Novel therapy for Goodpasture syndrome

古德帕斯彻综合征的新疗法

基本信息

批准号：
9458269
负责人：
JAMES W LARRICK
金额：
$ 22.44万
依托单位：
LARIX BIOSCIENCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9458269
关键词：
Adverse effects Affect Affinity Alternative Complement Pathway Alveolar Animals Antibodies Antigen Targeting Autoantibodies Autoimmune Diseases Autoimmune Process Basement membrane Binding Bispecific Antibodies Blocking Antibodies C-terminal Cessation of life Chimeric Proteins Collagen Collagen Type IV Complement Complement Activation Complement Inactivators Complement-Dependent Cytotoxicity Data Deposition Disease Drug Kinetics Engineering Etiology Glomerular basement membrane antibody Glomerulonephritis Goodpasture Syndrome Human IgG1 IgG4 Immune response Immunoglobulin G Immunosuppressive Agents In Vitro Inflammation Injury Kidney Kidney Diseases Kidney Failure Link Lung diseases Measures Mediating Monoclonal Antibodies Necrosis Neuromyelitis Optica Outcome Pathogenicity Pathology Patients Phase Point Mutation Recombinants Residual state Role Serum Time Tissues Toxic effect Variant Work antigen binding aquaporin 4 base cytotoxicity effective therapy glomerular basement membrane high risk human monoclonal antibodies in vivo mouse model novel novel therapeutics pre-clinical prevent

项目摘要

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.

古德帕斯特综合征的新疗法抽象的古德帕斯彻综合征 (GS) 是一种罕见的自身免疫性肺部疾病，由肾小球疾病演变而来基底膜 (GBM) 疾病和 GS 进展迅速，导致肾衰竭。目前的治疗方法是免疫抑制且无效的，并且存在很高的风险。 IV 型胶原蛋白 α3 链非胶原蛋白 1 (NC1) 结构域的自身抗体。 (α3(IV)NC1) 是肾小球和肺泡基底膜的组成部分，可引发免疫反应导致抗体沉积在基底上，随后发生炎症和坏死。涉及介导的细胞毒性（ADCC）和补体介导的细胞毒性（CDC）。缺乏效应器功能已被证明可以有效治疗具有类似病因的其他自身免疫性疾病（例如，视神经脊髓炎）在第一阶段项目中，我们将设计一种高亲和力的抗 IV 型胶原蛋白。人单克隆抗体可消除所有残留效应子功能，从而连接到强大的补体产生的双功能融合蛋白将抑制致病性抗体与 GBM 的结合。这项工作的成果将是一种基于机制的新型疗法。古德帕斯特综合症。