Selective degradation of pathogenic autoantibodies by lysosomal targeting chimeras for the treatment of myasthenia gravis

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Abstract Myasthenia gravis, an autoimmune disease characterized by muscle weakness that can manifest in bulbar dysfunction and respiratory distress, is driven in a subset of patients by autoantibodies against muscle-specific receptor tyrosine kinase (MuSK MG). MuSK MG and other autoantibody mediated disorders are generally treated with broad immunosuppressive approaches such as corticosteroids, plasmapheresis, B cell depletion, or FcRn inhibition, which can impact patient care via systemic side effects, variable responsiveness, and increased susceptibility to infection. We developed a lysosomal targeting chimera (LYTAC) therapeutic (MuSK LYTAC) that combines a MuSK antigen “Bait” capable of selectively binding to the disease-driving antibodies with asialoglycoprotein receptor (ASGPR) ligands that target the resulting immune complexes for degradation by ASGPR-expressing hepatocytes. Our optimized MuSK Bait effectively depleted pathogenic antibodies from the serum of 10 donors with MuSK MG, supporting broad applicability across the patient population. In vitro assays using both Hep G2 cells and primary human hepatocytes demonstrated that MuSK LYTAC is pharmacologically active, promoting uptake and lysosomal degradation of autoantibodies through an ASGPR-dependent mechanism. Mouse pharmacodynamic and passive immunization disease models showed that MuSK LYTAC rapidly eliminates autoantibodies from the serum and alleviates related disease symptoms, without impacting circulating IgG levels. These results support the promise of Autoantibody Bait LYTACs (ABLates) as precision treatments for MuSK MG and other autoantibody-driven diseases that avoid generalized immunosuppression.

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