Novel Methods for Dissolving Blood Clots

描述（由申请人提供）：心血管疾病是全球主要的死亡原因。目前的心血管疾病治疗与部分成功、限制进入、延迟、可能的神经毒性和其他重要限制相关。我们的目标是开发一种新的治疗剂，更安全，更有效地溶解导致心脏病发作和中风的血栓（血栓）。对终身缺乏α 2-抗纤溶酶（α 2AP）的人和小鼠的研究表明，它是血凝块溶解的主要调节剂。我们已经产生了诱导功能性α 2 AP缺陷的高亲和力单克隆抗体。我们已经证明，这些单克隆抗体导致静脉血栓和肺栓塞溶解在体内。它们还能加速脑动脉血栓的溶解，从而在不增加出血的情况下减少中风面积。在这个I期申请中，我们将通过分子工程技术修饰这些有前途的抗体，将其转化为适合人体试验的潜在治疗药物。在目标1中，我们将工程化并表达嵌合抗体和抗体片段（Fab）。在目的2中，我们将评估抗体和抗体片段结合和抑制α 2 AP以及增强血凝块溶解的相对能力。随着这些目标的成功完成，我们将进行II期申请，以优化这些分子的生产，从而在合适的临床前模型中检查其安全性和有效性。 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160万美国人遭受心脏病发作或中风。由此造成的死亡和残疾每年给美国造成惊人的3160亿美元。目前的治疗与部分成功、限制进入、延迟、可能的神经毒性和其他重要限制相关。该项目旨在开发一种新的治疗心脏病发作和中风的方法，可以显着降低死亡，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.