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- Title
Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris.
- Authors
Jinmin Lee; Lundgren, Daniel K.; Xuming Mao; Manfredo-Vieira, Silvio; Nunez-Cruz, Selene; Williams, Erik F.; Assenmacher, Charles-Antoine; Radaelli, Enrico; Sangwook Oh; Baomei Wang; Ellebrecht, Christoph T.; Fraietta, Joseph A.; Milone, Michael C.; Payne, Aimee S.; Lee, Jinmin; Mao, Xuming; Oh, Sangwook; Wang, Baomei
- Abstract
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. In a PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. DSG3 autoantibodies stimulated DSG3-CAART IFN-γ secretion and homotypic clustering, consistent with an activated phenotype. Toxicology screens using primary human cells and high-throughput membrane proteome arrays did not identify off-target cytotoxic interactions. These preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical development for other antibody-mediated diseases.
- Subjects
B cells; PEMPHIGUS; CHIMERIC antigen receptors; ANTIBODY formation; EPITHELIUM; PEMPHIGUS treatment; BIOLOGICAL models; AUTOANTIBODIES; RESEARCH; IMMUNIZATION; ANIMAL experimentation; RESEARCH methodology; IMMUNOSUPPRESSION; ISOANTIGENS; EVALUATION research; MEDICAL cooperation; INTERFERONS; COMPARATIVE studies; RESEARCH funding; ANTIGENS; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 12, p6317
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI138416