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.

抽象的随着小儿麻痹症的近乎映射，Guillain-Barr¿综合征（GB）已成为最常见的原因急性脆性瘫痪。当前的免疫调节治疗仅在一部分患者中有效。为了示例Ivig-A在GBS-Hasten恢复中的第一线治疗方式中，仅约50％接受此处理药物。尽管有免疫疗法的电流可用，但很大一部分患者仍有严重和永久的神经系统后遗症，包括无法独立行走。有迫切需要在疾病的急性阶段，可以限制轴突损伤的较新/其他治疗方法恢复期间的修复是可取的。在过去的20年中，没有进入新的治疗方法 GBS的临床领域。正是在这种情况下通过阻止新生儿FC受体（FCRN）的IgG降解，适合于人类用作自动启动特异性 GB的临床前模型中的免疫疗法。抗旋转抗体抗体（ABS）是最常见的公认的GBS中的自身免疫反应。我们专注于抗聚糖抗体相关疾病模型授予作为实质性的实验数据支持这些自动AB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个不同的被动转移动物模型抗聚糖ABS，该ABS将用于拟议的研究。我们的初步研究表明，小鼠缺乏新生儿FC受体（FCRN）并不易受抗链肽AB介导的神经损伤的影响在动物模型中清除这些ABS。根据这些观察，我们假设Abdegs将是在我们的抗周期性AB介导的神经损伤的动物模型中保护性。该假设将通过以下具体目的：AIM 1将通过测量ABDEG（MST-HN）在动物研究中的效率致病性实验和人类抗聚糖ABS的循环半衰期与它们的相关性对完整和受伤的轴突的致病作用； AIM 2将比较IVIG的效率和/或协同作用 Abdeg MST-HN在抑制动物模型中抑制抗聚糖AB介导的神经损伤中。用于翻译目的是在临床前模型中确定A）是否：Abdeg（MST-HN）和IVIG 没有拮抗作用； b）这两种药物具有协同作用。这两个问题都是从道德和试验设计的角度使用，如果这种疗法扩展到人类研究。这个项目可能有助于开发新的治疗策略，旨在加快自动启动的清除，并且没有相关性仅针对GB，但其他神经免疫性疾病，包括肌无力重症肌无力和神经肌炎。