Complement inhibition in Myasthenia – from basics to RCT data

S. Jacob
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Abstract

Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder causing fatiguable muscle weakness either limited to the ocular muscles or becoming generalised involving the limb and bulbar muscles. Nine out of 10 generalised MG patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). AChR antibodies cause neuromuscular weakness by internalisation of AChR, receptor blockade and by activating the complement pathway. Complement activation causes formation of the membrane attack complex (MAC) leading to degradation of the neuromuscular junction (NMJ). Several animal models have confirmed the role of complement in the pathogenesis of MG, with the experimental models (EAMG) often needing complement inhibitory therapies to prevent or reverse the disease. Various molecules that target the complement system have now been developed to treat myasthenia gravis. The vast majority of the currently studied molecules target the C5 protein, thereby preventing the formation of MAC and subsequent NMJ destruction. The currently studied anti-complement therapies for MG include Eculizumab, Zilucoplan, Ravulizumab, Pozelimab, Cemdisiran, Gefurilimab, Danicopan and few others in the pipeline.  Eculizumab has been shown in clinical trials to be effective in the treatment of refractory MG, but further sub-group analysis and real-life experience have shown that this can be beneficial in various patients including those receiving regular IVIG, plasma exchange or Rituximab. It was approved for use by FDA in Oct 2017. Ravulizumab is a long-acting monoclonal antibody which has similar mechanism of action to Eculizumab and was approved for use in MG by FDA in April 2022. Zilucoplan is a macrocyclic peptide which binds to C5 and C5b thus preventing terminal complement activation, which can be given subcutaneously (FDA new drug application accepted in Nov 2022). Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Patients would need to be vaccinated against Neisseria meningitidis because of the risk of Gram-negative septicaemia, although no major safety signatures have been noted in the studies so far. Future studies may be able to identify specific biomarkers which might aid in selecting the most appropriate patients who might respond to these therapies.
补体抑制在重症肌无力-从基础到RCT数据
重症肌无力(MG)是一种典型的自身免疫性神经系统疾病,可引起疲劳性肌肉无力,或局限于眼肌,或变得普遍累及肢体和球肌。10个全身性MG患者中有9个有针对乙酰胆碱受体(AChR)的IgG1或IgG3抗体。AChR抗体通过AChR内化、受体阻断和激活补体途径引起神经肌肉无力。补体激活引起膜攻击复合物(MAC)的形成,导致神经肌肉连接处(NMJ)的降解。一些动物模型已经证实了补体在MG发病机制中的作用,实验模型(EAMG)通常需要补体抑制治疗来预防或逆转疾病。针对补体系统的各种分子现已被开发用于治疗重症肌无力。目前研究的绝大多数分子靶向C5蛋白,从而阻止MAC的形成和随后的NMJ破坏。目前研究的MG抗补体疗法包括Eculizumab、Zilucoplan、Ravulizumab、Pozelimab、Cemdisiran、Gefurilimab、Danicopan和其他一些正在开发中的药物。Eculizumab已在临床试验中被证明对难治性MG有效,但进一步的亚组分析和实际经验表明,这可能对各种患者有益,包括接受常规IVIG、血浆置换或利妥昔单抗的患者。它于2017年10月被FDA批准使用。Ravulizumab是一种长效单克隆抗体,其作用机制与Eculizumab相似,于2022年4月被FDA批准用于MG。Zilucoplan是一种与C5和C5b结合的大环肽,可以阻止末端补体活化,可以皮下给药(FDA新药申请于2022年11月接受)。其中许多也被证明对不同亚组的MG患者有长期的益处。由于革兰氏阴性败血症的风险,患者需要接种脑膜炎奈瑟菌疫苗,尽管迄今为止的研究还没有注意到主要的安全性特征。未来的研究可能能够确定特定的生物标志物,这可能有助于选择可能对这些治疗有反应的最合适的患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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