Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
Exp Neurol. 2019 Jul;317:133-143. doi: 10.1016/j.expneurol.2019.03.001. Epub 2019 Mar 6.
Myasthenia gravis is hallmarked by fatigable muscle weakness resulting from neuromuscular synapse dysfunction caused by IgG autoantibodies. The variant with muscle-specific kinase (MuSK) autoantibodies is characterized by prominent cranial and bulbar weakness and a high frequency of respiratory crises. The majority of MuSK MG patients requires long-term immunosuppressive treatment, but the result of these treatments is considered less satisfactory than in MG with acetylcholine receptor antibodies. Emergency treatments are more frequently needed, and many patients develop permanent facial weakness and nasal speech. Therefore, new treatment options would be welcome. The neonatal Fc receptor protects IgG from lysosomal breakdown, thus prolonging IgG serum half-life. Neonatal Fc receptor antagonism lowers serum IgG levels and thus may act therapeutically in autoantibody-mediated disorders. In MuSK MG, IgG4 anti-MuSK titres closely correlate with disease severity. We therefore tested efgartigimod (ARGX-113), a new neonatal Fc receptor blocker, in a mouse model for MuSK myasthenia gravis. This model involves 11 daily injections of purified IgG4 from MuSK myasthenia gravis patients, resulting in overt myasthenic muscle weakness and, consequently, body weight loss. Daily treatment with 0.5 mg efgartigimod, starting at the fifth passive transfer day, reduced the human IgG4 titres about 8-fold, despite continued daily injection. In muscle strength and fatigability tests, efgartigimod-treated myasthenic mice outperformed control myasthenic mice. Electromyography in calf muscles at endpoint demonstrated less myasthenic decrement of compound muscle action potentials in efgartigimod-treated mice. These substantial in vivo improvements of efgartigimod-treated MuSK MG mice following a limited drug exposure period were paralleled by a tendency of recovery at neuromuscular synaptic level (in various muscles), as demonstrated by ex vivo functional studies. These synaptic improvements may well become more explicit upon longer drug exposure. In conclusion, our study shows that efgartigimod has clear therapeutic potential in MuSK myasthenia gravis and forms an exciting candidate drug for many autoantibody-mediated neurological and other disorders.
重症肌无力的特征是神经肌肉突触功能障碍导致的肌肉无力，这种功能障碍是由 IgG 自身抗体引起的。具有肌肉特异性激酶（MuSK）自身抗体的变异型以明显的颅神经和延髓肌无力以及呼吸危机的高频率为特征。大多数 MuSK MG 患者需要长期免疫抑制治疗，但这些治疗的结果被认为不如乙酰胆碱受体抗体阳性的 MG 患者令人满意。需要更频繁地进行紧急治疗，许多患者会出现永久性面部无力和鼻音。因此，欢迎新的治疗选择。新生 Fc 受体可防止 IgG 被溶酶体破坏，从而延长 IgG 的血清半衰期。新生 Fc 受体拮抗作用可降低血清 IgG 水平，因此可能在自身抗体介导的疾病中发挥治疗作用。在 MuSK MG 中，IgG4 抗-MuSK 滴度与疾病严重程度密切相关。因此，我们在 MuSK 重症肌无力的小鼠模型中测试了新型新生 Fc 受体阻断剂 efgartigimod（ARGX-113）。该模型涉及 MuSK 重症肌无力患者的 IgG4 纯化液的 11 次每日注射，导致明显的肌无力和体重减轻。从第 5 天开始每天给予 0.5mg efgartigimod 治疗，尽管持续每天注射，但可使 IgG4 滴度降低约 8 倍。在肌肉力量和疲劳性测试中，efgartigimod 治疗的肌无力小鼠的表现优于对照组的肌无力小鼠。在终点时的腓肠肌肌电图显示，efgartigimod 治疗的小鼠的复合肌肉动作电位的肌电衰减程度较低。在有限的药物暴露期间，MuSK MG 小鼠的这些实质性体内改善与神经肌肉突触水平（在各种肌肉中）的恢复趋势平行，这在体外功能研究中得到了证明。随着药物暴露时间的延长，这些突触改善可能会变得更加明显。总之，我们的研究表明，efgartigimod 在 MuSK 重症肌无力中具有明确的治疗潜力，并成为许多自身抗体介导的神经和其他疾病的令人兴奋的候选药物。
