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

FcRn 的调节：预防自身抗体介导的神经损伤的策略

基本信息

批准号：
8684787
负责人：
KAZIM A SHEIKH
金额：
$ 19万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8684787
关键词：
Acute Affinity Animal Model Animals Antibodies Antigen Targeting Antigen-Antibody Complex Applications Grants Area Arthritis Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Axon Binding Blood-Nerve Barrier Cell surface Clinical Clinical Trials Clinical Trials Design Complement Data Development Disease Disease model Engineering Enhancing Antibodies Ethics Future Gangliosides Glycosphingolipids Grant Guillain-Barré Syndrome Half-Life Human IgG Receptors IgG1 Immune Immune system Immunoglobulin G Immunotherapy Inflammation Injury Intravenous Immunoglobulins Left Measures Mediating Modality Modeling Mus Myasthenia Gravis Natural regeneration Neonatal Nerve Crush Nerve Fibers Neurologic Neuromyelitis Optica Neuropathy Paralysed Pathogenicity Pathology Patients Peripheral Nerves Pharmaceutical Preparations Phase Poliomyelitis Polysaccharides Pre-Clinical Model Property Publishing Ranvier&apos s Nodes Recovery Research Role Schedule Sialic Acids Surface Syndrome Testing Therapeutic Therapy Evaluation Transgenic Mice Up-Regulation Variant Walking antibody engineering axon regeneration base comparative efficacy design injured neonatal Fc receptor nerve injury novel therapeutics prevent public health relevance randomized placebo controlled trial repaired research study synergism translational approach treatment strategy ward

项目摘要

Abstract With the near-eradication of polio, Guillain-Barr¿ 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 stratgies aiming to expedite clearnce of autoAbs and has relevance not only to GBS but other neuroimmunological disorders including myasthenia gravis and neuromyelitis optica.

抽象的随着脊髓灰质炎几近根除，格林-巴尔综合症（GBS）已成为最常见的原因目前的免疫调节治疗仅对部分患者有效。 IVIG 是 GBS 的一线治疗方式，仅约 50% 的患者能加速康复尽管目前有免疫疗法，但仍有很大一部分患者仍处于治疗状态。严重的神经系统后遗症，包括无法独立行走，迫切需要。更新/额外的治疗可以限制疾病急性期的轴突损伤，在恢复期加强修复是可取的。过去 20 年来没有出现新的治疗方法。正是在这种背景下，我们想要测试一种 Abdeg（Fc 工程抗体，可以增强 GBS 的临床效果）。通过阻断新生儿 Fc 受体 (FcRn) 来降解 IgG，适合人类用作自身抗体特异性 GBS 临床前模型中最常见的是抗神经节苷脂抗体 (Abs) 的免疫治疗。 GBS 中公认的自身免疫反应，我们在此重点关注抗聚糖抗体相关疾病模型。授予大量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，我们的小组开发了两种不同的被动转移动物模型。抗聚糖抗体，我们的初步研究表明小鼠缺乏。新生儿 Fc 受体 (FcRn) 不易受到抗神经节苷脂抗体介导的快速神经损伤的影响基于这些观察，我们假设 Abdegs 在动物模型中被清除。在我们的动物模型中，抗神经节苷脂抗体介导的神经损伤具有保护作用，这一假设将通过以下方法进行检验。具体目标如下：目标 1 将通过测量来检验 Abdeg (MST-HN) 在动物研究中的功效致病性实验和人类抗聚糖抗体的循环半衰期，并将其与它们相关联对完整和受损轴突的致病作用；目标 2 将比较 IVIG 与 Abdeg MST-HN 在动物模型中抑制抗聚糖 Ab 介导的神经损伤。出于目的，重要的是确定在临床前模型中是否 a)：Abdeg (MST-HN) 和 IVIG 确实不具有拮抗作用；b) 这两种药物具有协同作用。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是相关的。可能有助于制定旨在加速自身抗体清除的新治疗策略，并且具有相关性仅针对GBS，还针对其他神经免疫性疾病，包括重症肌无力和视神经脊髓炎。