An Agonist Antibody to MuSK As A Theraputic For MuSK Myasthenia Gravis

New York University School Of Medicine, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is a debilitating autoimmune disease. Antibodies against muscle specific kinase (MuSK), a receptor tyrosine kinase that is essential for the maintenance of neuromuscular synapses, is an important cause. One third of MuSK MG patients experience a life-threatening respiratory crisis for which artificial ventilator support is necessary. Long-term immunosuppression is the only treatment option. A novel and specific therapeutic intervention is sorely needed. The Verschuuren and van der Maarel labs used passive transfer studies to show that IgG4 antibodies from MuSK MG patients cause disease without requiring complement or other immune components. The Burden lab showed that MuSK activation requires binding between lipoprotein related protein 4 (Lrp4) and MuSK. In collaboration, we showed that patient antibodies bind to the first Ig-like domain in MuSK, prevent association between MuSK and Lrp4 and block Agrin-stimulated MuSK phosphorylation. These findings insight suggest specific treatment options. We have used an agonist antibody to MuSK, generated by Genentech, to show that the MuSK agonist antibody reverses the inhibitory effects of the IgG4 patient antibodies in cultured myotubes and restores MuSK phosphorylation. We propose to use cultured muscle cells and passive transfer assays in mice to determine whether the pathogenic effects of the MuSK IgG4 antibodies can be reduced or prevented by the MuSK agonist antibody. If successful, this strategy could be transferred to a clinical setting.