Novel approaches for the treatment of autoimmune disease

治疗自身免疫性疾病的新方法

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该项目的总体目标是开发一种新的治疗方法来治疗免疫- 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进行治疗，死亡率将超过 90%。这是由于解整合素缺乏引起的金属蛋白酶血小板反应蛋白 1 型基序，成员 13 (ADAMTS13)，它是一种蛋白酶裂解超大聚集的血管性血友病因子 (VWF)。 VWF 的此类聚集体结合影响血小板，导致血栓。因此，ADAMTS13 缺乏会导致微血栓在小动脉和毛细血管中形成，iTTP 的特点是溶血性贫血，血小板减少和器官损伤，可能伴有严重的心脏、肾脏、神经系统和胃肠道影响。对于 iTTP，ADAMTS13 缺陷是由针对该蛋白酶的自身抗体引起的。因此，当前的治疗旨在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，最近发现了一种抑制 VWF-血小板相互作用的二价纳米抗体（caplacizumab）已被批准用于治疗 iTTP。然而，尽管进行了治疗，仍有 30-50% 的 iTTP 会出现复发患者。此外，治疗可能会产生副作用，例如异常出血（caplacizumab）和/或由于一般免疫抑制而增加感染风险。利妥昔单抗起效缓慢，与血浆置换联合使用。最后，需要开发对 iTTP 具有快速效果和高特异性的疗法疾病的致病因子，即自身抗体。该申请旨在通过以下方式满足 iTTP 新的和改进的疗法的需求产生工程化的、基于抗体的试剂，可以特异性地、快速地耗尽 ADAMTS13 特异性抗体。重要的是，这些消耗剂具有高度选择性，并且不会不具有一般的免疫抑制作用。这项一流的新技术已称为 Seldeg 技术（用于选择性降解）。该研究的具体目标是： 1. 设计并表达 Seldegs 以靶向 ADAMTS13 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 iTTP 的管理带来变革，并且还具有与在多种其他临床环境中使用基于 Seldeg 的策略的相关性致病性抗体引起疾病。