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.

项目总结/摘要 本项目的总体目标是开发一种新的治疗天疱疮的治疗方法。 天疱疮涉及皮肤或粘膜表面起泡，并可导致难以治疗。 吞咽、非常疼痛的病变以及死亡风险增加约2-3倍。大约90-95%的 天疱疮病例可由寻常天疱疮（PV）或落叶型天疱疮（PF）引起。 对桥粒核心蛋白1和3（Dsg 1和Dsg 3）具有特异性的IgG类自身抗体破坏 角质形成细胞的桥粒介导的粘附，并且是疾病的病原体。 PV可以作为涉及Dsg 3特异性自身抗体的粘膜优势形式存在，或者作为涉及Dsg 3特异性自身抗体的粘膜优势形式存在。 Dsg 1和Dsg 3特异性自身抗体影响皮肤和粘膜表面。PF是 皮肤显性疾病，仅涉及Dsg 1特异性自身抗体。 目前天疱疮的治疗，如皮质类固醇和B细胞的组合， 消耗抗体利妥昔单抗具有相关的副作用，例如骨质疏松症， 高血压此外，利妥昔单抗的作用开始需要几个月，因为这 治疗剂靶向B细胞，而不是自身抗体本身。的组合 利妥昔单抗与减量皮质类固醇也伴随着显著的复发率（25-60%） 以及由于B细胞耗竭的免疫抑制作用而增加的感染风险。其他 天疱疮的治疗方法包括使用静脉内丙种球蛋白， 血浆置换术或免疫吸附，并可导致不希望的副作用。因此，委员会认为， 开发具有快速发病和高风险的天疱疮治疗方法的需求尚未得到满足， 自身抗体的特异性。 本申请寻求解决对天疱疮的新的和改进的疗法的需要， 产生工程化的基于抗体的试剂，其特异性地和快速地消耗Dsg特异性抗体， 抗体的重要的是，这些消耗剂是高度选择性的，并且不影响细胞的水平。 其他对感染有保护作用的抗体。这种一流的新颖技术 Seldeg技术（选择性降解）。 研究的具体目标是： 1.设计和表达Seldegs以靶向Dsg特异性抗体。 2.分析Seldegs的稳定性和结合活性。 所提出的方法可能是天疱疮管理的变革， 与使用基于Seldeg的策略用于多种其他临床环境相关，其中 致病抗体导致疾病。