Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris
Jinmin Lee, … , Michael C. Milone, Aimee S. Payne
Jinmin Lee, … , Michael C. Milone, Aimee S. Payne
Published August 20, 2020
Citation Information: J Clin Invest. 2020;130(12):6317-6324. https://doi.org/10.1172/JCI138416.
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Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris

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.

Authors

Jinmin Lee, Daniel K. Lundgren, Xuming Mao, Silvio Manfredo-Vieira, Selene Nunez-Cruz, Erik F. Williams, Charles-Antoine Assenmacher, Enrico Radaelli, Sangwook Oh, Baomei Wang, Christoph T. Ellebrecht, Joseph A. Fraietta, Michael C. Milone, Aimee S. Payne

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Figure 1

DSG3-CAART specifically depletes primary human anti-DSG3 IgG B cells from PV patients.

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DSG3-CAART specifically depletes primary human anti-DSG3 IgG B cells fro...
B cells purified from PV or healthy donor (HD) PBMCs were cocultured with DSG3-CAART, CART19, or NTD cells, and then stimulated with IL-2 and R848 before incubation on plates coated with rhDSG3 and anti–human IgG (anti-hIgG) to quantify anti-DSG3 and total IgG B cells, respectively. BSA served as a negative control antigen. ELISpot analysis shows that anti-DSG3 IgG B cells, but not total IgG B cells, are depleted by DSG3-CAART in PV patients 1 and 2 (columns 1 and 4). In PV patient 3, anti-DSG3 B cells were not detectable (column 7). CART19 eliminates all IgG B cells from PV patients and the HD (rows 3 and 6). Number of spots detected in each well is shown on the top right corner of each well. Quantification discussed in Methods.