Novel treatments for Autoimmune Disease

自身免疫性疾病的新疗法

• 批准号: 10758915
• 负责人: Sunil Kannanganat Sidharthan
• 金额: $ 30.54万
• 依托单位: ASTERO ERADO INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758915
• 关键词: Acantholysis; Address; Adhesions; Adrenal Cortex Hormones; Adult; Adverse effects; Adverse event; Affect; Aftercare; Antibodies; Antibody Therapy; Antigens; Applications Grants; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Bacteria; Binding; Biological Assay; Bulla; Cell Surface Receptors; Chimeric Proteins; Chronic; Clinic; Clinical; Clinical Management; Combined Modality Therapy; Deglutition; Desmosomes; Development; Disadvantaged; Disease; Dose; Endothelial Cells; Engineering; Excision; Funding; Gamma globulin; General Population; Generations; Goals; Hypertension; IgG autoantibodies; Immune Tolerance; Immunoglobulin G; Immunosuppression; Immunosuppressive Agents; Infection; Infectious Agent; Inflammatory; Infusion procedures; Intravenous; Kupffer Cells; Laboratories; Lead; Lesion; Liver; Lysosomes; Mediating; Mucous Membrane; Names; Osteoporosis; Pain; Pathogenicity; Patients; Pemphigus; Pemphigus Vulgaris; Phase; Plasmapheresis; Procedures; Process; Property; Quality of life; Reaction; Reagent; Relapse; Research; Research Design; Role; Sampling; Serum; Skin; Specificity; Steroids; Surface; Technology; Texas; Therapeutic; Tissues; Translating; Universities; Virus; Work; commercialization; design; desmoglein 1; desmoglein III; experimental analysis; improved; in vivo; infection risk; keratinocyte; mortality; mortality risk; mouse model; mycophenolate mofetil; new technology; novel; novel strategies; novel therapeutics; oligodendrocyte-myelin glycoprotein; prevent; relapse patients; rituximab; side effect; skin lesion; targeted delivery; targeted treatment; therapy development; ward

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of pemphigus. Pemphigus involves blistering of the skin or mucosal surfaces and can lead to difficulty in swallowing, very painful lesions, and a ~2-3 fold increased risk of mortality. About 90-95% of pemphigus cases can be accounted for by pemphigus vulgaris (PV) or pemphigus foliaceus (PF). Autoantibodies of the IgG class that are specific for desmogleins 1 and 3 (Dsg1 and Dsg3) disrupt the desmosomal-mediated adhesion of keratinocytes and are the causative agents of disease. PV can present as a mucosal-dominant form involving Dsg3-specific autoantibodies, or a form with both Dsg1- and Dsg3-specific autoantibodies that affects skin and mucosal surfaces. PF is a skin-dominant disease, involving only Dsg1-specific autoantibodies. Current treatments for pemphigus, such as the combination of corticosteroids and the B cell- depleting antibody, rituximab, have associated adverse effects such as osteoporosis and hypertension. In addition, the onset of action of rituximab takes several months since this therapeutic agent targets B cells, rather than the autoantibodies themselves. The combination of rituximab with tapered corticosteroids is also accompanied by a significant relapse rate (25-60%) and increased infection risk due to the immunosuppressive effects of B cell depletion. Other therapeutic approaches for pemphigus include the use of intravenous gammaglobulin, plasmapheresis or immunoadsorption, and can lead to undesirable side effects. Consequently, there is an unmet need to develop therapies for pemphigus that have rapid onset and high specificity for the autoantibodies. This application seeks to address the need for new and improved therapies for pemphigus by generating engineered, antibody-based reagents that specifically and rapidly deplete Dsg-specific antibodies. Importantly, these depleting agents are highly selective and do not affect the levels of other antibodies that have a protective role against infection. This first-in-class, novel technology has been named Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target Dsg-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could be transformative for the management of pemphigus, and also has relevance to the use of Seldeg-based strategies for multiple other clinical settings where pathogenic antibodies cause disease.

项目摘要/摘要 该项目的总体目标是开发一种治疗天疱疮的新疗法。 天疱疮涉及皮肤或粘膜表面起泡，可导致 吞咽，非常痛苦的皮损，以及~2-3倍的死亡风险。约90%-95%的 天疱疮病例可由寻常型天疱疮(PV)或叶型天疱疮(PF)引起。 针对Desmoglein 1和3(DSG1和Dsg3)的Ig G类自身抗体破坏 桥粒介导的角质形成细胞的黏附是疾病的致病因素。 PV可以表现为粘膜占优势的形式，涉及Dsg3特异性自身抗体，或一种形式 具有DSG1和Dsg3特异性自身抗体，影响皮肤和粘膜表面。PF是 一种皮肤显性疾病，仅涉及DSG1特异性自身抗体。 目前天疱疮的治疗方法，如皮质类固醇和B细胞的联合治疗- 耗竭抗体，利妥昔单抗，有相关的不良反应，如骨质疏松和 高血压。此外，利妥昔单抗的起效时间为几个月后 治疗剂针对的是B细胞，而不是自身抗体本身。这两种技术的结合 使用锥形皮质类固醇的利妥昔单抗还伴有显著的复发率(25%-60%)。 由于B细胞耗尽的免疫抑制作用，感染风险增加。其他 治疗天疱疮的方法包括静脉注射丙种球蛋白， 血浆置换或免疫吸附，并可能导致不良副作用。因此， 有一种尚未得到满足的需求，即开发起病快、高发的天疱疮疗法。 自身抗体的特异性。 本申请旨在通过以下方式解决天疱疮新的和改进的治疗方法的需求 产生以抗体为基础的工程化试剂，特异性地快速耗尽DSG特异性 抗体。重要的是，这些耗竭剂具有很高的选择性，不会影响 对感染有保护作用的其他抗体。这项一流的、新颖的技术 已被命名为Seldeg Technology(用于选择性降解)。 这项研究的具体目的是： 1.设计并表达针对DSG特异性抗体的Seldegs。 2.分析Seldegs的稳定性和结合活性。 建议的方法可能会对天疱疮的管理产生变革，而且 与在多种其他临床环境中使用基于Seldeg的策略相关 致病抗体导致疾病。