Utilizing IgG Autoantibodies as Biomarkers in IgA Nephropathy

摘要 IgA肾病(IgAN)是最常见的原发性肾小球肾炎，也是肾脏的重要病因 失败了。这是一种系膜增生性肾小球疾病，以特征性的IgA1系膜沉积为特征。 这些系膜沉积可能起源于循环免疫复合体，其中含有IgA1和半乳糖 与免疫球蛋白自身抗体结合的(半乳糖)缺陷O-糖链(Gd-IgA1)。描述发病机制的模型 IGAN是一种自身免疫性疾病，其基础是发现了与Gd-IgA1结合的Ig G自身抗体。 阿拉巴马大学伯明翰分校Jan Novak博士的实验室。作为这些研究的一部分，Dr。 诺瓦克的实验室开发了检测和定量评估Gd-Ig A1和Ig G的方法 自身抗体。应用这些方法分析几组IgAN患者的血清样本 已经发表；Gd-IgA1检测和免疫球蛋白自身抗体检测都有可能成为 临床前检测IgAN，预测结果，监测治疗反应。已建立的 IgAN的发病机制模型使制药行业开始开发和测试治疗IgAN的方法 疾病。然而，只有二级指标(例如，蛋白尿和估计的肾小球滤过率[EGFR]) 目前被用作终点，增加了临床试验的时间和成本。因此，临床级别的测试 评估主要致病标志物是迫切需要的。为了满足这一要求，我们已授权 围绕着诺瓦克实验室开发的IgAN检测的UAB的知识产权。目标是 这项建议的目的是表征和验证免疫球蛋白自身抗体检测的成分，并建立 标准操作程序(SOP)，以使其能够被验证并商业化用于临床。

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 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. The goal of this proposal is to characterize and validate the components of the IgG autoantibody assay and establish standard operating procedures (SOPs) so that it can be validated and commercialized for clinical use.