Human alpha-folate receptor chimeric antigen receptor
View Patent ↗The invention provides compositions and methods for treating ovarian cancer. Specifically, the invention relates to administering a genetically modified T cell having α-folate receptor (FRα) binding domain and CD27 costimulatory domain to treat ovarian cancer. In an embodiment, the FRα binding domain is fully human, thereby preventing a host immune response.
1. A chimeric antigen receptor (CAR) comprising a fully human FRα antibody or an FRα-binding fragment thereof, an intracellular domain of a costimulatory molecule, and a CD3 zeta signaling domain, wherein the intracellular domain of the costimulatory molecule is a CD27 costimulatory domain comprising the amino acid sequence of SEQ ID NO: 9, and wherein the fully human FRα-binding fragment comprises the amino acid sequence of SEQ ID NO: 5.
2. A chimeric antigen receptor (CAR) comprising a fully human FRα-binding fragment, an intracellular domain of a costimulatory molecule, and a CD3 zeta signaling domain, wherein the intracellular domain of the costimulatory molecule is a CD27 costimulatory domain comprising the amino acid sequence of SEQ ID NO: 9, and wherein the CAR comprises the amino acid sequence of SEQ ID NO: 1.
3. The CAR of claim 1 , wherein the fully human FRα antibody or the FRα-binding fragment thereof is a Fab or a scFv.
4. The CAR of claim 1 , wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 11.
5. The CAR of claim 1 , further comprising a transmembrane domain.
6. The CAR of claim 1 , further comprising a ligand that specifically binds with CD83.
7. A chimeric antigen receptor (CAR), wherein the CAR comprises the amino acid sequence of SEQ ID NO: 1.
8. The CAR of claim 7 , further comprising a ligand that specifically binds with CD83.
9. A genetically modified immune cell comprising a chimeric antigen receptor (CAR), the CAR comprising a fully human FRα antibody or an FRα binding fragment thereof, an intracellular domain of a costimulatory molecule, and a CD3 zeta signaling domain, wherein the intracellular domain of the costimulatory molecule is a CD27 costimulatory domain comprising the amino acid sequence of SEQ ID NO: 9, and wherein the fully human FRα-binding fragment comprises the amino acid sequence of SEQ ID NO: 5.
10. The immune cell of claim 9 , wherein the fully human FRα antibody or the FRα-binding fragment thereof is a Fab or a scFv.
11. The immune cell of claim 9 , wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 11.
12. The immune cell of claim 9 , the CAR further comprising a transmembrane domain.
13. The immune cell of claim 9 , further comprising a ligand that specifically binds with CD83.
14. The immune cell of claim 9 , wherein the immune cell is a T-cell.
15. A vector comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), the CAR comprising a fully human FRα antibody or a FRα binding fragment thereof, an intracellular domain of a costimulatory molecule, and a CD3 zeta signaling domain, wherein the intracellular domain of the costimulatory molecule is a CD27 costimulatory domain comprising the amino acid sequence of SEQ ID NO: 9, and wherein the FRα binding fragment comprises the amino acid sequence of SEQ ID NO: 5.
16. The vector of claim 15 , wherein the fully human FRα antibody or the FRα-binding fragment thereof is a Fab or a scFv.
17. The vector of claim 15 , wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 11.
18. The vector of claim 15 , the CAR further comprising a transmembrane domain.
19. The vector of claim 15 , further comprising a ligand that specifically binds with CD83.
20. The vector of claim 15 , wherein the vector is in an immune cell.
21. The vector of claim 20 , wherein the immune cell is a T cell.