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

描述（由申请人提供）：随着脊髓灰质炎的接近根除，格林-巴利综合征（GBS）已成为急性弛缓性麻痹的最常见原因。目前的免疫调节治疗仅对一部分患者有效。例如，IVIG-GBS的一线治疗方式-仅在用该药物治疗的患者中加速约50%的恢复。尽管目前的免疫疗法可用，但相当一部分患者留下了严重和永久性的神经系统后遗症，包括无法独立行走。迫切需要更新/额外的治疗，其可以限制疾病急性期的轴突损伤并增强恢复期的修复。在过去的20年里，没有新的治疗方法进入GBS的临床竞技场。正是在这种情况下，我们想要测试一种Abdeg（通过阻断新生儿Fc受体（FcRn）来增强IgG降解的Fc工程化抗体），其适合于在GBS的临床前模型中作为autoAb特异性免疫疗法用于人类。抗神经节苷脂抗体（Abs）是GBS中最常见的自身免疫反应。我们专注于抗聚糖抗体相关的疾病模型，在此授权大量的实验数据支持的主要致病作用，这些autoAb在GBS，特别是在其轴突变异。我们的小组已经开发了两种不同的被动转移动物模型与抗聚糖抗体，这将用于拟议的研究。我们的初步研究表明，缺乏新生儿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，由于这些抗体在动物模型中的快速清除。基于这些观察结果，我们假设Abdegs在我们的抗神经节苷脂Ab介导的神经损伤的动物模型中具有保护作用。目标1将通过测量致病性实验和人抗聚糖Ab的循环半衰期并将其与其对完整和受损轴突的致病作用相关联来检查Abdeg（MST-HN）在动物研究中的功效;目的2将在动物模型中比较IVIG与Abdeg MST-HN在抑制抗聚糖Ab介导的神经损伤中的功效和/或协同作用。为了转化的目的，重要的是在临床前模型中确定a）Abdeg（MST-HN）和IVIG是否不具有拮抗作用;和B）这两种药物是否具有协同作用。如果这种疗法扩展到人体研究，从伦理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autoAb的清除，不仅与GBS相关，还与其他神经免疫性疾病（包括重症肌无力和视神经肌无力）相关。

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.