FcRn Inhibitors for Antibody-Mediated Immune Conditions

描述（由申请人提供）：大约有2000万美国人受到自身免疫性疾病的影响，其中免疫系统发起针对自身抗原的攻击。对于大约80种自身免疫性疾病中的许多疾病，免疫攻击是由自身反应性抗体介导的（即，自身抗体）。在该实验室中进行的最近的工作已经表明，高剂量静脉内免疫球蛋白（IVIG），一种用于许多自身免疫性病症的有效疗法，增加了自身免疫性疾病的动物模型中病原性抗体的清除率。在FcRn敲除小鼠中进行的研究和药代动力学-药效学分析支持了IVIG通过FcRn的竞争性抑制增强抗体消除的假设，FcRn是一种保护免疫γ球蛋白（IgG）免受细胞内catalysis的转运蛋白。 基于这些发现，我们假设FcRn抑制剂（例如，抗-FcRn抗体）可以作为一种新的免疫抑制剂疗法，具有治疗抗体介导的免疫病症的广泛用途。初步研究已经显示，抗FcRn抗体在增加体内致病性抗体的清除（即，相对于IVIG）。本提案将研究抗FcRn抗体的药理学，检验与以下相关的假设：（a）抗FcRn治疗在自身免疫动物模型中的作用（目标#1），（B）FcRn和FcRn抑制剂对IgG组织分布的影响（目标#2），和（c）抗人FcRn抗体对FcRn介导的人IgG体外转运的影响（目标#3）。从拟议的研究中收集的发现可能证明FcRn抑制在疾病动物模型中的效用，提高我们对FcRn对IgG处置的影响的理解，并且还开发新的药物，人FcRn抑制剂，具有在未来临床研究中使用的潜力

DESCRIPTION (provided by applicant): Approximately 20 million Americans are affected by autoimmune conditions, where the immune system mounts an attack directed against self-antigens. For many of the approximately 80 autoimmune diseases, the immune attack is mediated by self-reactive antibodies (i.e., autoantibodies). Recent work conducted in this laboratory has shown that high-dose intravenous immunoglobulin (IVlG), an effective therapy for many autoimmune conditions, increases the rate of clearance of pathogenic antibody in an animal model of autoimmune disease. Studies conducted in FcRn-knockout mice and pharmacokinetic-pharmacodynamic analyses have supported the hypothesis that IVlG enhances antibody elimination via competitive inhibition of FcRn, a transport protein that protects immune gamma globulin (IgG) from intracellular catabolism. Based on these findings, we have hypothesized that FcRn-inhibitors (e.g., anti-FcRn antibodies) may serve as a novel immunosuppressant therapy with broad utility for treatment of antibody-mediated immune conditions. Preliminary studies have shown that anti-FcRn antibodies are much more potent and much more effective in increasing the clearance of pathogenic antibodies in vivo (i.e., relative to IVIG). The present proposal will investigate the pharmacology of anti-FcRn antibodies, testing hypotheses related to: (a) the effects of anti-FcRn therapy in an animal model of autoimmunity (Aim #1), (b) the influence of FcRn and FcRn inhibitors on the tissue disposition of IgG (Aim #2), and (c) the effects of anti-human-FcRn antibodies on FcRn-mediated transport of human IgG in vitro (Aim #3). Findings gathered from the proposed studies may demonstrate the utility of FcRn inhibition in an animal model of disease, improve our understanding of the influence of FcRn on IgG disposition, and also develop new agents, inhibitors of human FcRn, with potential for use in future clinical studies