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

基本信息

批准号：
10484616
负责人：
BRUCE A JULIAN
金额：
$ 66.77万
依托单位：
RELIANT GLYCOSCIENCES LLC
依托单位国家：
美国
项目类别：
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/10484616
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 Characteristics Chronic Kidney Failure Clinic Clinical Clinical Laboratory Improvement Amendments Clinical Trials Cohort Studies 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 Immunoglobulin G 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 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 base cohort commercialization cost detection assay disease diagnostic field study outcome prediction pilot lot production pre-clinical prognostication repository specific biomarkers tool treatment response validation studies

项目摘要

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，也是肾脏的重要原因失败。它是一种由特征性IgA1肾小球沉积物定义的肾小球增生性肾小球疾病。这些肾小球沉积物可能起源于循环中的免疫复合物，这些免疫复合物含有带有半乳糖的IgA1 （GAL） - 缺乏IgG自身抗体约束的缺陷O-Glycans（GD-IGA1）。描述的发病机理模型 Igan作为一种自身免疫性疾病是基于发现与GD-IGA1结合的IgG自身抗体的发现伯明翰（UAB）的阿拉巴马大学Jan Novak博士实验室。作为这些研究的一部分，博士诺瓦克的实验室开发了用于检测和定量评估GD-IGA1和IgG的测定法自动抗体。这些测定法用于分析来自几个IGAN患者的血清样品已出版； GD-IGA1分析和IgG自身抗体（IgG-AA）测定都有潜力临床前检测IGAN，预测结果以及监测对治疗的反应的标志物。这 Igan建立的发病机制模型使制药行业能够开始开发和测试治疗该疾病。但是，仅次级标记（例如蛋白尿和估计的肾小球过滤率[EGFR]）目前用作终点，增加了临床试验的时间和成本。因此，迫切需要评估主要因果标记的临床级测试。为了解决这个必要的问题，我们已从UAB获得了围绕Novak博士开发的IGAN测定法的知识产权实验室。在第一阶段，我们将IGG-AA测定法转移到合同研究组织的实验室环境中要执行协议的标准化，请充分表征测定的组件，然后执行详细的资格研究将其作为商业化过程的第一步。在第二阶段，我们将完成IGAN IgG-AA测试的开发，包括血清控制的开发，试剂采购，对ELISA板的大规模打印以及合作伙伴使用的标准化测定说明和/或临床实验室改进修订（CLIA）认证实验室。我们将执行一系列内部以及与关键意见领导者和其他可访问的生物重定位者的外部验证研究。到结束第二阶段，我们将准备通过Clia Lab Partnershs将IGAN IGG-AA测试引入诊所。