Novel Methods for Dissolving Blood Clots

溶解血栓的新方法

• 批准号: 7801661
• 负责人: Guy L Reed
• 金额: $ 16.77万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801661
• 关键词: Acute; Affinity; American; Animal Model; Antibodies; Antiplasmin; Arteries; Binding; Blood Clot; Blood Vessels; Blood coagulation; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cerebrum; Cessation of life; Chinese Hamster Ovary Cell; Clinical Trials; Coagulation Process; Development; Disease; Early treatment; Embolism; Engineering; Ensure; Evaluation; Event; FDA approved; Goals; Guidelines; Half-Life; Health Care Costs; Hemorrhage; Human; Immune; Immunoglobulin Fragments; Legal patent; Life; Lung; Mediating; Methods; Molecular; Monoclonal Antibodies; Mus; Myocardial Infarction; Parents; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasminogen Activator; Pre-Clinical Model; Preparation; Process; Production; Qualifying; Reaction; Recommendation; Relative (related person); Risk; Role; Safety; Small Business Technology Transfer Research; Specificity; Stroke; Techniques; Therapeutic; Therapeutic Agents; Thrombosis; Thrombus; Veins; Venous; Viral; cardiovascular disorder therapy; chimeric antibody; cost; disability; effective therapy; established cell line; in vivo; inhibitor/antagonist; neurotoxicity; novel; novel therapeutics; pre-clinical research; preclinical study; public health relevance; restoration; success; Acute; Affinity; American; Animal Model; Antibodies; Antiplasmin; Arteries; Binding; Blood Clot; Blood Vessels; Blood coagulation; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cerebrum; Cessation of life; Chinese Hamster Ovary Cell; Clinical Trials; Coagulation Process; Development; Disease; Early treatment; Embolism; Engineering; Ensure; Evaluation; Event; FDA approved; Goals; Guidelines; Half-Life; Health Care Costs; Hemorrhage; Human; Immune; Immunoglobulin Fragments; Legal patent; Life; Lung; Mediating; Methods; Molecular; Monoclonal Antibodies; Mus; Myocardial Infarction; Parents; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasminogen Activator; Pre-Clinical Model; Preparation; Process; Production; Qualifying; Reaction; Recommendation; Relative (related person); Risk; Role; Safety; Small Business Technology Transfer Research; Specificity; Stroke; Techniques; Therapeutic; Therapeutic Agents; Thrombosis; Thrombus; Veins; Venous; Viral; cardiovascular disorder therapy; chimeric antibody; cost; disability; effective therapy; established cell line; in vivo; inhibitor/antagonist; neurotoxicity; novel; novel therapeutics; pre-clinical research; preclinical study; public health relevance; restoration; success

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.

描述（由申请人提供）：心血管疾病是全球死亡的主要原因。当前的心血管疾病疗法与部分成功，限制通道，延误，可能的神经毒性和其他重要局限性有关。我们的目标是开发一种新型的治疗剂，该治疗剂更安全，更有效地溶解引起心脏病发作和中风的血凝块（血栓）。对A2-抗血压素（A2AP）终生缺乏的人类和小鼠的研究表明，它是血块溶解的主要调节剂。我们产生了诱导功能性A2AP缺乏的高亲和力单克隆抗体。我们已经表明，这些单克隆抗体会导致静脉血栓和肺栓塞在体内溶解。他们还加速了脑动脉血栓形成的溶解，从而减小了中风的大小而不会增加出血。在此I阶段应用中，我们将通过分子工程技术修改这些有希望的抗体，以将其转化为适合人类试验的潜在治疗剂。在AIM 1中，我们将设计并表达嵌合抗体和抗体片段（FAB）。在AIM 2中，我们将评估抗体和抗体片段的相对能力结合和抑制A2AP并增强血凝块溶解。通过成功完成这些目标，我们将追求II期应用程序，以优化这些分子的生产，以便在适当的临床前模型中检查它们的安全性和功效。 公共卫生相关性：心血管疾病是全球死亡的主要原因。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使美国造成了惊人的3160亿美元。当前的疗法与部分成功，限制访问，延迟，可能的神经毒性和其他重要局限性有关。该项目旨在为心脏病发作和中风开发一种新颖的疗法，可以显着降低死亡，残疾和成本。