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 随着脊髓灰质炎接近根除，格林-巴利综合征(GBS)已成为 急性迟缓性瘫痪。目前的免疫调节治疗只对部分患者有效。为 实例IVIG-GBS的一线治疗方式-仅在接受此疗法的患者中加速恢复约50% 药物治疗。尽管目前有可用的免疫疗法，但相当大比例的患者仍留在 严重和永久性的神经后遗症，包括无法独立行走。迫切需要…… 在疾病急性期可以限制轴突损害的新的/附加的治疗方法和 在恢复期加强修复是可取的。在过去的20多年里，没有新的治疗方法进入 GBS的临床领域。正是在这种情况下，我们想测试一种Abdeg(Fc工程抗体)，它可以增强 通过阻断适合人类使用的新生儿Fc受体(FcRN)来降解免疫球蛋白 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中可识别的自身免疫反应。我们将重点放在抗多糖抗体相关疾病模型上。 GRANT作为大量实验数据支持这些自身抗体在GBS中的主要致病作用 尤其是在它的轴突变体中。我们的团队已经开发出两种不同的被动移植动物模型 抗多聚糖抗体，将在拟议的研究中使用。我们的初步研究表明，老鼠缺乏 新生儿Fc受体(FcRN)对抗神经节苷脂抗体介导的神经损伤不敏感 在动物模型中清除这些抗体。根据这些观察结果，我们推测阿布德格斯 抗神经节苷脂抗体介导的神经损伤动物模型的保护作用。这一假设将通过以下方式检验 以下具体目标：目标1将通过测量以下指标来检查Abdeg(MST-HN)在动物研究中的疗效 致病性实验性和人源性抗多糖抗体的循环半衰期及其与其相关性的研究 对完整和受损轴突的致病作用；AIM 2将比较IVIG和 Abdeg MST-HN抑制抗多糖抗体介导的动物模型神经损伤。对于翻译版本 目的在临床前模型中确定a)：Abdeg(MST-HN)和IVIG是否起作用是很重要的 无拮抗作用；b)这两种药物具有协同作用。这两个问题都是 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。这个项目 可能有助于开发旨在加速清除自身抗体的新治疗策略，但与此无关 仅对GBS，但其他神经免疫性疾病，包括重症肌无力和视神经脊髓炎。