Exploring the mechanisms of action of anti-ADAMTS 13 antibodies in immune thrombotic thrombocytopenic purpura

探讨抗 ADAMTS 13 抗体在免疫性血栓性血小板减少性紫癜中的作用机制

基本信息

批准号：
10685963
负责人：
Konstantine Halkidis
金额：
$ 16.52万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-18 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685963
关键词：
Advisory Committees Affect Affinity Agglutination Agreement Antibodies Area Autoantibodies Autoimmune Binding Binding Sites Biological Assay Blood Platelets Blood Vessels Cell Therapy Clinic Clinical Clinical Management Coupled Data Deuterium Development Plans Diagnostic Diagnostic tests Disease Disease Management Disintegrins Distal Endothelium Enzyme Inhibition Enzymes Epitopes Functional disorder Goals Hematologic Neoplasms Hematological Disease Human Hydrogen IgG autoantibodies Immune Immunodiagnostics Immunoglobulin G Immunotherapy Individual Informal Social Control Internal Medicine Kansas Life Mass Spectrum Analysis Mediating Medical center Mentors Metalloproteases Molecular Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Non-Neoplastic Hematologic and Lymphocytic Disorder Organ Outcome Pathogenesis Patients Phage Display Physicians Physiological Plasma Plasmapheresis Process Prognosis Recurrent disease Research Research Personnel Role Scientist Site Source Specificity Structure Techniques Temperature Tertiary Protein Structure Testing Therapeutic Agents Therapeutic Intervention Thrombosis Thrombospondins Thrombotic Thrombocytopenic Purpura Time Training Translating Universities Work career career development cleavage factor disorder risk enzyme activity human monoclonal antibodies improved in vitro activity in vivo in-vitro diagnostics inhibiting antibody inhibitor insight meetings mortality novel diagnostics novel strategies novel therapeutic intervention prevent professor structural biology tenure track thrombotic von Willebrand Factor

Advisory Committees Affect Affinity Agglutination Agreement Antibodies Area Autoantibodies Autoimmune Binding Binding Sites Biological Assay Blood Platelets Blood Vessels Cell Therapy Clinic Clinical Clinical Management Coupled Data Deuterium Development Plans Diagnostic Diagnostic tests Disease Disease Management Disintegrins Distal Endothelium Enzyme Inhibition Enzymes Epitopes Functional disorder Goals Hematologic Neoplasms Hematological Disease Human Hydrogen IgG autoantibodies Immune Immunodiagnostics Immunoglobulin G Immunotherapy Individual Informal Social Control Internal Medicine Kansas Life Mass Spectrum Analysis Mediating Medical center Mentors Metalloproteases Molecular Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Non-Neoplastic Hematologic and Lymphocytic Disorder Organ Outcome Pathogenesis Patients Phage Display Physicians Physiological Plasma Plasmapheresis Process Prognosis Recurrent disease Research Research Personnel Role Scientist Site Source Specificity Structure Techniques Temperature Tertiary Protein Structure Testing Therapeutic Agents Therapeutic Intervention Thrombosis Thrombospondins Thrombotic Thrombocytopenic Purpura Time Training Translating Universities Work career career development cleavage factor disorder risk enzyme activity human monoclonal antibodies improved in vitro activity in vivo in-vitro diagnostics inhibiting antibody inhibitor insight meetings mortality novel diagnostics novel strategies novel therapeutic intervention prevent professor structural biology tenure track thrombotic von Willebrand Factor

