Department of Neurology with Institute of Translational Neurology, University Hospital Münster, 48149 Münster, Germany.
Int J Mol Sci. 2021 May 28;22(11):5755. doi: 10.3390/ijms22115755.
(MG) is an autoimmune disease in which immunoglobulin G (IgG) antibodies (Abs) bind to acetylcholine receptors (AChR) or to functionally related molecules in the postsynaptic membrane at the neuromuscular junction. IgG crystallizable fragment (Fc)-mediated effector functions, such as antibody-dependent complement deposition, contribute to disease development and progression. Despite progress in understanding Ab-mediated disease mechanisms, immunotherapy of MG remained rather unspecific with corticosteroids and maintenance with immunosuppressants as first choice drugs for most patients. More specific therapeutic IgG Fc-based platforms that reduce serum half-life or effector functions of pathogenic MG-related Abs are currently being developed, tested in clinical trials or have recently been successfully translated into the clinic. In this review, we illustrate mechanisms of action and clinical efficacies of emerging Fc-mediated therapeutics such as neonatal Fc receptor (FcRn)-targeting agents. Furthermore, we evaluate prospects of therapies targeting classical Fc receptors that have shown promising therapeutic efficacy in other antibody-mediated conditions. Increased availability of Fc- and Fc receptor-targeting biologics might foster the development of personalized immunotherapies with the potential to induce sustained disease remission in patients with MG.
(MG)是一种自身免疫性疾病,其中免疫球蛋白 G(IgG)抗体(Abs)与乙酰胆碱受体(AChR)或神经肌肉接头后膜中功能相关的分子结合。IgG 可结晶片段(Fc)介导的效应功能,如抗体依赖性补体沉积,有助于疾病的发展和进展。尽管对 Ab 介导的疾病机制的理解取得了进展,但 MG 的免疫疗法仍然相当不具体,皮质类固醇和免疫抑制剂作为大多数患者的首选药物。目前正在开发更具特异性的基于 IgG Fc 的平台,以降低致病性 MG 相关 Abs 的血清半衰期或效应功能,这些平台正在临床试验中进行测试,或最近已成功转化为临床应用。在这篇综述中,我们说明了新兴的 Fc 介导治疗药物(如新生儿 Fc 受体(FcRn)靶向剂)的作用机制和临床疗效。此外,我们评估了靶向经典 Fc 受体的疗法的前景,这些疗法在其他抗体介导的疾病中显示出有希望的治疗效果。Fc 和 Fc 受体靶向生物制剂的可用性增加可能会促进个体化免疫疗法的发展,从而有可能诱导 MG 患者持续缓解疾病。