An mRNA-encoded Bispecific T-Cell Engager Targeting Muscle-Specific Tyrosine Kinase for Myasthenia Gravis.

Abstract

Muscle-specific tyrosine kinase antibody-positive myasthenia gravis (MuSK-MG) is a severe autoimmune disease with limited effective treatment options. We designed an mRNA-encoded bispecific T-cell engager (MuSK×CD3 TCE) comprising the human MuSK extracellular domain and an anti-CD3 single-chain variable fragment (scFv), delivered via a lipid nanoparticles (LNPs) to the liver to enable in vivo protein synthesis, which redirects cytotoxic T cells to eliminate B cells expressing anti-MuSK B cell receptors (BCR). In vitro, the MuSK×CD3 TCE mediated dose-dependent cytotoxicity against MuSK+ target cells and induced robust T cell activation. In human PBMC-engrafted NOG mice, mRNA-LNP administration led to dose-dependent and specific inhibition of tumor growth in anti-MuSK BCR-positive tumors, with no significant impact on non-target B cells. Importantly, the TCE retained potent cytotoxic activity in the presence of physiological concentrations of MuSK autoantibodies-a key consideration for clinical translation, as patients with MuSK-MG typically harbor circulating autoantibodies. This "off-the-shelf" mRNA-LNP platform offers a precise, controllable and potent immunotherapy strategy for MuSK-MG and may be broadly applicable for other autoantibody-mediated diseases to eliminate pathogenic BCR+ B cells.

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