Promising Antigen-specific Immunotherapy for the Treatment of Myasthenia Gravis

Eleni Ntoukaki, María Fernández-Santoscoy, Vasiliki Baltatzidou, B. Löwenadler, Charlotte Fribert, K. Lazaridis
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Abstract

Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated, autoimmune disorder with well-established antigenic targets at the neuromuscular junction. MG autoantibodies mainly target the nicotinic acetylcholine receptor (AChR) and especially epitopes located in the extracellular domain of the α1 subunit (α1-ECD). Today, most therapeutic regimens for MG are non-specific and not curative, requiring chronic treatments that are associated with significant side effects. We aim to develop an antigen-specific therapeutic approach, based on reestablishing tolerance towards the AChR, the dominant autoantigen in MG. To this end, we used a soluble mutated form of the human α1-ECD, which incorporates a major fraction of MG autoreactive T cell epitopes and examined the therapeutic efficiency of intravenous administration in a rat experimental autoimmune MG model. We found that repeated intravenous administration of α1-ECD for up to 12 days led to a robust amelioration of disease symptoms in a dose and time-dependent manner. The observed therapeutic effect of α1-ECD was significantly better than the effect of two current mainstay drugs for MG treatment. There were no signs of toxicity in α1-ECD-treated animals and further studies are underway to fully elucidate the immunological mechanism underlying the treatment effect. Taken together, our preclinical data strongly suggest that intravenous administration of α1-ECD may represent an efficacious and safe strategy to treat MG and thus α1-ECD represents a new drug candidate for clinical application in MG. 
抗原特异性免疫疗法治疗重症肌无力的前景
重症肌无力(MG)是一种T细胞依赖性、抗体介导的自身免疫性疾病,其抗原靶点位于神经肌肉交界处。MG自身抗体主要靶向烟碱乙酰胆碱受体(AChR),尤其是α1亚基胞外结构域的表位(α1- ecd)。今天,大多数MG的治疗方案都是非特异性的,不能治愈,需要长期治疗,并且有明显的副作用。我们的目标是开发一种抗原特异性治疗方法,基于重建对AChR的耐受性,这是MG的主要自身抗原。为此,我们使用了一种可溶性突变形式的人α1-ECD,其中包含了MG自身反应性T细胞表位的主要部分,并在大鼠实验性自身免疫性MG模型中检测了静脉注射给药的治疗效果。我们发现,反复静脉注射α1-ECD长达12天,导致疾病症状以剂量和时间依赖的方式得到强有力的改善。观察到α1-ECD的治疗效果明显优于目前治疗MG的两种主流药物。α1- ecd治疗的动物没有毒性迹象,进一步的研究正在进行中,以充分阐明治疗效果的免疫学机制。综上所述,我们的临床前数据有力地表明,静脉给药α1-ECD可能是一种有效且安全的治疗MG的策略,因此α1-ECD代表了一种新的MG临床应用候选药物。
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