Chimeric autoantibody receptor T cells for targeted depletion of myeloperoxidase-specific anti-neutrophil cytoplasmic antibody-producing B cells.

Anti-neutrophil cytoplasmic antibody (ANCA) vasculitides are autoimmune disorders driven by autoantibodies against neutrophil granule proteins, myeloperoxidase (MPO) and proteinase 3, which cause necrotizing small-vessel inflammation with prominent lung and kidney involvement, resulting in pulmonary hemorrhage and glomerulonephritis. Current remission-induction regimens rely on broad immunosuppression and global B cell depletion, which are effective but associated with substantial infection risk and relapse that often necessitates repetitive, long-term treatment. Here, we develop MPO chimeric autoantibody receptor (CAAR) T cells as a target-specific therapy to eliminate MPO-autoreactive B cells. MPO CAAR T cells selectively eliminated anti-MPO BCR-expressing B cell lines in vitro and in vivo. In primary murine autoreactive B cell cultures, MPO CAAR T cells suppressed anti-MPO IgG production without inducing global B cell depletion. Together, these findings support MPO CAAR T cells as a precision approach to eliminate pathogenic B cells in ANCA vasculitis, potentially eliminating the need for generalized humoral immunosuppression.