Chimeric antigen receptors targeting CD37
Described herein are chimeric antigen receptors (CARs) targeting CD37, as well as related molecules and methods.
1. A chimeric antigen receptor (CAR) polypeptide comprising:
a) an extracellular domain comprising a CD37-binding sequence comprising an antibody light chain variable domain of SEQ ID NO: 4 and an antibody heavy chain variable domain of SEQ ID NO: 2;
b) a transmembrane domain; and
c) a T cell intracellular signaling domain.
2. The CAR polypeptide of claim 1 , wherein the CAR polypeptide comprises a single-chain variable fragment (scFv).
3. The CAR polypeptide of claim 2 , wherein the scFv comprises the antibody light chain variable domain N-terminal to the antibody heavy chain variable domain.
4. The CAR polypeptide of claim 2 , wherein the scFv comprises the antibody heavy chain variable domain N-terminal to the antibody light chain variable domain.
5. The CAR polypeptide of claim 1 , wherein the CAR polypeptide comprises a sequence selected from SEQ ID NO: 1 or 5.
6. The CAR polypeptide of claim 1 , wherein the transmembrane domain comprises the transmembrane domain from CD8 or 4-1BB.
7. The CAR polypeptide of claim 1 , wherein the CAR polypeptide further comprises a co-stimulatory domain comprising the co-stimulatory domain of 4-1BB.
8. The CAR polypeptide of claim 7 , wherein the co-stimulatory domain comprises the sequence of SEQ ID NO: 13.
9. The CAR polypeptide of claim 1 , wherein the T cell intracellular domain comprises a CD3ζ intracellular signaling domain.
10. The CAR polypeptide of claim 9 , wherein the CD3ζ intracellular signaling domain comprises the sequence of SEQ ID NO: 14.
11. The CAR polypeptide of claim 9 , wherein the CD3ζ intracellular signaling domain comprises 1 or 2 immunoreceptor tyrosine-based activation motifs (ITAMs), and the native tyrosine residues of the ITAM(s) are maintained.
12. The CAR polypeptide of claim 1 , comprising the sequence of SEQ ID NO: 9 or comprising the sequence of SEQ ID NO: 15.
13. A mammalian cell comprising:
a) the CAR polypeptide of claim 1 ; or
b) a nucleic acid encoding the CAR polypeptide of claim 1 .
14. The cell of claim 13 , wherein the cell is a T cell.
15. A method of treating cancer, a plasma cell disorder, or an autoimmune disease in a subject in need thereof, the method comprising:
a) engineering a T cell to comprise a CAR polypeptide of claim 1 on the T cell surface;
b) administering the engineered T cell to the subject.
16. A method of treating cancer, a plasma cell disorder, or an autoimmune disease in a subject in need thereof, the method comprising:
a) selecting a subject who is non-responsive to anti-CD19 and/or anti-CD20 therapy;
b) engineering a T cell to comprise a CAR polypeptide of claim 1 on the T cell surface;
c) administering the engineered T cell to the subject;
wherein the subject is non-responsive to anti-CD19 and/or anti-CD20 therapy.
17. The CAR polypeptide of claim 1 , comprising the sequence of SEQ ID NO: 15.