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 population of T cells that express a chimeric antigen receptor (CAR), the 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 CD3ζ intracellular T cell signaling domain.
2. The population of T cells of claim 1 , wherein the antigen binding domain comprises a single chain variable fragment (scFv) of a monoclonal antibody that binds BCMA.
3. The population of T cells of claim 1 , wherein the variable region comprises a heavy chain variable region of a monoclonal antibody that binds BCMA.
4. The population of T cells of claim 1 , wherein the hinge domain comprises a CD8α hinge domain.
5. The population of T cells of claim 1 , wherein the hinge domain comprises a CD28 hinge domain.
6. The population of T cells of claim 1 , wherein the transmembrane domain is a CD8α transmembrane domain.
7. The population of T cells of claim 1 , wherein the transmembrane domain is a CD28 transmembrane domain.
8. The population of T cells 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 population of T cells 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. The population of T cells of claim 1 , wherein the T cells comprise CD8+ T cells.
11. The population of T cells of claim 1 , wherein the T cells comprise CD4+ T cells.
12. The population of T cells of claim 1 , wherein the T cells comprise CD8+ T cells and CD4+ T cells.
13. A population of T cells that express a CAR, the 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 CD3ζ intracellular T cell signaling domain.
14. A population of T cells that express a CAR, the 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 CD3ζ intracellular T cell signaling domain.
15. A population of T cells comprising a polynucleotide encoding a 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 CD3ζ intracellular T cell signaling domain.
16. The population of T cells of claim 15 , wherein the antigen binding domain comprises a single chain variable fragment (scFv) of a monoclonal antibody that binds BCMA.
17. The population of T cells of claim 15 , wherein the variable region comprises a heavy chain variable region of a monoclonal antibody that binds BCMA.
18. The population of T cells of claim 15 , wherein the hinge domain comprises a CD8α hinge domain.
19. The population of T cells of claim 15 , wherein the hinge domain comprises a CD28 hinge domain.
20. The population of T cells of claim 15 , wherein the transmembrane domain is a CD8α transmembrane domain.
21. The population of T cells of claim 15 , wherein the transmembrane domain is a CD28 transmembrane domain.
22. The population of T cells of claim 15 , wherein the antigen binding domain comprises an scFv that binds BCMA and the transmembrane domain comprises the CD28 transmembrane domain.
23. The population of T cells of claim 15 , 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.
24. The population of T cells of claim 15 , wherein the T cells comprise CD8+ T cells.
25. The population of T cells of claim 15 , wherein the T cells comprise CD4+ T cells.
26. The population of T cells of claim 15 , wherein the T cells comprise CD8+ T cells and CD4+ T cells.
27. The population of T cells of claim 15 , wherein:
(a) the antigen binding domain comprises an scFv that binds BCMA;
(b) the transmembrane domain comprises a human CD 28 transmembrane domain;
(c) the 4-1BB intracellular T cell signaling domain comprises a human 4-1BB intracellular T cell signaling domain; and
(d) the CD3ζ intracellular T cell signaling domain comprises a human CD3 intracellular T cell signaling domain.
28. The population of T cells of claim 15 , wherein:
(a) the antigen binding domain comprises a variable region of a monoclonal antibody that binds BCMA;
(b) the hinge domain comprises a human CD8α hinge domain;
(c) the transmembrane domain comprises a human CD8α transmembrane domain;
(d) the 4-1BB intracellular T cell signaling domain comprises a human 4-1BB intracellular T cell signaling domain; and
(e) the CD3ζ intracellular T cell signaling domain comprises a human CD3ζ intracellular T cell signaling domain.