Compositions and methods of chimeric autoantibody receptor t cells

Abstract

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 sequence encoding a chimeric autoantibody receptor (CAAR), wherein the isolated nucleic acid sequence comprises a nucleic acid sequence of an autoantigen or fragment thereof, a nucleic acid sequence of a transmembrane domain, a nucleic acid sequence of an intracellular domain of a costimulatory molecule, and a nucleic acid sequence of a signaling domain. 
     
     
         2 . The isolated nucleic acid sequence of  claim 1 , wherein the autoantigen is selected from the group consisting of Dsg1, Dsg3, and a fragment thereof. 
     
     
         3 . The isolated nucleic acid sequence of  claim 2 , wherein the autoantigen comprises Dsg3 comprising 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, SEQ ID NO:12, and SEQ ID NO:36. 
     
     
         4 . The isolated nucleic acid sequence of  claim 2 , wherein the autoantigen comprises Dsg3 and the isolated nucleic acid sequence further comprises a nucleic acid sequence encoding a propeptide of Dsg3. 
     
     
         5 . The isolated nucleic acid sequence of  claim 4 , wherein the Dsg3 propeptide comprises an amino acid sequence of SEQ ID NO:2. 
     
     
         6 . The isolated nucleic acid sequence of  claim 1  further comprises a nucleic acid sequence of a CD8 alpha chain signal peptide. 
     
     
         7 . The isolated nucleic acid sequence of  claim 7 , wherein the CD8 alpha chain signal peptide comprises an amino acid sequence of SEQ ID NO:1. 
     
     
         8 . The isolated nucleic acid sequence of  claim 1 , wherein the nucleic acid sequence of the transmembrane domain encodes a CD8 alpha chain hinge and transmembrane domain. 
     
     
         9 . The isolated nucleic acid sequence of  claim 8 , wherein the CD8 alpha chain hinge and transmembrane domain comprises an amino acid sequence of SEQ ID NO:13. 
     
     
         10 . The isolated nucleic acid sequence of  claim 1  further comprises a nucleic acid sequence of a peptide linker. 
     
     
         11 . The isolated nucleic acid sequence of  claim 10 , wherein the peptide linker comprises an amino acid sequence of SEQ ID NO:14. 
     
     
         12 . The isolated nucleic acid sequence of  claim 1 , wherein the nucleic acid sequence of the intracellular signaling domain comprises a nucleic acid sequence encoding a CD137 intracellular domain. 
     
     
         13 . The isolated nucleic acid sequence of  claim 12 , wherein the CD137 intracellular domain comprises an amino acid sequence of SEQ ID NO:15. 
     
     
         14 . The isolated nucleic acid sequence of  claim 1 , wherein the nucleic acid sequence of the intracellular signaling domain comprises a nucleic acid sequence encoding a CD3 zeta signaling domain. 
     
     
         15 . The isolated nucleic acid sequence of  claim 14 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO:16. 
     
     
         16 . A vector comprising the isolated nucleic acid sequence of  claim 1 . 
     
     
         17 - 18 . (canceled) 
     
     
         19 . An isolated chimeric autoantibody receptor (CAAR) comprising an extracellular domain comprising an autoantigen or fragment thereof, a transmembrane domain, and an intracellular signaling domain. 
     
     
         20 . The isolated CAAR of  claim 19 , wherein the autoantigen is selected from the group consisting of Dsg1, Dsg3, and a fragment thereof. 
     
     
         21 - 33 . (canceled) 
     
     
         34 . A genetically modified cell comprising the CAAR of  claim 20 . 
     
     
         35 - 39 . (canceled) 
     
     
         40 . A method for treating an autoimmune disease in a subject, the method comprising: administering to the subject an effective amount of a genetically modified T cell comprising an isolated nucleic acid sequence encoding a chimeric autoantibody receptor (CAAR), wherein the isolated nucleic acid sequence comprises an extracellular domain comprising an autoantigen or fragment thereof, a nucleic acid sequence of a transmembrane domain, and a nucleic acid sequence of an intracellular signaling domain, thereby treating the autoimmune disease in the subject. 
     
     
         41 - 43 . (canceled)