ARGX-119, a therapeutic agonist antibody targeting MuSK
ARGX-119 is a novel, humanized, agonist monoclonal SIMPLE Antibody specific for muscle-specific kinase (MuSK) that is being developed for treatment of patients with neuromuscular diseases. ARGX-119 is the first monoclonal antibody (mAb) that binds with high affinity to the Frizzled-like domain of human, non-human primate, rat and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc-region, ARGX-119 harbors L234A, L235A mutations to diminish potential immune-activating effector functions. Its mode-of-action is to activate MuSK without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors (AChRs) in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model for DOK7 congenital myasthenia (CM), ARGX-119 prevented early postnatal lethality and reversed disease relapse by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic (PK) studies in non-human primates, rats and mice revealed non-linear PK behavior of ARGX-119, indicative of target-mediated-drug disposition (TMDD) and in vivo target engagement. Instability of neuromuscular synapses contributes to symptoms in many neuromuscular diseases for example congenital myasthenia (CM), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). ARGX-119 is a novel, first-in-class MuSK agonist mAb in clinical development. Based on this proof-of-concept study, it has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function. One sentence summaryARGX-119 is a novel first-in-class MuSK agonist monoclonal antibody in clinical development for treatment of neuromuscular diseases.