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

• 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
• 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' 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

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.

摘要 随着脊髓灰质炎的几乎根除，格林-巴利综合征（GBS）已成为脊髓灰质炎最常见的病因。 急性弛缓性麻痹目前的免疫调节治疗仅对一部分患者有效。为 实施例IVIG-GBS的一线治疗方式-仅约50%的接受该治疗的患者加速恢复 药尽管目前的免疫疗法是可用的，但仍有相当一部分患者留下了免疫缺陷。 严重和永久性神经系统后遗症，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， 希望在恢复期间加强修复。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（Fc工程化抗体，其增强免疫原性）。 通过阻断新生儿Fc受体（FcRn）降解IgG），适用于人用作autoAb特异性抗体 GBS临床前模型的免疫治疗。抗神经节苷脂抗体（Abs）是最常见的 GBS中的自身免疫反应。我们专注于抗聚糖抗体相关的疾病模型， 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。本课题组建立了两种不同的被动转移动物模型， 抗聚糖抗体，将用于拟定研究。我们的初步研究表明， 新生儿Fc受体（FcRn）对抗神经节苷脂Ab介导的神经损伤不敏感， 这些抗体在动物模型中的清除。根据这些观察，我们假设阿布德格斯 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。这一假设将由以下人员进行检验： 以下具体目标：目标1将通过测量Abdeg（MST-HN）在动物研究中的功效， 病原性实验性和人抗聚糖Ab的循环半衰期，并将其与 对完整和受损轴突的致病作用;目的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。用于平移 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）这两种药物具有协同作用。这两个问题都是 从伦理和试验设计的角度来看，如果这种疗法扩展到人体研究，则具有相关性。这个项目 可能有助于开发新的治疗策略，旨在加快自身抗体的清除， 也可用于其他神经免疫疾病，包括重症肌无力和视神经肌无力。