Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury

描述(申请人提供)：随着脊髓灰质炎接近根除，格林-巴利综合征(GBS)已成为急性迟缓性瘫痪最常见的原因。目前的免疫调节治疗只对部分患者有效。例如，静脉注射免疫球蛋白是GBS的一线治疗方法，在接受这种药物治疗的患者中，只有50%的人加速康复。尽管目前有多种免疫疗法可用，但仍有相当一部分患者留下严重和永久性的神经后遗症，包括无法独立行走。迫切需要新的/额外的治疗方法，以限制疾病急性期的轴突损害，并在恢复期加强修复。在过去的20多年里，没有新的治疗方法进入GBS的临床领域。正是在这种背景下，我们想要测试一种适合人类用于GBS临床前模型的自身抗体特异性免疫治疗的Abdeg(通过阻断新生儿Fc受体(FcRN)来增强IgG降解的Fc工程抗体)。抗神经节苷脂抗体(Abs)是GBS中最常见的自身免疫反应。由于大量的实验数据支持这些自身抗体在GBS中的主要致病作用，特别是在其轴突变体中，我们在这笔赠款中重点关注抗糖链抗体相关的疾病模型。本课题组已经建立了两种不同的抗多聚糖抗体被动转移动物模型，该模型将用于拟议的研究。我们的初步研究表明，缺乏新生Fc受体(FcRN)的小鼠不容易受到抗神经节苷脂抗体介导的神经损伤，因为这些抗体在动物模型中迅速清除。基于这些观察，我们推测Abdegs在我们的抗神经节苷脂抗体介导的神经损伤的动物模型中具有保护作用。这一假说将通过以下具体目标进行验证：目标1将通过测量致病实验抗体和人抗糖抗体的循环半衰期来检验Abdeg(MST-HN)在动物研究中的有效性，并将其与它们对完整和受损轴突的致病作用相关联；目标2将比较IVIG和Abdeg MST-HN在动物模型中抑制抗糖蛋白抗体介导的神经损伤的有效性和/或协同作用。出于翻译的目的，重要的是在临床前模型中确定a)：Abdeg(MST-HN)和IVIG是否具有拮抗作用；以及b)这两种药物具有协同作用。如果将这种疗法扩展到人体研究，从伦理学和试验设计的角度来看，这两个问题都是相关的。该项目可能有助于开发新的治疗策略，旨在加快自身抗体的清除，不仅与GBS有关，而且与其他神经免疫疾病有关，包括重症肌无力和视神经脊髓炎。

DESCRIPTION (provided by applicant): With the near-eradication of polio, Guillain-Barre syndrome (GBS) has become the most frequent cause of acute flaccid paralysis. Current immunomodulatory treatments are only effective in a proportion of patients. For example IVIG-a first line treatment modality in GBS-hasten recovery in only ~50% of those treated with this medication. Despite availability of current of immunotherapies, a significant proportion of patients are left with severe and permanent neurologic sequelae, including inability to walk independently. There is a dire need for newer/additional treatments that can limit the axonal damage during the acute phase of the disease and enhance repair during recovery period are desirable. For over last 20 years no new treatments have entered the clinical arena of GBS. It is in this context we want to test an Abdeg (Fc-engineered antibody that enhance IgG degradation by blocking neonatal Fc receptor (FcRn)) appropriate for human use as autoAb-specific immunotherapy in preclinical models of GBS. Anti-ganglioside antibodies (Abs) are the most frequently recognized autoimmune responses in GBS. We focus on anti-glycan Ab associated disease models in this grant as substantial experimental data support the primary pathogenic role of these autoAbs in GBS particularly in its axonal variants. Our group has developed two different passive transfer animal models with anti-glycan Abs, which will be used in the proposed studies. Our preliminary studies show that mice lacking neonatal Fc receptor (FcRn) are not susceptible to anti-ganglioside Ab-mediated nerve injury due to rapid clearance of these Abs in an animal model. Based on these observations we postulate that Abdegs would be protective in our animal models of anti-ganglioside Ab-mediated nerve injury. This hypothesis will be tested by the following specific aims: Aim 1 will examine the efficacy of Abdeg (MST-HN) in animal studies by measuring the circulating half-life of pathogenic experimental and human anti-glycan Abs and correlate this with their pathogenic effects on intact and injured axons; Aim 2 will compare efficacy and/or synergism of IVIG with Abdeg MST-HN in suppressing anti-glycan Ab-mediated nerve injury in animal models. For translational purposes it would be important to determine in preclinical models whether a): Abdeg (MST-HN) and IVIG do not have antagonistic effects; and b) these two medications have synergistic effects. Both these issues are relevant from ethical and trial design perspective if this therapy were to extend to human studies. This project may help in developing new treatment strategies aiming to expedite clearance of autoAbs and has relevance not only to GBS but other neuroimmunological disorders including myasthenia gravis and neuromyelitis optica.