Antigen-specific B cell depletion with desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) for targeted therapy of mucosal pemphigus vulgaris

Abstract

Abstract Chimeric autoantibody receptors (CAARs) direct T cells to kill autoantigen-specific B cells. We previously established proof-of-concept for the CAAR approach using gene-engineered T cells expressing CAARs comprising DSG3, the autoantigen in the autoimmune blistering disease mucosal pemphigus vulgaris, fused to CD137-CD3ζ signaling domains. Here, we present results of preclinical studies that supported the DSG3-CAART investigational new drug application. DSG3-CAART demonstrated activity related to dose in a passive transfer polyclonal anti-DSG3 hybridoma mouse model of mucosal pemphigus vulgaris, resulting in reversal of the rising serum anti-DSG3 antibody titers, target cell burden, and IgG deposition in epithelial tissues, as well as increased DSG3-CAART engraftment relative to dose. We further evaluated DSG3-CAART efficacy in a novel exploratory active immune mouse model with physiologic levels of circulating anti-DSG3 IgG, which demonstrated decreased antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. High-throughput screening of a membrane protein array with soluble DSG3 CAAR did not identify verifiable off-target toxicities. These preclinical studies have enabled a first-in-human clinical trial of DSG3-CAART in mucosal pemphigus vulgaris and provide a foundation that may inform the preclinical development of future CAAR T cell therapies for antigen-specific B cell depletion in other autoantibody-mediated diseases.