Developing non-immunosuppressive immune-based therapeutics for targeted treatment of autoimmune diseases

开发非免疫抑制性免疫疗法来靶向治疗自身免疫性疾病

基本信息

批准号：
10586562
负责人：
Mohammad Rashidian
金额：
$ 70.07万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-24 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586562
关键词：
Adhesions Adult Affect Affinity Agammaglobulinaemia tyrosine kinase Animal Model Animals Antibodies Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autologous B-Cell Antigen Receptor B-Lymphocytes Basement membrane Binding Biological Products Bioluminescence Bulla Bypass CD3 Antigens Cell Adhesion Molecules Cell-Mediated Cytolysis Cells Chimeric Proteins Clinic Clinical Data Desmosomes Development Disease Disease model Engineering Enzyme-Linked Immunosorbent Assay Epidermis Evaluation Fc domain Flow Cytometry Future Goals Human IgG1 Immune system Immunofluorescence Immunologic Immunological Models Immunosuppression Immunosuppressive Agents Immunotherapeutic agent In Vitro Life Mediating Methods Modeling Morbidity - disease rate Mucous Membrane Mus Natural Killer Cells Outcome Pain Pathogenicity Patients Pemphigus Pemphigus Vulgaris Peripheral Blood Mononuclear Cell Phagocytes Pharmaceutical Preparations Phase Principal Investigator Production Protein Engineering Proteins Regulatory T-Lymphocyte Relapse Resources Role Serum Skin Specificity Steroids Surface Plasmon Resonance T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Translating Treatment Efficacy Tyrosine Kinase Inhibitor Vaccines Writing antagonist autoreactive B cell autoreactivity cell type cost desmoglein III efficacy evaluation efficacy testing extracellular in vivo infection risk keratinocyte mortality mouse model neonatal Fc receptor novel personalized medicine pre-clinical prototype recruit response rituximab side effect standard care standard of care targeted treatment tool tositumomab treatment strategy

项目摘要

Project Summary Pemphigus vulgaris is a devastating B-cell mediated autoimmune disease. Autoantibodies produced by B cells targeting desmoglein-3 (Dsg3), a desmosomal protein, critical for intercellular adhesion, is responsible for the mucosal-dominant type of the disease and cause painful deep erosions in the mucosa. Anti-Dsg3 autoantibodies result in the disruption of the keratinocytes' connections, and, thereby, cause the formation of blisters and erosions. The direct pathogenic role of anti-Dsg3 autoantibodies in PV has been established. Monovalent antibodies have been shown to be sufficient to result in the formation of blisters. Standard treatments include immunosuppressive drugs that globally suppress the immune system. The goal of this project is to develop novel, targeted, immuno-therapeutic approaches to specifically and precisely target and deplete autoreactive B cells recognizing Dsg3. Established Dsg3 specific autoreactive B cells are used to optimize these methods. We will determine the efficacy and specificity of the approach using peripheral blood mononuclear cells (PBMCs) obtained from PV patients in different phases of the disease, including treatment- naive and relapse, and in vivo mouse models of the disease. Successful completion of this study will help translate the methods into a preclinical and, eventually, a clinical setting. The ease of production, low cost, compared to cell-based targeted approaches, and the lack of off-target side-effects compared to the existing treatments for PV make the proposed therapeutics breakthrough treatment options. Furthermore, the technology developed here can have wider applications to all autoantibody-driven diseases by directly targeting autoreactive cells without causing global immunosuppression.

项目概要寻常型天疱疮是一种毁灭性的 B 细胞介导的自身免疫性疾病。 B细胞产生的自身抗体靶向桥粒芯糖蛋白 3 (Dsg3)，一种桥粒蛋白，对细胞间粘附至关重要，负责粘膜为主的疾病类型，导致粘膜疼痛性深度糜烂。抗Dsg3 自身抗体会破坏角质形成细胞的连接，从而导致形成水泡和糜烂。抗 Dsg3 自身抗体在 PV 中的直接致病作用已经确定。单价抗体已被证明足以导致水疱的形成。标准治疗方法包括全面抑制免疫系统的免疫抑制药物。此举的目标该项目旨在开发新颖的、有针对性的免疫治疗方法，以特异性、精确地靶向和治疗消耗识别 Dsg3 的自身反应性 B 细胞。已建立的 Dsg3 特异性自身反应 B 细胞用于优化这些方法。我们将使用外周血确定该方法的有效性和特异性从 PV 患者的疾病不同阶段（包括治疗阶段）获得的单核细胞 (PBMC) 幼稚和复发，以及该疾病的体内小鼠模型。成功完成这项研究将有助于将这些方法转化为临床前，并最终转化为临床环境。生产方便、成本低、与基于细胞的靶向方法相比，与现有的方法相比，不存在脱靶副作用 PV 的治疗使所提出的疗法具有突破性的治疗选择。此外，这里开发的技术可以通过直接更广泛的应用来治疗所有自身抗体驱动的疾病靶向自身反应细胞而不引起整体免疫抑制。