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Depleting autoantibodies for the treatment of autoimmunity

消耗自身抗体来治疗自身免疫

基本信息

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
项目类别：
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

项目摘要

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/文摘