A T cell that expresses the CAR of claim 11 .
27. A composition comprising the T cell of claim 26 .
28. A pharmaceutical composition comprising the T cell of claim 26 and a pharmaceutically acceptable carrier.
29. A method of treating a subject that has multiple myeloma comprising administering to the subject the pharmaceutical composition of claim 28 .