Anti-BCMA chimeric antigen receptors
Provided herein are chimeric antigen receptors (CARs), such as those specific for BCMA, that have improved properties, including increased CAR T cell binding to BCMA and improved CAR T cell killing of BCMA-expressing cancer cells. Use of the CARs in immune cells (e.g., T cells), compositions (e.g., CARs and nucleic acid constructs encoding the same), and methods are also contemplated.
1. A chimeric antigen receptor (CAR) comprising:
(i) an anti-B-Cell Maturation Antigen (BCMA) binding domain;
(ii) a transmembrane domain; and
(iii) a cytoplasmic domain,
wherein the anti-BCMA binding domain comprises:
a heavy chain complementarity determining region 1 (CDRH1) comprising any one of SEQ ID NOs: 1-3;
a heavy chain complementarity determining region 2 (CDRH2) comprising any one of SEQ ID NOs: 4-6;
a heavy chain complementarity determining region 3 (CDRH3) comprising any one of SEQ ID NOs: 7-9;
a light chain complementarity determining region 1 (CDRL1) comprising any one of SEQ ID NOs: 10-11;
a light chain complementarity determining region 2 (CDRL2) comprising any one of SEQ ID NOs: 12-15; and
a light chain complementarity determining region 3 (CDRL3) comprising any one of SEQ ID NOs: 16-18;
provided that the anti-BCMA binding domain does not comprise all six of the following:
a CDRH1 comprising SEQ ID NO: 1;
a CDHR2 comprising SEQ ID NO: 4;
a CDHR3 comprising SEQ ID NO: 7;
a CDRL1 comprising SEQ ID NO: 10;
a CDRL2 comprising SEQ ID NO: 12; and
a CDRL3 comprising SEQ ID NO: 16.
2. The CAR of claim 1 , wherein the CDRH3 comprises SEQ ID NO: 7.
3. The CAR of claim 1 , wherein the CDRH3 comprises SEQ ID NO: 8.
4. The CAR of claim 1 , wherein the CDRH3 comprises SEQ ID NO: 9.
5. The CAR of claim 1 , wherein the CDRL3 comprises SEQ ID NO: 16.
6. The CAR of claim 1 , wherein the CDRL3 comprises SEQ ID NO: 17.
7. The CAR of claim 1 , wherein the CDRL3 comprises SEQ ID NO: 18.
8. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 3;
(ii) the CDRH2 comprises SEQ ID NO: 4;
(iii) the CDRH3 comprises SEQ ID NO: 7;
(iv) the CDRL1 comprises SEQ ID NO: 10;
(v) the CDRL2 comprises SEQ ID NO: 12; and
(vi) the CDRL3 comprises SEQ ID NO: 16.
9. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 1;
(ii) the CDRH2 comprises SEQ ID NO: 4;
(iii) the CDRH3 comprises SEQ ID NO: 8;
(iv) the CDRL1 comprises SEQ ID NO: 10;
(v) the CDRL2 comprises SEQ ID NO: 12; and
(vi) the CDRL3 comprises SEQ ID NO: 16.
10. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 1;
(ii) the CDRH2 comprises SEQ ID NO: 4;
(iii) the CDRH3 comprises SEQ ID NO: 7;
(iv) the CDRL1 comprises SEQ ID NO: 11;
(v) the CDRL2 comprises SEQ ID NO: 14; and
(vi) the CDRL3 comprises SEQ ID NO: 17.
11. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 1;
(ii) the CDRH2 comprises SEQ ID NO: 4;
(iii) the CDRH3 comprises SEQ ID NO: 7;
(iv) the CDRL1 comprises SEQ ID NO: 11;
(v) the CDRL2 comprises SEQ ID NO: 14; and
(vi) the CDRL3 comprises SEQ ID NO: 18.
12. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 2;
(ii) the CDRH2 comprises SEQ ID NO: 6;
(iii) the CDRH3 comprises SEQ ID NO: 9;
(iv) the CDRL1 comprises SEQ ID NO: 10;
(v) the CDRL2 comprises SEQ ID NO: 12; and
(vi) the CDRL3 comprises SEQ ID NO: 16.
13. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 3;
(ii) the CDRH2 comprises SEQ ID NO: 5;
(iii) the CDRH3 comprises SEQ ID NO: 8;
(iv) the CDRL1 comprises SEQ ID NO: 10;
(v) the CDRL2 comprises SEQ ID NO: 12; and
(vi) the CDRL3 comprises SEQ ID NO: 16.
14. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 3;
(ii) the CDRH2 comprises SEQ ID NO: 4;
(iii) the CDRH3 comprises SEQ ID NO: 9;
(iv) the CDRL1 comprises SEQ ID NO: 10;
(v) the CDRL2 comprises SEQ ID NO: 12; and
(vi) the CDRL3 comprises SEQ ID NO: 18.
15. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 2;
(ii) the CDRH2 comprises SEQ ID NO: 6;
(iii) the CDRH3 comprises SEQ ID NO: 9;
(iv) the CDRL1 comprises SEQ ID NO: 11;
(v) the CDRL2 comprises SEQ ID NO: 13; and
(vi) the CDRL3 comprises SEQ ID NO: 17.
16. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 1;
(ii) the CDRH2 comprises SEQ ID NO: 4;
(iii) the CDRH3 comprises SEQ ID NO: 7;
(iv) the CDRL1 comprises SEQ ID NO: 10;
(v) the CDRL2 comprises SEQ ID NO: 15; and
(vi) the CDRL3 comprises SEQ ID NO: 16.
17. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 2;
(ii) the CDRH2 comprises SEQ ID NO: 6;
(iii) the CDRH3 comprises SEQ ID NO: 9;
(iv) the CDRL1 comprises SEQ ID NO: 11;
(v) the CDRL2 comprises SEQ ID NO: 14; and
(vi) the CDRL3 comprises SEQ ID NO: 17.
18. The CAR of claim 1 , wherein:
(i) the CDRH1 comprises SEQ ID NO: 2;
(ii) the CDRH2 comprises SEQ ID NO: 6;
(iii) the CDRH3 comprises SEQ ID NO: 9;
(iv) the CDRL1 comprises SEQ ID NO: 11;
(v) the CDRL2 comprises SEQ ID NO: 14; and
(vi) the CDRL3 comprises SEQ ID NO: 18.
19. The CAR of claim 1 , wherein the CDRH1 comprises SEQ ID NO: 1.
20. The CAR of claim 1 , wherein the CDRH1 comprises SEQ ID NO: 2.
21. The CAR of claim 1 , wherein the CDRH1 comprises SEQ ID NO: 3.
22. The CAR of claim 1 , wherein the CDRH2 comprises SEQ ID NO: 4.
23. The CAR of claim 1 , wherein the CDRH2 comprises SEQ ID NO: 5.
24. The CAR of claim 1 , wherein the CDRH2 comprises SEQ ID NO: 6.
25. The CAR of claim 1 , wherein the CDRL1 comprises SEQ ID NO: 10.
26. The CAR of claim 1 , wherein the CDRL1 comprises SEQ ID NO: 11.
27. The CAR of claim 1 , wherein the CDRL2 comprises SEQ ID NO: 12.
28. The CAR of claim 1 , wherein the CDRL2 comprises SEQ ID NO: 13.
29. The CAR of claim 1 , wherein the CDRL2 comprises SEQ ID NO: 14.
30. The CAR of claim 1 , wherein the CDRL2 comprises SEQ ID NO: 15.