To investigate the efficacy and safety of a novel gene-engineered cellular immunotherapy for antigen-specific B cell depletion in myasthenia gravis.

Myasthenia gravis (MG) is a B cell-mediated autoimmune disorder caused by autoantibodies that interrupt signaling at the neuromuscular junction (NMJ), resulting in life-threatening muscle weakness. A subset of MG patients (6-7.5%) is sero-positive for autoantibodies targeting muscle-specific tyrosine kinase (MuSK); a disease subtype with high unmet clinical need and limited treatment options. Current therapies rely on broad immunosuppression to reduce autoantibody production, which risks serious infections. By expressing the MuSK autoantigen, which is the target of autoantibody attack in MuSK MG, on the surface of a human T cell, fused to CD137 and CD3zeta cytoplasmic domains, MuSK CAAR T cells direct cytotoxicity toward antigen-specific memory B cells expressing anti-MuSK autoantibodies as surface B cell receptors (BCRs).

The efficacy and safety of MuSK CAAR T cells were investigated using in vitro cytotoxicity assays, in vitro screens for off-target toxicity, and a mouse model to evaluate the efficacy of human MuSK CAAR T cells against anti-MuSK B cells in vivo.

MuSK CAAR T cells demonstrated specific cytotoxicity toward a panel of anti-MuSK B cells targeting different MuSK epitopes. Cytotoxicity toward cells expressing the MuSK ligand LRP4 was not observed. In a NOD-SCID-gamma (NSG) mouse model, MuSK CAAR T cells, but not non-transduced or control CAAR T cells, suppressed the expansion of Nalm6 B cells expressing anti-MuSK BCRs.

These data establish the preliminary safety and efficacy of MuSK CAAR T cells in achieving antigen-specific B cell depletion in MuSK MG. MuSK CAAR T cells represent a precision medicine cellular immunotherapy that offers the potential for durable remissions of MG.