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.

项目摘要/摘要 该项目的总体目标是开发一种新型的治疗方法 （特发性）膜性肾病（MN）。 MN是肾病综合征的主要原因 成人，有可变的临床过程。大约三分之一的患者自发缓解， 而其余的则具有持续的蛋白尿，可以导致末期肾脏疾病和 甚至死亡。 2009年，存在于足细胞上的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。这样的 自身抗体用作MN的诊断标记，并且具有高PLA2R特异性的患者 抗体水平通常的预后较差。 尽管目前有几种用于MN的疗法，但它们一般可以导致 免疫抑制和其他严重的副作用。例如，高剂量类固醇和 烷基化剂可导致癌症，骨质疏松症和糖尿病，复发发生在多达30％的情况下 治疗后五年内患者。 B耗尽细胞的抗体，例如利妥昔单抗 也与增加感染风险相关，并结合显着的复发率。作为 MN现有疗法的局限性的结果，对开发的需求未满足 改进的选择性治疗方法。 该项目旨在通过开发工程， 基于抗体的试剂，这些试剂专门耗尽了PLA2R特异性抗体。 重要的是，这些耗尽剂不会影响具有 防御感染的保护作用等。这种一流的新技术被命名为塞尔德 技术（用于选择性退化）。 第一阶段项目的目的是通过设计塞尔德（Seldeg）来提供概念证明 分子并使用体外测定法显示其对临床发育的适用性。在这个阶段II 应用程序，我们建议通过执行塞尔德格在开发过程中向前迈进 必要的体外表征和动物模型中的研究。具体目的是： 1。使用体外分析对PLA2R-甲壳虫进行药物开发和测试。 2。分析PLA2R-甲壳虫和靶向自身抗体的体内行为。 提出的方法不仅可以对此进行变革 潜在毁灭性疾病，但也将为基于塞尔德的类似的基础奠定基础 在许多其他临床环境中采取的策略会导致疾病。