Novel approaches for the treatment of autoimmune disease

项目摘要/摘要 该项目的总体目标是开发一种治疗免疫性疾病的新疗法。 介导的血栓性血小板减少性紫癜(ITTP)。ITTP是一种急性的、危及生命的疾病 如果不进行治疗，会导致90%的死亡率。它是由一种去整合素缺乏引起的。 和金属蛋白酶血栓反应蛋白1基序，成员13(ADAMTS13)，是一种蛋白酶 这裂解了von Willebrand因子(VWF)的超大聚集体。这种VWF结合的聚集体 到血小板，导致血栓形成。因此，ADAMTS13缺乏会导致微血栓 在小动脉和毛细血管形成，iTTP以溶血性贫血为特征， 血小板减少和器官损害，可能有严重的心脏、肾脏、神经和 胃肠道反应。 对于iTTP，ADAMTS13缺乏症是由该酶的特异性自身抗体引起的。 因此，目前的治疗方法旨在通过以下方式降低这些抗体的水平 血浆置换和一般免疫抑制剂(皮质类固醇、美罗华)的使用。在……里面 此外，一种抑制VWF-血小板相互作用的二价纳米体(Caplacizumab)最近已经 已被批准用于治疗iTTP。然而，尽管接受了治疗，30%-50%的iTTP仍会复发 病人。此外，这些治疗可能会产生副作用，如异常出血。 (Caplacizumab)和/或由于全身免疫抑制而增加感染风险。利妥昔单抗 也具有缓慢的起效，与血浆交换结合使用。因此， 有必要开发对iTTP具有快速起效和高度特异性的治疗方法 疾病的病因，即自身抗体。 本申请旨在通过以下方式解决对iTTP新疗法和改进疗法的需求 产生以抗体为基础的工程化试剂，特异性和快速耗尽 ADAMTS13特异性抗体。重要的是，这些耗竭剂具有很高的选择性 不具有全身免疫抑制作用。这项一流的、新颖的技术已经 命名为Seldeg技术(用于选择性降解)。 这项研究的具体目的是： 1.设计并表达针对ADAMTS13特异性抗体的Seldegs。 2.分析Seldegs的稳定性和结合活性。 建议的方法可能会对iTTP的管理产生变革，而且还 与在多种其他临床环境中使用基于Seldeg的策略的相关性 致病抗体导致疾病。

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.