Compositions and methods of chimeric autoantibody receptor T cells
The invention includes compositions comprising at least one chimeric autoantibody receptor (CAAR) specific for an autoantibody, vectors comprising the same, compositions comprising CAAR vectors packaged in viral particles, and recombinant T cells comprising the CAAR. The invention also includes methods of making a genetically modified T cell expressing a CAAR (CAART) wherein the expressed CAAR comprises a desmoglein extracellular domain.
1. An isolated nucleic acid encoding a chimeric receptor comprising an extracellular domain comprising Dsg1, Dsg3, or a fragment thereof that binds an autoantibody expressed on a B-cell, and a transmembrane domain, wherein the chimeric receptor, when present on the surface of a cell, binds the autoantibody expressed on the B-cell or induces killing of the B-cell expressing the autoantibody.
2. The isolated nucleic acid of claim 1 , wherein the cell is selected from the group consisting of a helper T cell, a cytotoxic T cell, a memory cell, a regulatory T cell, a gamma delta T cell, a natural killer cell, a cytokine induced killer cell, and a cell line thereof.
3. The isolated nucleic acid of claim 1 , wherein the extracellular domain comprises Dsg3 or a fragment thereof.
4. The isolated nucleic acid of claim 3 , wherein the extracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36.
5. The isolated nucleic acid of claim 1 , wherein the chimeric receptor further comprises a CD8 alpha chain signal peptide.
6. The isolated nucleic acid of claim 5 , wherein the CD8 alpha chain signal peptide comprises the amino acid sequence of SEQ ID NO:1.
7. The isolated nucleic acid of claim 1 , wherein the extracellular domain comprises Dsg3 or a fragment thereof and the chimeric receptor further comprises a propeptide of Dsg3.
8. The isolated nucleic acid of claim 1 , wherein the transmembrane domain comprises a KIR transmembrane domain.
9. The isolated nucleic acid of claim 1 , wherein the transmembrane domain comprises a CD8 alpha chain hinge and transmembrane domain.
10. The isolated nucleic acid of claim 9 , wherein the CD8 alpha chain hinge and transmembrane domain comprises the amino acid sequence of SEQ ID NO:13.
11. The isolated nucleic acid of claim 1 , wherein the chimeric receptor further comprises a peptide linker.
12. The isolated nucleic acid of claim 11 , wherein the peptide linker comprises the amino acid sequence of SEQ ID NO:14.
13. The isolated nucleic acid of claim 1 , wherein the chimeric receptor further comprises a KIR cytoplasmic domain.
14. The isolated nucleic acid of claim 1 , wherein the chimeric receptor further comprises an intracellular signaling domain.
15. The isolated nucleic acid of claim 14 , wherein the intracellular signaling domain comprises a CD137 intracellular domain.
16. The isolated nucleic acid of claim 15 , wherein the CD137 intracellular domain comprises the amino acid sequence of SEQ ID NO:15.
17. The isolated nucleic acid of claim 14 , wherein the intracellular signaling domain comprises a CD3 zeta signaling domain.
18. The isolated nucleic acid of claim 17 , wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO:16.
19. The isolated nucleic acid of claim 1 , wherein the chimeric receptor, when present on the surface of a cell, has limited toxicity toward a healthy cell.
20. A vector comprising the isolated nucleic acid sequence of claim 1 .
21. The vector of claim 20 , wherein the vector is selected from the group consisting of a lentiviral vector, and an RNA vector.