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 human T cell comprising a nucleic acid that encodes a chimeric antigen receptor (CAR) comprising:
(a) an antigen recognition moiety that binds human B-Cell Maturation Antigen (BCMA);
(b) a CD8α hinge domain;
(c) a CD8α transmembrane domain;
(d) a 4-1BB intracellular T cell signaling domain; and
(e) a CD3ζ intracellular T cell signaling domain.
2. The human T cell of claim 1 , wherein the antigen recognition moiety is an antigen binding portion of an antibody.
3. The human T cell of claim 1 , wherein the antigen recognition moiety comprises a variable region.
4. The human T cell of claim 1 , wherein the antigen recognition moiety comprises two variable regions.
5. The human T cell of claim 3 , wherein the antigen recognition moiety comprises a heavy chain variable (VH) region.
6. The human T cell of claim 1 , wherein the antigen recognition moiety comprises a complementarity determining region (CDR) 1, a CDR2 and a CDR3.
7. The human T cell of claim 5 , wherein the VH region comprises VH CDR1, VH CDR2 and VH CDR3.
8. The human T cell of claim 4 , wherein each of the variable regions comprises a CDR1, CDR2 and CDR3.
9. The human T cell of claim 1 , wherein the CAR further comprises a signal sequence.
10. The human T cell of claim 9 , wherein the signal sequence is a CD8α signal sequence.
11. The human T cell of claim 1 , wherein the CD32 intracellular T cell signaling domain comprises the CD32 intracellular T cell signaling domain in SEQ ID NO: 10.
12. The human T cell of claim 1 , wherein the 4-1BB intracellular T cell signaling domain comprises the 4-1BB intracellular T cell signaling domain in SEQ ID NO: 10.
13. The human T cell of claim 1 , wherein the CD35 intracellular T cell signaling domain comprises the CD3ζ intracellular T cell signaling domain in SEQ ID NO: 10 and the 4-1BB intracellular T cell signaling domain comprises the 4-1BB intracellular T cell signaling domain in SEQ ID NO: 10.
14. The human T cell of claim 1 , wherein the CD8a transmembrane domain is the CD8α transmembrane domain of SEQ ID NO: 10.
15. The human T cell of claim 1 , wherein the CD32 intracellular T cell signaling domain comprises the CD32 intracellular T cell signaling domain in SEQ ID NO: 10; the 4-1BB intracellular T cell signaling domain comprises the 4-1BB intracellular T cell signaling domain in SEQ ID NO: 10 and the CD8α transmembrane domain is the CD8α transmembrane domain of SEQ ID NO: 10.
16. The human T cell of claim 10 , wherein the signal sequence is the CD8α signal sequence of SEQ ID NO: 10.
17. The human T cell of claim 9 , wherein the CD3ζ intracellular T cell signaling domain comprises the CD32 intracellular T cell signaling domain in SEQ ID NO: 10; the 4-1BB intracellular T cell signaling domain comprises the 4-1BB intracellular T cell signaling domain in SEQ ID NO: 10; the CD8α transmembrane domain is the CD8α transmembrane domain of SEQ ID NO: 10 and the signal sequence is the CD8α signal sequence of SEQ ID NO: 10.
18. The human T cell of claim 1 , wherein the T cell is from a human subject having multiple myeloma.
19. The human T cell of claim 1 , wherein the human T cell is a tumor infiltrating T cell.
20. The human T cell of claim 1 , wherein the human T cell is a CD4+ T cell, a CD8+ T cell, or a memory T cell.