Novel approaches for the treatment of autoimmune disease

治疗自身免疫性疾病的新方法

• 批准号: 10601899
• 负责人: Sunil Kannanganat Sidharthan
• 金额: $ 27.52万
• 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: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601899
• 关键词: ADAMTS; Acute; Address; Adrenal Cortex Hormones; Adverse effects; Adverse event; Affect; Antibodies; Antibody Response; Antibody Therapy; Antigens; Applications Grants; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Bacteria; Binding; Biological Assay; Blood Platelets; Blood capillaries; Blood coagulation; Cardiac; Cell Surface Receptors; Chimeric Proteins; Clinic; Clinical; Deposition; Disadvantaged; Disease; Disintegrins; Dose; Endothelial Cells; Engineering; Excision; Funding; Gene Proteins; Generations; Goals; Hemolytic Anemia; Hemorrhage; Immune; Immune Tolerance; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infection; Infectious Agent; Inflammatory; Infusion procedures; Ischemia; Kidney; Kupffer Cells; Laboratories; Lead; Life; Liver; Lysosomes; Mediating; Metalloproteases; Modality; Mutation; Names; Neurologic; Organ; Pathogenicity; Patients; Peptide Hydrolases; Phase; Plasma; Plasma Exchange; Platelet aggregation; Process; Property; Proteins; Reaction; Reagent; Research; Research Design; Sampling; Specificity; Technology; Texas; Therapeutic; Thrombocytopenia; Thrombosis; Thrombospondins; Thrombotic Thrombocytopenic Purpura; Thrombus; Translating; Universities; Virus; Work; aggregation factor; arteriole; commercialization; design; gastrointestinal; improved; in vivo; infection risk; member; mortality; mouse model; nanobodies; new technology; novel; novel strategies; novel therapeutics; oligodendrocyte-myelin glycoprotein; pathogenic autoantibodies; relapse patients; rituximab; side effect; targeted delivery; targeted treatment; therapy development; thrombotic; von Willebrand Factor; ward

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of immune- mediated thrombotic thrombocytopenic purpura (iTTP). iTTP is an acute, life-threatening disease that without treatment, leads to a >90% mortality rate. It is caused by deficiency of a disintegrin and metalloprotease thrombospondin type 1 motif, member 13 (ADAMTS13), which is a protease that cleaves ultra large aggregates of von Willebrand factor (VWF). Such aggregates of VWF bind to platelets, resulting in blood clots. Consequently, ADAMTS13 deficiency leads to microthrombus formation in arterioles and capillaries, and iTTP is characterized by hemolytic anemia, thrombocytopenia and organ damage, with possible severe cardiac, renal, neurological and gastrointestinal effects. For iTTP, ADAMTS13 deficiency is caused by autoantibodies specific for this protease. Current treatments are therefore directed towards reducing the levels of these antibodies by plasma exchange and the use of general immunosuppressants (corticosteroids, rituximab). In addition, a bivalent nanobody (caplacizumab) that inhibits VWF-platelet interactions has recently been approved to treat iTTP. Despite treatment, however, relapses occur in 30-50% iTTP patients. Further, the treatments can have adverse effects such as abnormal bleeding (caplacizumab) and/or increased risk of infection due to general immunosuppression. Rituximab also has a slow onset of action and is used in combination with plasma exchange. Consequently, there is a need to develop therapies for iTTP that have rapid effects and high specificity for the causal agent of disease, namely the autoantibodies. This application seeks to address the need for new and improved therapies for iTTP by generating engineered, antibody-based reagents that specifically and rapidly deplete ADAMTS13-specific antibodies. Importantly, these depleting agents are highly selective and do not have general immunosuppressive effects. 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 ADAMTS13-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could be transformative for the management of iTTP, 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 该项目的总体目标是开发一种新的治疗免疫- 介导的血栓性血小板减少性紫癜（iTTP）。iTTP是一种急性、危及生命的疾病 如果不治疗，死亡率会超过90%它是由于缺乏一种去整合素引起的 以及金属蛋白酶血小板反应蛋白1型基序，成员13（ADAMTS 13），其是蛋白酶 切割血管性血友病因子（VWF）的超大聚集体。VWF的这种聚集体结合 血小板导致血栓因此，ADAMTS 13缺陷导致微血栓 在小动脉和毛细血管中形成，并且iTTP的特征在于溶血性贫血， 血小板减少症和器官损伤，可能伴有重度心脏、肾脏、神经系统和 胃肠道影响。 对于iTTP，ADAMTS 13缺陷是由对该蛋白酶具有特异性的自身抗体引起的。 因此，目前的治疗针对通过以下方式降低这些抗体的水平： 血浆置换和使用一般免疫抑制剂（皮质类固醇，利妥昔单抗）。在 此外，抑制VWF-血小板相互作用的二价纳米抗体（caplacizumab）最近已被 已被批准用于治疗iTTP。然而，尽管进行了治疗，30-50%的iTTP患者仍会复发。 患者此外，治疗可能会产生不良反应，如异常出血 （caplacizumab）和/或由于全身免疫抑制导致的感染风险增加。美罗华 也具有缓慢的起效并与血浆置换联合使用。因此，委员会认为， 需要开发对iTTP具有快速疗效和高特异性的治疗方法 疾病的病原体，即自身抗体。 本申请旨在通过以下方式解决对iTTP的新的和改进的疗法的需求： 产生工程化的、基于抗体的试剂， ADAMTS 13特异性抗体。重要的是，这些消耗剂是高度选择性的， 没有一般的免疫抑制作用。这种一流的新颖技术已经被 Seldeg技术（用于选择性降解）。 研究的具体目标是： 1.设计和表达Seldegs以靶向ADAMTS 13特异性抗体。 2.分析Seldegs的稳定性和结合活性。 所提出的方法可能对iTTP的管理具有变革性， 与使用基于Seldeg的策略用于多种其他临床环境的相关性，其中 致病抗体导致疾病。