Chimeric antigen receptors targeting BCMA and methods of use thereof
The present application provides single-domain antibodies targeting BCMA, and chimeric antigen receptors (such as monovalent CAR, and multivalent CAR including bi-epitope CAR) comprising one or more anti-BCMA single-domain antibodies. Further provided are engineered immune effector cells (such as T cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating cancer are also provided.
1. A chimeric antigen receptor (CAR) comprising a polypeptide comprising:
(a) an extracellular antigen binding domain comprising a first anti-BCMA single domain antibody (sdAb), and a second anti-BCMA sdAb; and wherein each of the first and second sdAb is a VHH domain;
(b) a transmembrane domain; and
(c) an intracellular signaling domain,
wherein:
(i) the first anti-BCMA sdAb comprises a CDR1, a CDR2 and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 124, and
(ii) the second anti-BCMA sdAb comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 117.
2. The CAR of claim 1 , wherein the first anti-BCMA sdAb is located at the N-terminus of the second anti-BCMA sdAb, or wherein the first anti-BCMA sdAb is located at the C-terminus of the second anti-BCMA sdAb.
3. The CAR of claim 1 , wherein the first anti-BCMA sdAb and the second anti-BCMA sdAb are directly fused to each other via a peptide bond or linked to each other via a peptide linker.
4. The CAR of claim 3 , wherein the first anti-BCMA sdAb and the second anti-BCMA sdAb are linked to each other via a peptide linker and the peptide linker comprises no more than 50 amino acid residues.
5. The CAR of claim 1 , wherein the transmembrane domain is derived from a molecule selected from the group consisting of CD8a, CD4, CD28, CD137, CD80, CD86, CD152 and PD1.
6. The CAR of claim 5 , wherein the transmembrane domain is derived from CD8α or CD28.
7. The CAR of claim 1 , wherein the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell.
8. The CAR of claim 7 , wherein the primary intracellular signaling domain is derived from CD3ζ.
9. The CAR of claim 1 , wherein the intracellular signaling domain comprises a co-stimulatory signaling domain.
10. The CAR of claim 9 , wherein the co-stimulatory signaling domain is derived from a co-stimulatory molecule selected from the group consisting of CD27, CD28, CD137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 and combinations thereof.
11. The CAR of claim 10 , wherein the co-stimulatory signaling domain comprises a cytoplasmic domain of CD28 or a cytoplasmic domain of CD137.
12. The CAR of claim 1 , further comprising a hinge domain located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain.
13. The CAR of claim 12 , wherein the hinge domain is derived from CD8α.
14. The CAR of claim 1 , further comprising a signal peptide located at the N-terminus of the polypeptide.
15. The CAR of claim 14 , wherein the signal peptide is derived from CD8α.
16. An engineered immune effector cell, comprising the CAR of claim 1 .
17. The engineered immune effector cell of claim 16 , wherein the immune effector cell is a T cell.
18. A pharmaceutical composition, comprising the engineered immune effector cell of claim 17 , and a pharmaceutically acceptable carrier.
19. A method of treating a cancer that expresses BCMA in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 18 .
20. The method of claim 19 , wherein the cancer is multiple myeloma.
21. The method of claim 19 , wherein the cancer is refractory or relapsed multiple myeloma.