Depleting autoantibodies for the treatment of autoimmunity

项目总结/摘要 该项目的总体目标是开发一种新的治疗原发性 （特发性）膜性肾病（MN）。肾病综合征的病因有哪些？ 成人，并具有可变的临床过程。大约三分之一的患者进入自发缓解， 而其余的患者具有可导致终末期肾病的持续性蛋白尿， 甚至死亡2009年，足细胞上的M型磷脂酶A2受体（PLA 2 R） 在约70-80%的MN患者中，被鉴定为自身抗体的靶标。等 自身抗体被用作MN的诊断标志物，并且具有高PLA 2 R特异性的患者 抗体水平通常具有不良预后。 虽然目前有几种治疗MN的方法，但它们通常会导致 免疫抑制和其他严重副作用。例如，高剂量类固醇和 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5年内的患者。B细胞耗竭抗体如利妥昔单抗是 还与感染风险增加以及显著的复发率相关。作为 由于MN的现有疗法的局限性，存在对开发 改良的选择性治疗方法。 本申请寻求通过产生用于MN的新疗法来解决对MN的新疗法的需求。 工程化的，基于抗体的试剂，其特异性地和快速地消耗PLA 2 R特异性 与疾病相关的抗体。重要的是，这些消耗剂不影响 水平的其他抗体，有一个保护作用，防止感染等。这是一流的，新的 该技术被命名为Seldeg技术（用于选择性降解）。 研究的具体目标是： 1.设计和表达Seldegs以靶向PLA 2 R特异性抗体。 2.分析Seldegs的稳定性和结合活性。 拟议的方法不仅可以改变这种管理， 潜在的毁灭性疾病，但也将奠定基础，类似的Seldeg为基础的 在致病抗体导致疾病的许多其他临床环境中，可以采取这些策略。

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.