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(Ig G-AA)检测都有可能成为 临床前检测免疫球蛋白肾病、预测结果和监测治疗反应的标志物。这个 免疫球蛋白肾病发病机制模型的建立使制药行业开始开发和测试 对这种疾病的治疗。然而，只有辅助标志物(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， 迫切需要临床级别的检测来评估主要的致病标志。为了满足这一要求，我们 我已经从UAB获得了围绕Novak博士开发的IgAN检测的知识产权 实验室。在第一阶段，我们将免疫球蛋白-AA检测转移到合同研究组织的实验室环境 为了执行方案的标准化，充分表征化验的成分，并执行 作为商业化进程的第一步，对其性能进行详细的资格研究。在第二阶段， 我们将完成IgAN免疫球蛋白-AA检测的开发，包括血清对照、试剂的开发 供合作伙伴和/或使用的采购、大规模打印酶联免疫吸附试验试板和标准化化验说明 临床实验室改进修正案(CLIA)-认证实验室。我们将执行一系列内部 以及与关键意见领袖和其他可访问的生物信息库的外部验证研究。到年底的时候 第二阶段，我们将准备通过CLIA实验室合作伙伴关系将我们的IgAN免疫球蛋白-AA检测引入临床。

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 (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.