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