Utilizing IgG Autoantibodies As Biomarkers In IgA Nephropathy

利用 IgG 自身抗体作为 IgA 肾病的生物标志物

• 批准号: 10608214
• 负责人: BRUCE A JULIAN
• 金额: $ 61.63万
• 依托单位: RELIANT GLYCOSCIENCES LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608214
• 关键词: Address; Affect; Age; Agreement; Alabama; Ancillary Study; Antigen-Antibody Complex; Asian population; Autoantibodies; Autoantigens; Autoimmune Diseases; Automobile Driving; Awareness; Binding; Biological Assay; Biological Markers; Caucasians; Certification; Characteristics; Chronic Kidney Failure; Clinic; Clinical; Clinical Laboratory Improvement Amendments; Clinical Trials; Collaborations; Data; Deposition; Detection; Development; Disease; Drug Industry; Enzyme-Linked Immunosorbent Assay; Evaluation; Funding; Galactose; Gender; Glomerular Filtration Rate; Glomerulonephritis; Goals; IGA Glomerulonephritis; IgA1; IgG autoantibodies; Injury to Kidney; Instruction; Intellectual Property; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Lead; Licensing; Measurement; Medical center; Modeling; Monitor; Nephrology; New York; Outcome; Pathogenesis; Pathologic; Patients; Performance; Persons; Pharmacologic Substance; Phase; Polysaccharides; Preparation; Printing; Procedures; Process; Prospective Studies; Proteinuria; Protocols documentation; Publications; Publishing; Qualifying; Reagent; Renal glomerular disease; Reproducibility; Research; Research Contracts; Sampling; Sensitivity and Specificity; Series; Serum; Site; Source; Specimen; Standardization; Testing; Time; Training; United States National Institutes of Health; Universities; Validation; biobank; cohort; commercialization; cost; detection assay; disease diagnostic; field study; observational cohort study; outcome prediction; pilot lot production; pre-clinical; prognostication; specific biomarkers; tool; treatment response; validation studies

Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of kidney failure. It is a mesangioproliferative glomerular disease defined by characteristic IgA1 mesangial deposits. These mesangial deposits likely originate from circulating immune complexes that contain IgA1 with Galactose (Gal)-deficient O-glycans (Gd-IgA1) that are bound by IgG autoantibodies. The pathogenesis model describing IgAN as an autoimmune disease was based on the discovery of IgG autoantibodies that bind Gd-IgA1 in the laboratory of Dr. Jan Novak at the University of Alabama at Birmingham (UAB). As part of these studies, Dr. Novak's laboratory developed assays for the detection and quantitative assessment of both Gd-IgA1 and IgG autoantibodies. The use of these assays for analysis of serum samples from several cohorts of IgAN patients has been published; both the Gd-IgA1 assay and the IgG autoantibody (IgG-AA) assay have potential as markers for preclinical detection of IgAN, prediction of outcome, and monitoring the response to therapy. The established pathogenesis model of IgAN enabled pharmaceutical industry to start developing and testing treatment for the disease. However, only secondary markers (e.g., proteinuria and estimated glomerular filtration rate [eGFR]) are currently used as the endpoints, adding to the time and cost of clinical trials. Thus, clinical-grade tests that assess primary causative markers are urgently needed. To address this requisite, we have licensed the intellectual property from UAB that surrounds the IgAN assays developed in Dr. Novak's laboratory. In Phase I, we transferred the IgG-AA assay to a contract research organization laboratory setting to perform standardization of the protocol, fully characterize the components of the assay, and perform a detailed qualification study on its performance as an initial step in the commercialization process. In Phase II, we will complete the development of the IgAN IgG-AA test, including development of serum controls, reagent sourcing, large-scale printing of ELISA plates, and standardized assay instructions for use by partner and/or Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. We will perform a series of internal and external validation studies with key opinion leaders and other accessible bio-repositories. By the end of Phase II, we will be ready to introduce our IgAN IgG-AA test into the clinic through CLIA lab partnerships.

摘要 伊加肾病（IgAN）是最常见的原发性肾小球肾炎，是肾脏损害的重要原因， 失败它是一种系膜增生性肾小球疾病，由特征性IgA 1系膜沉积物定义。 这些系膜沉积物可能来源于含有半乳糖的IgA 1的循环免疫复合物 由IgG自身抗体结合的（Gal）缺陷型O-聚糖（Gd-IgA 1）。发病机制模型描述 IgAN作为一种自身免疫性疾病是基于发现IgG自身抗体结合Gd-IgA 1， 在伯明翰的亚拉巴马大学（UAB）的Jan Novak博士的实验室。作为这些研究的一部分，博士。 Novak的实验室开发了用于检测和定量评估Gd-IgA 1和IgG的检测方法 自身抗体使用这些测定法分析来自几个IgAN患者队列的血清样品， 已发表; Gd-IgA 1测定和IgG自身抗体（IgG-AA）测定均具有作为 用于IgAN临床前检测、预测结果和监测对治疗的反应的标志物。的 IgAN发病机制模型的建立使制药业开始开发和测试 治疗疾病。然而，只有次要标记（例如，蛋白尿和估计肾小球 滤过率[eGFR]）目前被用作终点，增加了临床试验的时间和成本。因此，在本发明中， 迫切需要评估主要致病标志物的临床级测试。为了满足这一要求，我们 已经从UAB获得了围绕诺瓦克博士开发的IgAN测定的知识产权。 实验室在第一阶段，我们将IgG-AA检测转移到合同研究组织实验室设置 执行方案标准化，充分表征测定组分，并执行 作为商业化进程的第一步，对其性能进行详细的鉴定研究。在第二阶段， 我们将完成IgAN IgG-AA检测的开发，包括血清对照品、试剂盒的开发， 采购、大规模印刷ELISA平板和供合作伙伴使用的标准化检测说明书，和/或 临床实验室改进修正案（CLIA）-认证实验室。我们将进行一系列的内部 与关键意见领袖和其他可访问的生物储存库进行外部验证研究。年底前 第二阶段，我们将准备通过CLIA实验室合作伙伴关系将IgAN IgG-AA测试引入临床。