Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells
Nature Biotechnology | January 19, 2023
Muscle-specifc tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efcacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, refecting MuSK-specifc B cell depletion. Specifc of-target interactions of MuSK-CAART were not identifed in vivo, in primary human cell screens or by high-throughput human membrane proteome array.These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.
Characterization of DSG3-CAART cells prior to & following adoptive transfer in mPV
ESGCT Congress | October 13, 2022
A Phase 1 trial of DSG3-CAART cells in mucosal-dominant pemphigus vulgaris patients: preliminary data
EADV Congress | September 10, 2022
A Phase 1 trial of DSG3-CAART cells in mucosal-dominant pemphigus vulgaris patients: preliminary data
EADV Congress (Abstract Only) | August 29, 2022
A Phase 1 Trial Of DSG3-CAART Cells In mPV Patients: Early Cohort Clinical and Translational Data
SID 2022 | May 20, 2022
Characterization of DSG3-CAART Cells Prior To & Following Adoptive Transfer in mPV
ASGCT 2022 | May 17, 2022
A Phase 1 Trial of Targeted DSG3-CAART Cell Therapy in mPV Patients: Early Cohort Data
ASGCT 2022 | May 17, 2022
Chimeric autoantibody receptor (CAAR) T cells as a precision therapy for antigen-specific B cell depletion in PLA2R membranous nephropathy
ASN Kidney Week 2021 | November 5, 2021
Antigen-specific B-cell depletion for precision therapy of mucosal pemphigus vulgaris
The Journal of Clinical Investigation | August 20, 2020
Desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3ζ signaling domains, represent a precision cellular immunotherapy approach for antigen-specific B cell depletion. Here, we present definitive preclinical studies enabling a first-in-human trial of DSG3-CAART for mucosal PV. DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity consistent with a threshold dose in vivo, resulting in decreased target cell burden, decreased serum and tissue-bound autoantibodies, and increased DSG3-CAART engraftment.
MuSK chimeric autoantibody receptor (CAAR) T cells for antigen-specific cellular immunotherapy of myasthenia gravis
AAN 2020 Abstract 2769 | May 18, 2020
Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease
Science | July 8, 2016
Autoimmune diseases such as lupus and rheumatoid arthritis lack therapies that specifically target only the disease-causing cells. Inspired by the clinical success of using chimeric antigen receptor T cells to treat certain types of cancers, Ellebrecht et al. asked whether a similar approach might also work against antibody-driven autoimmune diseases.