FcRn Inhibitors for Antibody-Mediated Immune Conditions

描述（由申请人提供）：大约2000万美国人受到自身免疫性疾病的影响，免疫系统对自身抗原进行攻击。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（即自身抗体）介导的。该实验室最近开展的工作表明，在自身免疫性疾病的动物模型中，高剂量静脉注射免疫球蛋白（IVlG）可以提高致病性抗体的清除率，这是一种治疗许多自身免疫性疾病的有效方法。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IVlG通过竞争性抑制FcRn来增强抗体消除的假设，FcRn是一种保护免疫球蛋白（IgG）免受细胞内分解代谢的转运蛋白。

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