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.

项目概要/摘要 该项目的总体目标是开发一种新的治疗方法来治疗原发性 （特发性）膜性肾病（MN）。 MN 是肾病综合征的主要原因 成人并具有可变的临床病程。大约三分之一的患者进入自发缓解， 而其余的人则有持续性蛋白尿，可能导致终末期肾病， 甚至死亡。 2009年，足细胞上存在M型磷脂酶A2受体（PLA2R） 被确定为约 70-80% MN 患者自身抗体的靶点。这样的 自身抗体被用作 MN 的诊断标志物，以及具有高 PLA2R 特异性的患者 抗体水平通常预示着不良预后。 尽管目前有多种治疗 MN 的疗法，但它们的结果通常是 免疫抑制和其他严重的副作用。例如，高剂量类固醇的循环和 烷化剂可导致癌症、骨质疏松症和糖尿病，并且复发率高达 30% 治疗后五年内的患者。 B 细胞消耗抗体，例如利妥昔单抗 还与感染风险增加和显着的复发率相关。作为一个 由于 MN 现有疗法的局限性，开发需求尚未得到满足 改进的选择性治疗方法。 该项目旨在通过开发工程化的、 基于抗体的试剂，可特异性且快速地消耗 PLA2R 特异性抗体。 重要的是，这些消耗剂不会影响其他抗体的水平 防止感染等的保护作用。这项一流的新技术被命名为 Seldeg 技术（用于选择性降解）。 第一阶段项目的目标是通过设计 Seldeg 来提供概念验证 分子并通过体外测定显示其适合临床开发。在本次第二阶段 应用程序中，我们建议通过执行以下措施来推动 Seldeg 的开发过程 必要的体外表征和动物模型研究。具体目标是： 1. 利用体外分析对 PLA2R-Seldeg 进行药物开发和测试。 2. 分析PLA2R-Seldeg和靶向自身抗体的体内行为。 所提出的方法不仅可以为这一管理带来变革 潜在的毁灭性疾病，但也将为类似的基于 Seldeg 的疾病奠定基础 在致病性抗体导致疾病的许多其他临床环境中采取的策略。