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项目摘要

Project Summary/Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by autoimmune inhibition of the enzyme ADAMTS13. The only known substrate of ADAMTS13 is von Willebrand factor (VWF). Cleavage of VWF by ADAMTS13 is needed to prevent accumulation of ultralarge VWF multimers in the microvasculature, leading to end-organ damage and potentially life-threatening consequences. Anti-ADAMTS13 IgGs are responsible for the inhibition of the enzyme. The vast majority of inhibitory antibodies target a region of ADAMTS13 that is principally responsible for binding to the domain of VWF cleaved by the enzyme. However, the mechanism of inhibition of these antibodies is currently an area of active research, and it is not known if they primarily prevent substrate binding or decrease catalytic turnover, or if different antibodies inhibit by different mechanisms. Recent work has shown that ADAMTS13 in iTTP patient plasma exists primarily in a conformation that exposes a cryptic epitope otherwise hidden when ADAMTS13 is in its latent state. The current paradigm of ADAMTS13 activity defines this as a so-called “Open” state, and the latent state as “Closed”. A third state also appears to exist in which ADAMTS13 has the cryptic episode exposed, but also is able to cleave VWF; this is referred to here as the “Open and Primed” state. Anti-ADAMTS13 IgGs that target distal domains of the protein appear capable of inducing both the “Open” and “Open and Primed” state. The role of the different conformations of ADAMTS13 in the pathophysiology of iTTP is unclear, as is the potential role of the distal domain-targeting IgGs in the disease. Lastly, it is not known if ADAMTS13 activity can be rescued by introducing moieties capable of competing for the binding of anti-ADAMTS13 IgGs with ADAMTS13. This project aims to elucidate the mechanism(s) of inhibition of anti-ADAMTS13 antibodies, characterize the role of distal domain-targeting anti- ADAMTS13 antibodies in the pathophysiology of the disease, and explore molecular mimics of the binding epitopes of anti-ADAMTS13 IgGs as a rescue strategy for the disease. My career goal is to become an independent investigator as a physician scientist, with a focus on the pathophysiology of iTTP. I am currently on the tenure-track as an Assistant Professor in the Department of Internal Medicine, Division of Hematologic Malignancies and Cellular Therapeutics, at the University of Kansas Medical Center (KUMC), a large academic center. My research mentor is Dr. X. Long Zheng, a world-renowned researcher in iTTP. I am afforded 80% protected time for research under my agreement with the University. My career development plan includes regular meetings with my Career Advisory Committee, hands-on training in the structural biology techniques included in this proposal, and ongoing clinical responsibilities, including a half-day of clinic weekly where I see patients with non-malignant hematologic disorders.

项目摘要/摘要免疫血栓性血小板减少紫癜（ITTP）是由自身免疫性引起的血栓性微血管病抑制酶ADAMTS13。 ADAMTS13的唯一已知底物是Von Willebrand因子（VWF）。需要通过ADAMTS13对VWF进行裂解，以防止在超级vwf多聚体中积累微举行，导致最终器官损害和潜在的威胁生命的后果。抗ADAMTS13 IgG是负责抑制酶的。绝大多数抑制性抗体针对主要负责与酶裂解的VWF域结合的ADAMTS13。然而，这些抗体抑制的机制目前是一个积极研究的领域，尚不清楚它们是否主要防止底物结合或降低催化转移，或者如果不同的抗体被不同的抗体抑制机制。最近的工作表明，ITTP患者血浆中的ADAMTS13以构象为基础当Adamts13处于潜在状态时，这会暴露出一个隐藏的加密表位。当前的范式 Adamts13活动将其定义为所谓的“开放”状态，而潜在状态为“封闭”。也是第三个州 Adamts13似乎存在加密剧集，但也能够清除VWF。这是在这里称为“开放和启动”状态。靶向蛋白质远端结构域的抗ADAMTS13 IgGs 表现出诱导的“开放”和“开放和启动”状态。不同构象的作用 ITTP病理生理学中AdAMTS13的尚不清楚，远端靶向的潜在作用也不清楚疾病中的IgG。最后，尚不知道是否可以通过引入有能力的部分来挽救ADAMTS13活动争夺抗ADAMTS13 IgG与ADAMTS13的结合。该项目旨在阐明抑制抗ADAMTS13抗体的机制，表征了远端域靶向抗体的作用 ADAMTS13疾病病理生理学中的抗体，并探索结合的分子模仿抗ADAMTS13 IgG的表位作为该疾病的救援策略。我的职业目标是成为一个独立研究者作为物理科学家，重点是ITTP的病理生理。我目前正在作为血液学系的内科系助理教授的任期堪萨斯大学医学中心（KUMC）的Malignancys和Cellular Therapeutics，这是一个大型学术中心。我的研究心理是X. Long Zheng博士，他是ITTP的世界知名研究员。我有80％根据我与大学同意的研究时间。我的职业发展计划包括与我的职业咨询委员会定期会议，结构生物学技术的动手培训包括在此提案中以及正在进行的临床责任中，包括每周半天的诊所非恶性血液学疾病的患者。