Depleting autoantibodies for the treatment of autoimmunity

项目摘要/摘要 该项目的总体目标是开发一种治疗原发性高血压的新疗法。 (特发性)膜性肾病。锰是#年肾病综合征的主要原因。 成人，有不同的临床病程。大约三分之一的患者进入自发缓解状态， 而其余的人有持续性蛋白尿，可能导致终末期肾脏疾病和 甚至是死亡。2009年，足细胞上存在的M型磷脂酶A2受体(PLA2R) 在约70-80%的MN患者中被确定为自身抗体的靶标。是这样的 自身抗体被用作MN的诊断标志，以及PLA2R特异性高的患者 抗体水平通常预后很差。 虽然目前有几种治疗MN的方法，但它们通常可以导致 免疫抑制和其他严重副作用。例如，大剂量类固醇周期和 烷化剂可导致癌症、骨质疏松症和糖尿病，复发率高达30% 治疗后五年内的患者。利妥昔单抗等耗尽B细胞的抗体 也与感染风险增加和显着的复发率有关。作为一名 结果由于现有治疗MN的局限性，开发MN的需求尚未得到满足 改进的、选择性的治疗方法。 此应用程序旨在通过生成以下内容来解决MN的新疗法需求 以抗体为基础的工程化试剂，能迅速特异性地耗尽PLA2R特异性 与疾病相关的抗体。重要的是，这些耗竭剂不会影响 对感染具有保护作用的其他抗体的水平等。这是一种第一流的，新颖的 这项技术被命名为Seldeg Technology(选择性降解)。 这项研究的具体目的是： 1.设计并表达针对PLA2R特异性抗体的Seldegs。 2.分析Seldegs的稳定性和结合活性。 拟议的方法不仅可以对这一管理进行变革 潜在的毁灭性疾病，但也将为类似的基于Seldeg的 在致病抗体导致疾病的许多其他临床环境中采取的策略。

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of primary (idiopathic) membranous nephropathy (MN). MN is a leading cause of nephrotic syndrome in adults and has a variable clinical course. About one third of patients enter spontaneous remission, whereas the remainder have persistent proteinuria that can lead to end stage renal disease and even death. In 2009, the M-type phospholipase A2 receptor (PLA2R) that is present on podocytes was identified as the target of autoantibodies in about 70-80% of MN patients. Such autoantibodies are used as a diagnostic marker for MN, and patients with high PLA2R-specific antibody levels typically have a poor prognosis. Although there are currently several therapies for MN, they can result in general immunosuppression and other severe side effects. For example, cycles of high dose steroids and alkylating agents can lead to cancer, osteoporosis and diabetes, and relapses occur in up to 30% patients within five years following treatment. B cell-depleting antibodies such as rituximab are also associated with increased risk of infection combined with a significant relapse rate. As a result of the limitations of existing therapies for MN, there is an unmet need for the development of improved, selective therapeutic approaches. This application seeks to address the need for new therapies for MN by generating engineered, antibody-based reagents that specifically and rapidly deplete PLA2R-specific antibodies that are associated with disease. Importantly, these depleting agents do not affect the levels of other antibodies that have a protective role against infection etc. This first-in-class, novel technology has been named Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target PLA2R-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could not only be transformative for the management of this potentially devastating disease, but would also lay the foundations for analogous Seldeg-based strategies to be taken in many other clinical settings where pathogenic antibodies lead to disease.