Depleting autoantibodies for the treatment of autoimmunity

消耗自身抗体来治疗自身免疫

• 批准号: 10698700
• 负责人: Sunil Kannanganat Sidharthan
• 金额: $ 101.6万
• 依托单位: ASTERO ERADO INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-11 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698700
• 关键词: Address; Adult; Adverse event; Affect; Aftercare; Alkylating Agents; Allografting; Alternative Therapies; Animal Model; Antibodies; Antibody Therapy; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacteria; Behavior; Binding; Biological Markers; Calcineurin inhibitor; Cell Surface Receptors; Cessation of life; Chimeric Proteins; Chlorambucil; Clinical; Clinical Management; Clinical Trials; Cyclophosphamide; DNA; Development; Diabetes Mellitus; Diagnosis; Disadvantaged; Disease; Disease remission; Dose; Drug Kinetics; End stage renal failure; Endothelial Cells; Engineering; Excision; Failure; Foundations; Funding; Generations; Goals; Human; Immune Tolerance; Immunoglobulin G; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Infectious Agent; Kidney; Kupffer Cells; Laboratories; Lead; Liver; Lymphoid Tissue; Lysosomes; MS4A1 gene; Malignant Neoplasms; Mediating; Membranous Glomerulonephritis; Names; Nephrotic Syndrome; Osteoporosis; Pathogenicity; Patients; Phase; Phospholipase A2; Plasmablast; Preparation; Procedures; Process; Production; Prognosis; Property; Proteinuria; Reagent; Regimen; Relapse; Research; Resistance; Role; Spontaneous Remission; Steroids; Tacrolimus; Technology; Texas; Therapeutic; Thrombocytopenia; Transgenic Mice; Universities; Virus; Work; allergic response; clinical development; commercialization; design; diagnostic biomarker; drug development; drug testing; first-in-human; improved; improved outcome; in vitro Assay; in vivo; infection risk; mycophenolate mofetil; neonatal Fc receptor; new technology; nonhuman primate; novel; novel strategies; novel therapeutics; podocyte; prevent; prognostic; receptor; rituximab; side effect; targeted delivery; ward

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 project seeks to address the need for new therapies for MN by developing engineered, antibody-based reagents that specifically and rapidly deplete PLA2R-specific antibodies. 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 goal of the Phase I project was to provide a proof-of-concept by designing a Seldeg molecule and showing its suitability for clinical development using in vitro assays. In this Phase II application, we propose to move the Seldeg forward in the development process by carrying out the necessary in vitro characterization and studies in animal models. The Specific aims are: 1. To carry out drug development and testing of the PLA2R-Seldeg using in vitro analyses. 2. To analyze the in vivo behavior of the PLA2R-Seldeg and targeted autoantibodies. 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.

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。 该项目旨在通过开发工程化的， 基于抗体的试剂，其特异性且快速地耗尽PLA 2 R特异性抗体。 重要的是，这些消耗剂不影响具有免疫原性的其他抗体的水平。 这种一流的新技术被命名为Seldeg 技术（选择性降解）。 第一阶段项目的目标是通过设计Seldeg提供概念验证。 分子并使用体外测定显示其适用于临床开发。在此第二阶段 应用程序，我们建议通过执行将Seldeg在开发过程中向前推进 必要的体外表征和动物模型研究。具体目标是： 1.使用体外分析进行PLA 2 R-Seldeg的药物开发和检测。 2.分析PLA 2 R-Seldeg和靶向自身抗体的体内行为。 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。