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.

项目概要/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，并可能导致治疗困难 吞咽、非常痛苦的病变以及死亡风险增加约 2-3 倍。大约90-95% 天疱疮病例可归因于寻常型天疱疮 (PV) 或落叶型天疱疮 (PF)。 桥粒芯糖蛋白 1 和 3（Dsg1 和 Dsg3）特异性的 IgG 类自身抗体会破坏 桥粒介导的角质形成细胞粘附，是疾病的致病因素。 PV 可以表现为粘膜为主的形式，涉及 Dsg3 特异性自身抗体，或者是一种形式 具有影响皮肤和粘膜表面的 Dsg1 和 Dsg3 特异性自身抗体。 PF 为 一种以皮肤为主的疾病，仅涉及 Dsg1 特异性自身抗体。 目前天疱疮的治疗方法，例如皮质类固醇和 B 细胞的联合治疗 消耗抗体利妥昔单抗具有相关的副作用，例如骨质疏松症和 高血压。此外，利妥昔单抗起效需要几个月的时间。 治疗剂针对的是 B 细胞，而不是自身抗体本身。的组合 利妥昔单抗联合递减皮质类固醇还伴有显着的复发率 (25-60%) 由于 B 细胞耗竭的免疫抑制作用，感染风险增加。其他 天疱疮的治疗方法包括使用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。最后， 开发起病快、发病率高的天疱疮疗法的需求尚未得到满足。 自身抗体的特异性。 该申请旨在通过以下方式满足对新的和改进的天疱疮疗法的需求 生成工程化的、基于抗体的试剂，可特异性且快速地耗尽 Dsg 特异性 抗体。重要的是，这些消耗剂具有高度选择性，不会影响 其他具有抗感染保护作用的抗体。这项一流的新技术 被命名为 Seldeg 技术（选择性降解）。 该研究的具体目标是： 1.设计并表达Seldegs以靶向Dsg特异性抗体。 2.分析Seldegs的稳定性和结合活性。 所提出的方法可能会对天疱疮的治疗带来变革，而且 与基于 Seldeg 的策略在多种其他临床环境中的使用相关，其中 致病性抗体引起疾病。