Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and 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 in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

中文翻译：

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ARGX-119 是一种人 MuSK 激动剂抗体，可在先天性肌无力综合征小鼠模型中逆转疾病复发


肌肉特异性激酶 （MuSK） 对于神经肌肉突触的形成、功能和保存至关重要。MuSK 激动剂抗体激活 MuSK 可以稳定或改善 NMJ 疾病（如先天性肌无力 （CM））患者的神经肌肉接头 （NMJ） 功能。在这里，我们生成并表征了 ARGX-119，这是一种针对 MuSK 的一流人源化激动剂单克隆抗体，正在开发用于治疗神经肌肉疾病患者。我们进行了体外配体结合测定，表明 ARGX-119 以高亲和力结合人、非人灵长类动物、大鼠和小鼠 MuSK 的卷曲样结构域，没有脱靶结合，使其适合临床开发。在 Fc 区域内，ARGX-119 携带 L234A 和 L235A 突变，以减少潜在的免疫激活效应器功能。其作用方式是激活 MuSK，不干扰其天然配体神经 Agrin，并以剂量依赖性方式聚集乙酰胆碱受体，从而稳定神经肌肉功能。在 DOK7 CM 小鼠模型中，ARGX-119 通过以剂量依赖性方式恢复神经肌肉功能并减少肌肉无力和疲劳性，防止成年 Dok7 CM 小鼠的出生后早期致死并逆转疾病复发。在非人灵长类动物、大鼠和小鼠中的药代动力学研究揭示了 ARGX-119 的非线性 PK 行为，表明靶点介导的药物处置和体内靶点参与。在这项概念验证研究的基础上，ARGX-119 有可能缓解以神经肌肉突触功能受损为特征的神经肌肉疾病，需要进一步的临床开发。