FcRn Inhibitors for Antibody-Mediated Immune Conditions

描述(申请人提供)：大约2000万美国人受到自身免疫疾病的影响，免疫系统对自身抗原发动攻击。对于大约80种自身免疫性疾病中的许多，免疫攻击是由自身反应性抗体(即自身抗体)介导的。该实验室最近进行的工作表明，大剂量静脉注射免疫球蛋白(IVlG)是治疗许多自身免疫性疾病的有效方法，在自身免疫性疾病的动物模型中提高了致病抗体的清除率。在FcRN基因敲除小鼠中进行的研究和药代动力学-药效学分析支持了这样的假设，即IVlG通过竞争性抑制FcRN来增强抗体消除，FcRN是一种运输蛋白，可以保护免疫丙种球蛋白(IgG)免受细胞内分解代谢的影响。 基于这些发现，我们假设FcRN抑制剂(例如，抗FcRN抗体)可能作为一种新的免疫抑制疗法，在治疗抗体介导的免疫疾病方面具有广泛的实用价值。初步研究表明，抗FcRN抗体在增加体内致病抗体清除(即相对于IVIG)方面要有效得多。本提案将研究抗FcRN抗体的药理学，测试与以下假设有关的假设：(A)抗FcRN治疗在自身免疫动物模型中的效果(目标1)，(B)FcRN和FcRN抑制剂对免疫球蛋白组织处置的影响(目标2)，以及(C)抗人FcRN抗体对FcRN介导的人免疫球蛋白体外转运的影响(目标3)。从拟议的研究中收集的结果可能证明在疾病的动物模型中抑制FcRN的有效性，提高我们对FcRN对免疫球蛋白处置的影响的理解，并开发新的药物，人类FcRN的抑制剂，有可能在未来的临床研究中使用

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