Clot-Targeted Antithrombotics for Venous Thromboprophylaxis

用于预防静脉血栓的凝块靶向抗血栓药物

• 批准号: 10229398
• 负责人: Elliot Chaikof
• 金额: $ 48.82万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229398
• 关键词: Antibodies; Anticoagulants; Antiplatelet Drugs; Automobile Driving; Biological; Blood Platelets; Charge; Clinical; Coagulation Process; Complex; Development; Effectiveness; Event; Fibrin; Fibrinolytic Agents; Fibrosis; Generations; HMGB1 gene; Hemorrhage; Hemostatic Agents; Hospital Mortality; Hospitals; Human; Hybrids; Immune response; In Vitro; Inflammatory Response; Leukocytes; Maintenance; Maps; Molecular Conformation; Morbidity - disease rate; Pathway interactions; Peptides; Peripheral Blood Mononuclear Cell; Platelet Activation; Play; Population; Postphlebitic Syndrome; Process; Production; Property; Proteins; Recombinants; Resolution; Risk; Role; Site; Surface; T-Lymphocyte Epitopes; Therapeutic; Thrombin; Thrombosis; Thrombus; Ticks; Transgenic Mice; Urokinase; Variant; Veins; Venous; Venous Thrombosis; base; computerized tools; de-immunization; design; effective therapy; experimental study; immunogenic; immunogenicity; in vivo; lead candidate; mouse model; neutrophil; pharmacokinetics and pharmacodynamics; prevent; response; venous thromboembolism

Project Summary We currently lack effective therapies that reduce the risk of venous thromboembolism without an attendant risk of bleeding. The assembled investigative team has recently identified single chain antibodies that selectively block activated platelets and enrich therapeutics at the site of a developing thrombus. In the process, we have discovered that selective targeting of activated platelets allows a wide variety of antithrombotic agents to be efficacious, well below systemic concentrations that cause bleeding. In this proposal, we postulate that selective targeting to activated platelets provides a means to locally concentrate antiplatelet, anticoagulant, and fibrinolytic agents at the site of a growing venous thrombus without disrupting essential hemostatic processes. We believe that this strategy will enable the design of high potency agents for venous thromboprophylaxis, but without an increased risk of major bleeding. In this proposal, we intend to: (1) Define the ability of clot-targeted “dual pathway” antithrombotics to prevent venous thrombosis and inhibit postthrombotic vein wall fibrosis without hemostatic disturbance. The efficacy of “dual pathway” antithrombotics based on SCE5-TAP, a single chain antibody with both antiplatelet and anticoagulant activity will be defined using murine models of venous thrombosis. These studies will evaluate the capacity of SCE5-TAP and related new variants to prevent venous thrombosis, limit early and late inflammatory responses, and inhibit thrombus-induced remodeling of the vein wall without hemostatic disturbance. (2) Determine the capacity of clot-targeted antithrombotics that display anti-platelet and fibrinolytic activity to inhibit venous thrombosis and postthrombotic vein wall remodeling. The effectiveness of antithrombotics based on SCE5-scuPA, a single chain antibody with both antiplatelet and fibrinolytic activity will be defined using murine models of venous thrombosis alone or in combination with SCE5-TAP or related new variants. We will also design recombinant clot-targeted hybrid constructs (SCE5-TAP-scuPA) that display antiplatelet, anticoagulant, and fibrinolytic activity. The ability of these agents to inhibit thrombosis, promote thrombus resolution, and limit the development of vein wall fibrosis will be defined. (3) Mitigate the immune response to clot-targeted antithrombotics with the design of functionally deimmunized TAP variants through deletion of immunogenic T cell epitopes. The cellular immunogenicity of TAP (tick anticoagulant peptide) will be assessed and T cell epitopes, which drive the response mapped in naïve human peripheral blood mononuclear cells. Computational tools will be used to design functionally deimmunized TAP variants that will be evaluated in vitro and ex vivo for their maintenance of FXa inhibitory activity and their reduction of cellular immunogenicity. The wild type and resulting lead candidate will be assessed for cellular and humoral immunogenicity in vivo in humanized HLA transgenic mice. The successful deimmunization of TAP will allow us to generate deimmunized clot-targeted antithrombotics.

项目摘要 我们目前缺乏有效的疗法，可以降低静脉血栓栓塞的风险 伴随出血的风险。组装的调查团队最近确定了单链抗体 这有选择地阻止活化的血小板并在发育中的血栓部位富集治疗。在 过程，我们发现，有选择性靶向激活的血小板可以多种多样 抗血栓形成剂有效，远低于导致出血的全身浓度。在这个 提案，我们假设针对激活血小板的选择性靶向提供了一种局部浓缩的手段 抗血小板，抗凝剂和纤维蛋白水解剂在生长的静脉血栓的部位而不会破坏 必需的止血过程。我们认为，这种策略将使高效力代理的设计 静脉血栓预防，但没有大量出血的风险增加。在此提案中，我们打算： （1）定义凝结凝结的“双途径”抗血栓形成的能力防止静脉血栓形成 并抑制脉动静脉壁纤维化而没有止血灾难。 “双重效率 途径”基于SCE5-TAP的抗血栓形成，一种抗血小板和抗凝剂的单链抗体 活动将使用静脉血栓形成的鼠模型来定义。这些研究将评估 SCE5-TAP和相关的新变体，以防止静脉血栓形成，限制早期和晚期炎症 反应，并抑制血栓引起的静脉壁的重塑而没有止血灾难。 （2）确定凝块靶向的抗血栓形成的能力 活性以抑制静脉血栓形成和脉动静脉壁重塑。有效性 基于SCE5-SCUPA的抗肉眼药，具有抗血小板和纤维蛋白溶液活性的单链抗体将 可以单独使用静脉血栓形成的鼠模型或与SCE5-TAP或相关新的新模型定义 变体。我们还将设计重组凝块靶向的混合构建体（SCE5-TAP-SCUPA） 抗血小板，抗凝剂和纤维蛋白水解活性。这些药物抑制血栓形成的能力，促进 将定义血栓分辨率并限制静脉壁纤维化的发展。 （3）通过功能设计来缓解对凝块靶向的抗血栓形成的免疫反应 通过删除免疫原性T细胞表位的脱膜化TAP变体。细胞 将评估TAP（tick抗凝肽）的免疫原性，并评估T细胞表位，以驱动驱动 反应映射在人外周血单核细胞中。计算工具将用于 设计在功能上脱离了TAP变体，该变体将在体外进行评估，并在体内进行维护 FXA抑制活性及其降低细胞免疫原性。野生型和产生的铅 人源化HLA转基因小鼠的体内细胞和人类免疫原性的评估。 TAP的成功脱节将使我们能够生成靶向凝块靶向的抗血栓形成。