Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models

Abstract

AbstractMuscle-specific kinase (MuSK) orchestrates establishment and maintenance of neuromuscular synapses, which enable muscle contraction. Autoantibodies targeting MuSK cause myasthenia gravis (MG), a disease characterized by fatigable skeletal muscle weakness which requires chronic immunosuppressive treatment and ventilatory support at some point in ∼30% of patients. MuSK autoantibodies are predominantly IgG4 and are bispecific, functionally monovalent antibodies due to Fab-arm exchange. Through monovalent binding, MuSK IgG4 autoantibodies act as antagonists on the MuSK signalling pathway, impairing neuromuscular synaptic function. In contrast, bivalent MuSK antibodies act as agonists of the MuSK signalling pathway. Since symptoms in MuSK MG are largely caused by antagonistic monovalent MuSK antibodies, we hypothesized that a bivalent MuSK agonist could rescue MuSK MG, bypassing the need for generalized immunosuppression. In this study, we investigated whether an agonist antibody targeting the Frizzled-like domain of MuSK, ARGX-119, can ameliorate disease in MuSK MG models induced by passive transfer of polyclonal IgG4 from unrelated patients. For each patient material we first established the minimal dose for a progressive MG phenotype based on muscle function tests. ARGX-119 significantly improved survival and muscle weakness in a mouse model induced by one patient material, but not by three others. Mechanistically, this patient-specific efficacy could not be explained by autoantibody epitope specificity, titer or competition for ARGX-119 binding, but rather correlated to the presence of MuSK activating antibodies in some patients. We further provide evidence that anin vitroassay may predict which patients potentially benefit from ARGX-119 and that this treatment, when effective in MuSK MG mice, follows a bell-shaped dose-effect curve. These results provide first proof of concept of a MuSK agonist in a clinically relevant model for MuSK MG. We anticipate this to be a starting point for investigating the therapeutic benefit of ARGX-119 in MuSK MG and other neuromuscular diseases hallmarked by neuromuscular synaptic dysfunction.Graphical abstractHighlightsMuSK agonist ARGX-119 can rescue MuSK MG in a patient-specific mannerMuSK agonism follows a bell-shaped efficacy curve in this MuSK MG mouse modelVariation in ARGX-119 efficacy between patient models is not explained by competition for binding on MuSK, but rather appears related to an agonistic fraction of patient antibodiesAnin vitroassay is potentially predictive for treatment efficacy of the MuSK agonist