Novel Methods for Dissolving Blood Clots

描述(申请人提供)：心血管疾病是全球主要的死亡原因。目前心血管疾病的治疗方法与部分成功、准入受限、延迟、可能的神经毒性和其他重要限制有关。我们的目标是开发一种新的治疗剂，它在溶解导致心脏病发作和中风的血液凝块(血栓)方面更加安全和有效。对终生缺乏a2-抗纤溶酶(A2AP)的人和小鼠的研究表明，a2-抗纤溶酶是血栓溶解的主要调节因子。我们已经生产了高亲和力的单抗，可以诱导功能性a2AP缺乏症。我们已经证明，这些单抗可以在体内引起静脉血栓和肺血栓的溶解。它们还加速了脑动脉血栓的溶解--从而在不增加出血的情况下缩小了中风的范围。在这一阶段的应用中，我们将通过分子工程技术对这些有希望的抗体进行修饰，将它们转化为适合于人体试验的潜在疗法。在目标1中，我们将设计并表达一种嵌合抗体和抗体片段(Fab)。在目标2中，我们将评估抗体和抗体片段结合和抑制a2AP以及促进血栓溶解的相对能力。随着这些目标的成功完成，我们将继续进行第二阶段的应用，以优化这些分子的生产，以便在合适的临床前模型中检查它们的安全性和有效性。 公共卫生相关性：心血管疾病是全球主要的死亡原因。每年约有160万美国人心脏病发作或中风。由此导致的死亡和残疾每年给美国造成的损失高达3160亿美元。目前的治疗方法与部分成功、访问受限、延迟、可能的神经毒性和其他重要限制有关。该项目寻求开发一种治疗心脏病发作和中风的新疗法，可以显著减少死亡、残疾和成本。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death worldwide. Current therapies for cardiovascular disease are associated with partial success, restricted access, delays, possible neurotoxicity and other important limitations. Our goal is to develop a novel therapeutic agent that is safer and more effective at dissolving the blood clots (thrombi) that cause heart attacks and strokes. Studies of humans and mice with lifelong deficiency of a2-antiplasmin (a2AP) have shown that it is the major regulator of blood clot dissolution. We have produced high affinity monoclonal antibodies that induce functional a2AP deficiency. We have shown that these monoclonal antibodies cause venous thrombi and pulmonary emboli to dissolve in vivo. They also accelerate the dissolution of cerebral arterial thrombi-thereby reducing stroke size without increasing bleeding. In this Phase I application, we will modify these promising antibodies by molecular engineering techniques to convert them into potential therapeutics suitable for human trials. In Aim 1 we will engineer and express a chimerized antibody and antibody fragment (Fab). In Aim 2 we will evaluate the relative abilities of the antibody and antibody fragment to bind and inhibit a2AP and enhance blood clot dissolution. With successful completion of these aims we will pursue a Phase II application to optimize the production of these molecules in order to examine their safety and efficacy in suitable pre-clinical models. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death worldwide. Each year ~ 1.6 million Americans suffer a heart attack or stroke. The resulting death and disability costs the U.S. a staggering $316 billion a year. Current therapies are associated with partial success, restricted access, delays, possible neurotoxicity and other important limitations. This project seeks to develop a novel therapy for heart attacks and strokes that could markedly reduce death, disability and costs.