MuSK agonistic antibody has therapeutic potential for MuSK antibody-positive myasthenia gravis.

Muscle-specific tyrosine kinase (MuSK)-antibody-positive myasthenia gravis (MG) is caused by MuSK autoantibodies that disrupt acetylcholine receptor clustering at neuromuscular junctions, resulting in muscle weakness and often a severe myasthenic crisis. Given the limited efficacy of conventional treatments involving immunosuppressants and steroids for patients with MuSK-MG, novel treatment approaches have been actively explored. In this study, we investigated the potential of the MuSK agonistic antibody, a novel therapeutic tool, to recover MuSK signaling in the presence of varying levels of autoantibodies. We obtained MuSK agonistic antibodies that bind to the Fz domain of MuSK. The efficacy of the antibody was demonstrated in a MuSK-MG mouse model. The effect of MuSK signaling recovery by our MuSK agonistic antibody was evaluated in the presence of autoantibodies in sera collected from 12 patients with MuSK-MG. We found that a decreasing trend of MuSK signaling recovery by MuSK agonistic antibody was observed upon increasing the serum concentration in some cases. Our findings imply that, for the future clinical development of a MuSK agonistic antibody, there is a need to identify those who will respond well to such an antibody or to develop an add-on treatment to reduce autoantibody levels. This would mitigate the potential risk of insufficient efficacy of such an antibody in patients with MuSK-MG who have high autoantibody concentrations.