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.

抽象的 IgA肾病（IgAN）是最常见的原发性肾小球肾炎，也是肾病的重要病因。 失败。它是一种以特征性 IgA1 系膜沉积为特征的系膜增生性肾小球疾病。 这些系膜沉积物可能源自含有 IgA1 和半乳糖的循环免疫复合物 与 IgG 自身抗体结合的 (Gal) 缺陷型 O-聚糖 (Gd-IgA1)。发病机制模型描述 IgAN 作为一种自身免疫性疾病是基于在体内结合 Gd-IgA1 的 IgG 自身抗体的发现。 阿拉巴马大学伯明翰分校 (UAB) 的 Jan Novak 博士实验室。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-IgA1 和 IgG 的检测方法 自身抗体。使用这些测定法分析多个 IgAN 患者队列的血清样本 已发表； Gd-IgA1 测定和 IgG 自身抗体 (IgG-AA) 测定都有潜力 用于 IgAN 临床前检测、结果预测和监测治疗反应的标记物。这 IgAN发病机制模型的建立使制药行业开始开发和测试 治疗该疾病。然而，只有次要标志物（例如蛋白尿和估计肾小球 目前使用滤过率[eGFR]）作为终点，增加了临床试验的时间和成本。因此， 迫切需要评估主要致病标志物的临床级测试。为了满足这个要求，我们 已获得 UAB 的知识产权许可，该知识产权围绕 Novak 博士开发的 IgAN 检测方法 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环境中 执行方案的标准化，充分表征测定的组成部分，并执行 作为商业化过程的第一步，对其性能进行详细的资格研究。在第二阶段， 我们将完成IgAN IgG-AA检测的开发，包括血清质控品、试剂的开发 采购、大规模打印 ELISA 板以及供合作伙伴和/或使用的标准化检测说明 临床实验室改进修正案 (CLIA) 认证的实验室。我们将进行一系列的内部 以及与关键意见领袖和其他可访问的生物存储库进行的外部验证研究。到年底 第二阶段，我们将准备通过 CLIA 实验室合作伙伴将我们的 IgAN IgG-AA 测试引入临床。