Novel therapy for Goodpasture syndrome

古德帕斯图尔综合征的新疗法 摘要 古德帕斯普雷综合征(GS)是一种罕见的由肾小球演变而来的自身免疫性肺部疾病 基底膜病。基底膜病和GS进展迅速，导致肾功能衰竭 如果不治疗就会死亡。目前的治疗方法是免疫抑制和无效的，并且有很高的风险 不良影响。抗IV型胶原α3链非胶原性1(Nc1)区的自身抗体 (α3(IV)Nc1)是肾小球和肺泡基底膜的一种成分，可触发免疫反应 导致抗体沉积在基底上，随后出现炎症和坏死。两种抗体- 包括介导的细胞毒作用(ADCC)和补体介导的细胞毒作用(CDC)。封闭抗体 缺乏效应器功能已被证明在其他类似病因的自身免疫性疾病中有效治疗 (如视神经脊髓炎)。在这个第一阶段的项目中，我们将设计一种高亲和力的抗IV型胶原 人源单抗消除所有残留的效应器功能以连接到强大的补体 抑制剂。由此产生的双功能融合蛋白将抑制致病抗体与GBM的结合，以及 局部靶向补体激活。这项工作的结果将是一种新的、基于机制的治疗方法 古德帕斯普雷综合征。

Novel therapy for Goodpasture syndrome Abstract Goodpasture syndrome (GS) is a rare autoimmune pulmonary disorder evolving from glomerular basement membrane (GBM) disease. GBM disease and GS are rapidly progressing, leading to renal failure and death if not treated. Current treatments are immunosuppressive and ineffective, and carry a high risk of adverse effects. Autoantibodies to the noncollagenous-1 (NC1) domain of the α3 chain of type IV collagen (α3(IV)NC1), a component of the basement membrane of glomeruli and alveoli, trigger an immune response leading to antibody deposition on the basement, with subsequent inflammation and necrosis. Both antibody- mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) are involved. Blocking antibodies lacking effector functions have proven effective therapies in other autoimmune disorders of similar etiology (e.g., neuromyelitis optica). During this Phase I project, we will engineer a high affinity anti-type IV collagen human monoclonal antibody to eliminate all residual effector functions for linkage to a robust complement inhibitor. The resulting dual function fusion protein will inhibit GBM-binding by pathogenic antibodies as well as locally target complement activation. The outcome of this work will be a novel, mechanism-based therapy for Goodpasture syndrome.