Preclinical studies of a MADCAM-Fc fusion protein in multiple sclerosis

MADCAM-Fc 融合蛋白治疗多发性硬化症的临床前研究

• 批准号: 8934116
• 负责人: Benjamin M Segal
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934116
• 关键词: Acute; Adverse effects; Alphavirus; Alphavirus Infections; Animal Model; Antiviral Agents; Autoimmune Diseases; Autoimmune Process; Axon; Binding; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CD4 Positive T Lymphocytes; CNS Demyelinating Autoimmune Diseases; Caring; Cell Adhesion Molecules; Central Nervous System Diseases; Central Nervous System Viral Diseases; Chimeric Proteins; Choroid Plexus Epithelium; Chronic; Clinical; Clinical Trials; Complex; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Effector Cell; Endothelial Cells; Engineering; Experimental Autoimmune Encephalomyelitis; Extracellular Domain; Goals; Healthcare Systems; Heavy-Chain Immunoglobulins; Human; Immune response; Immunity; Immunologic Monitoring; Immunologic Surveillance; Inflammatory; Integrin alpha4; Integrin alpha4beta1; Integrins; Interferon-beta; Laboratories; Latent Virus; Lead; Leukocytes; Ligands; Link; Literature; Mediating; Mitoxantrone; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Neuraxis; Neurologic; Opportunistic Infections; Optic Nerve; Patients; Pharmaceutical Preparations; Phase; Predisposition; Progressive Multifocal Leukoencephalopathy; Publishing; Reagent; Recombinant Fusion Proteins; Recombinants; Relapse; Relapsing-Remitting Multiple Sclerosis; Risk; Safety; Spinal Cord; Staging; Structure of choroid plexus; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tysabri; United States; United States Department of Veterans Affairs; United States Food and Drug Administration; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; Veterans; Viral; Viral Encephalitis; Virus Diseases; antimicrobial; chemotherapeutic agent; copolymer 1; design; disability; effective therapy; humanized monoclonal antibodies; integrin alpha4beta7; integrin beta7; mouse model; mucosal addressin cell adhesion molecule-1; natalizumab; novel; preclinical study; prevent; research study; treatment strategy; young adult

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is the most common non-traumatic cause of neurological disability among young adults in the United States. Exacerbations of the disease occur when inflammatory foci form in the optic nerves, brain or spinal cord, resulting in demyelination and damage to neighboring axons. A critical step in the formation of MS lesions is adhesion molecule mediated transmigration of leukocytes from the bloodstream into the CNS. The current proposal tests our hypothesis that targeted blockade of a particular adhesion molecule interaction (between a4b7, expressed on CNS-infiltrating T cells, and MAdCAM-1, expressed on inflamed CNS blood vessels) will prevent exacerbations of autoimmune demyelination in a mouse model of MS (experimental autoimmune encephalomyelitis or EAE). To do so, we have engineered a chimeric fusion protein (MAdCAM-1-Fc), composed of the extracellular domain of MAdCAM-1-Fc linked to the Fc region of mouse immunoglobulin heavy chain. This reagent prevents MAdCAM-1 from binding a4b7 expressing T cells. We will determine whether systemic administration of MAdCAM-1-Fc or control fusion proteins suppresses relapses or progression of EAE. Furthermore, in a test of its safety, we will administer MAdCAM-1-Fc to mice infected with an alphavirus and determine whether the treatment impedes viral clearance and/ or triggers reactivation of latent virus in the CNS. The specific aims of our proposal are as follows: 1. To study the temporal and spatial expression of a4b7 on CNS infiltrating CD4+ T cells and its cognate ligand, MAdCAM-1, on CNS vascular endothelium during the course of relapsing and chronic experimental autoimmune encephalomyelitis (EAE) in mice. Additional experiments are designed to examine the inflammatory factors that induce expression of a4b7 on myelin-specific effector cells and MAdCAM-1 on CNS endothelial cells. 2. To investigate the therapeutic consequences of a4b7 blockade in both relapsing and chronic EAE models. We will compare the therapeutic efficacy of a novel MAdCAM-1-Fc recombinant fusion protein (that specifically blocks a4b7 integrin) versus other adhesion molecule blocking agents, when given at different time points in the disease course. 3. To characterize the effects of systemic a4b7 blockade on acute viral infection of the CNS and reactivated latent viral infection in mice. We will use a mouse model of alphavirus infection to compare the effects of MAdCAM-1-Fc and other fusion proteins on anti-viral immunity and immunosurveillance.

描述（由申请人提供）： 多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 自身免疫性疾病，是美国年轻人神经功能障碍的最常见非创伤性原因。当视神经、大脑或脊髓中形成炎症灶，导致脱髓鞘和邻近轴突损伤时，疾病就会恶化。 MS 病变形成的关键步骤是粘附分子介导的白细胞从血流迁移到中枢神经系统。目前的提案测试了我们的假设，即有针对性地阻断特定粘附分子相互作用（在 CNS 浸润性 T 细胞上表达的 a4b7 和在发炎的 CNS 血管上表达的 MAdCAM-1 之间）将防止 MS（实验性自身免疫性脑脊髓炎或 EAE）小鼠模型中自身免疫性脱髓鞘的恶化。为此，我们设计了一种嵌合融合蛋白 (MAdCAM-1-Fc)，由与小鼠免疫球蛋白重链 Fc 区连接的 MAdCAM-1-Fc 胞外结构域组成。该试剂可防止 MAdCAM-1 结合表达 a4b7 的 T 细胞。我们将确定 MAdCAM-1-Fc 或对照融合蛋白的全身给药是否可以抑制 EAE 的复发或进展。此外，在测试其安全性时，我们将给感染甲病毒的小鼠施用 MAdCAM-1-Fc，并确定治疗是否会阻碍病毒清除和/或触发中枢神经系统中潜伏病毒的重新激活。我们提案的具体目的如下：1.研究小鼠复发性慢性实验性自身免疫性脑脊髓炎（EAE）过程中中枢神经系统浸润CD4+T细胞及其同源配体MAdCAM-1在中枢神经系统血管内皮上a4b7的时空表达。其他实验旨在检查诱导髓磷脂特异性效应细胞上 a4b7 表达和中枢神经系统内皮细胞上 MAdCAM-1 表达的炎症因子。 2. 研究a4b7阻断在复发性和慢性EAE模型中的治疗效果。我们将比较新型 MAdCAM-1-Fc 重组融合蛋白（特异性阻断 a4b7 整合素）与其他粘附分子阻断剂在病程不同时间点给予的治疗效果。 3. 表征全身a4b7阻断对小鼠中枢神经系统急性病毒感染和重新激活的潜伏病毒感染的影响。我们将使用甲病毒感染的小鼠模型来比较 MAdCAM-1-Fc 和其他融合蛋白对抗病毒免疫和免疫监视的影响。