Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
Provided herein are chimeric receptors, such as chimeric antigen receptors (CARs), comprising BCMA-binding molecules, such as anti-BCMA antibodies and antigen-binding fragments thereof, such as heavy chain variable (V H ) regions and single-chain antibody fragments, and encoding polynucleotides. In some embodiments, the anti-BCMA chimeric receptors specifically bind to BCMA. Among the anti-BCMA-binding molecules are human antibodies, including those that compete for binding to BCMA with reference antibodies, such as a non-human reference antibody. Also provided are genetically engineered cells expressing the CARs and uses thereof such as in adoptive cell therapy.
1. A polynucleotide encoding a chimeric antigen receptor, the polynucleotide comprising a nucleic acid sequence encoding: (a) an extracellular antigen-binding domain comprising a single-chain variable fragment (scFv) comprising a variable heavy chain (V H ) region and a variable light chain (V L ) region that specifically binds B cell maturation antigen (BCMA); (b) a spacer encoded by the nucleic acid sequence set forth in SEQ ID NO:622; (c) a transmembrane domain; and (d) an intracellular signaling region.
2. The polynucleotide of claim 1 , wherein:
(A) the V H region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within the V H region amino acid sequence set forth in SEQ ID NO:617; and the V L region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within the V L region amino acid sequence set forth in SEQ ID NO:618;
(B) the V H region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within the V H region amino acid sequence set forth in SEQ ID NO:609; and the V L region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within the V L region amino acid sequence set forth in SEQ ID NO:610;
(C) the V H region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within the V H region amino acid sequence set forth in SEQ ID NO:115; and the V L region comprises a CDR-LL a CDR-L2 and a CDR-L3 contained within the V L region amino acid sequence set forth in SEQ ID NO:536;
(D) the V H region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within the V H region amino acid sequence set forth in SEQ ID NO:519; and the V L region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within the V L region amino acid sequence set forth in SEQ ID NO:535; or
(E) the V H region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within the V H region amino acid sequence set forth in SEQ ID NO:256; and the V L region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within the V L region amino acid sequence set forth in SEQ ID NO:267.
3. The polynucleotide of claim 1 , wherein the V H region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within the V H region amino acid sequence set forth in SEQ ID NO:617; and the V L region comprises a CDR-LL a CDR-L2 and a CDR-L3 contained within the V L region amino acid sequence set forth in SEQ ID NO:618.
4. The polynucleotide of claim 1 , wherein:
(A) the V H region and the V L region comprise the amino acid sequences set forth in SEQ ID NOs:617 and 618, respectively;
(B) the V H region and the V L region comprise the amino acid sequences set forth in SEQ ID NOs:609 and 610, respectively;
(C) the V H region and the V L region comprise the amino acid sequences set forth in SEQ ID NOs:115 and 536, respectively;
(D) the V H region and the V L region comprise the amino acid sequences set forth in SEQ ID NOs:519 and 535, respectively; or
(E) the V H region and the V L region comprise the amino acid sequences set forth in SEQ ID NOs:256 and 267, respectively.
5. The polynucleotide of claim 1 , wherein the V H region and the V L region comprise the amino acid sequences set forth in SEQ ID NOs:617 and 618, respectively.
6. The polynucleotide of claim 1 , wherein the scFv comprises the amino acid sequence set forth in SEQ ID NO:478, SEQ ID NO:442, SEQ ID NO:560, SEQ ID NO:559, or SEQ ID NO:278.
7. The polynucleotide of claim 1 , wherein the scFv comprises the amino acid sequence set forth in SEQ ID NO:478.
8. The polynucleotide of claim 1 , wherein the transmembrane domain is from a human CD28.
9. The polynucleotide of claim 1 , wherein the intracellular signaling region comprises an activating cytoplasmic signaling domain that is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain.
10. The polynucleotide of claim 9 , wherein the intracellular signaling region further comprises an intracellular signaling domain of a CD28, a 4-1BB, or an ICOS.
11. The polynucleotide of claim 9 , wherein the intracellular signaling region further comprises an intracellular signaling domain of a 4-1BB.
12. The polynucleotide of claim 1 , wherein the transmembrane domain is from a human CD28, and the intracellular signaling region comprises an activating cytoplasmic signaling domain that is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and an intracellular signaling domain of a CD28 or a 4-1BB T cell costimulatory molecule.
13. The polynucleotide of claim 1 , wherein the transmembrane domain is from a human CD28, and the intracellular signaling region comprises a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and an intracellular signaling domain of a 4-1BB T cell costimulatory molecule.
14. A vector comprising the polynucleotide of claim 1 .
15. An engineered cell, comprising the polynucleotide of claim 1 .
16. A T cell, comprising the polynucleotide of claim 1 .
17. A composition comprising the engineered cell of claim 15 .
18. A composition comprising the T cell of claim 16 .
19. A chimeric antigen receptor encoded by the polynucleotide of claim 1 .
20. An engineered cell, comprising the chimeric antigen receptor of claim 19 .
21. A composition comprising the engineered cell of claim 20 .
22. A T cell, comprising the chimeric antigen receptor of claim 19 .
23. A composition comprising the T cell of claim 22 .