Commercialization Readiness Pilot for Amplifying Fibrinolysis in Ischemic Stroke

放大缺血性中风纤维蛋白溶解的商业化准备试点

基本信息

批准号：
10159310
负责人：
Guy L Reed
金额：
$ 171.3万
依托单位：
TRANSLATIONAL SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159310
关键词：
Activated Partial Thromboplastin Time measurement Acute Address Affect Alteplase Antibodies Antiplasmin Apoptosis Arteries Biological Markers Biomanufacturing Blood - brain barrier anatomy Blood coagulation Blood flow Bolus Infusion Brain Brain Injuries Brain Ischemia Cause of Death Cessation of life Chemicals Clinical Clinical Data Cyclic GMP Data Deep Vein Thrombosis Development Dose FDA approved Failure Fibrin Fibrin fragment D Fibrinogen Fibrinolysis Fostering Funding Gelatinase B Genetic Goals Grant Health Care Costs Hemorrhage Human Inflammation Inflammatory Ischemia Ischemic Stroke Laboratories Link Mediating Medical Minority Modeling Molecular Monoclonal Antibodies National Institute of Neurological Disorders and Stroke Neutrophil Infiltration Operative Surgical Procedures Outcome Patients Perfusion Pharmaceutical Preparations Phase II Clinical Trials Plasmin Plasminogen Activator Process Pulmonary Embolism Quality of life Readiness Reperfusion Therapy Research Support Risk Role Safety Serious Adverse Event Stroke Stroke prevention Swelling Testing Therapeutic Therapeutic antibodies Thrombosis Thrombus Time Toxicology United States National Institutes of Health Venous cerebral artery commercialization disability effective therapy first-in-human improved improved outcome insight member neurotoxicity neutrophil novel therapeutics phase I trial phase II trial pre-clinical preclinical study prevent protective effect safety testing stroke model stroke patient stroke therapy thromboembolic stroke tool

项目摘要

Ischemic stroke is the second leading cause of death and disability worldwide. Tissue plasminogen activator (TPA), the only approved treatment for ischemic stroke, dissolves the culprit fibrin thrombus to restore blood flow and relieve the brain from ischemia. Unfortunately, after prolonged ischemia, TPA restores full blood flow in only 30% of patients and may cause serious or fatal complications; this restricts TPA use to a minority of stroke patients. New insights into the molecular control of fibrin thrombus dissolution (fibrinolysis) assign a central role to alpha-2-antiplasmin (a2AP) in determining outcomes after ischemic stroke. High a2AP levels are linked to increased risk of ischemic stroke and of TPA failure. Pre-clinical studies have shown that a2AP markedly in- creases brain injury, in a dose-dependent fashion. Conversely, a2AP deficiency or monoclonal antibody inacti- vation of a2AP, profoundly reduces brain injury, apoptosis, hemorrhage, and swelling. Even after prolonged brain ischemia, a2AP inactivation reduces microvascular thrombosis and MMP-9 expression (a marker of acute inflammation). As a result, a2AP inactivation prevents death and disability after ischemic stroke. Thus, in pre-clinical studies, a2AP inactivation is safer, more effective and has a longer therapeutic window than TPA. Given the enormous treatment potential of this approach, we initiated the development of a novel therapeutic antibody for inactivating a2AP, with research support from NIH/NINDS. We have performed robust and rigorous pre-clinical studies and we have completed pivotal safety-toxicology studies showing safety and biomarker efficacy. In a Phase I trial in humans, a single bolus dose of the a2AP-inactivating antibody, induced dose-related neutralization of a2AP and endogenous fibrinolysis, as indicated by rising D-dimer levels. This a2AP inactivating antibody was well-tolerated and did not cause bleeding or serious adverse events. In partnership with key members of the StrokeNet team we are developing a Phase II trial of this a2AP inactivating antibody in ischemic stroke to examine safety, biomarker efficacy and proof of concept. To enable a Phase II trial, this proposal seeks needed funding to support cGMP biomanufacturing of this a2AP- inactivating antibody.

缺血性中风是全球死亡和残疾的第二大主要原因。组织纤溶酶原活化剂（TPA）是唯一获得缺血性中风的批准治疗方法，溶解罪魁祸首血栓以恢复血液流动并减轻缺血的大脑。不幸的是，长时间的缺血后，TPA恢复了全血流在仅30％的患者中，可能会引起严重或致命的并发症；这限制了TPA使用的少数中风患者。对纤维蛋白血栓溶解（纤维蛋白溶解）分子控制的新见解分配了中心作用 α-2-抗血解剂（A2AP）在缺血性中风后确定结果。高A2AP级别链接到增加缺血性中风和TPA衰竭的风险增加。临床前研究表明，A2AP明显以剂量依赖的方式折痕脑损伤。相反，A2AP缺乏或单克隆抗体无效 A2AP的外观可深刻地减少脑损伤，凋亡，出血和肿胀。即使延长脑缺血，A2AP灭活可降低微血管血栓形成和MMP-9表达（标志着急性炎症）。结果，A2AP失活阻止缺血性中风后死亡和残疾。因此，在临床前研究，A2AP灭活更安全，更有效，并且具有比TPA更长的治疗窗口。鉴于这种方法的巨大治疗潜力，我们启动了新型治疗的发展在NIH/NIND的研究支持下，用于灭活A2AP的抗体。我们表现出色，严格的临床前研究，我们已经完成了关键的安全性毒学研究，显示了安全性和生物标志物功效。在人类I期试验中，A2AP灭活抗体的单一大通剂量诱导 A2AP和内源性纤维蛋白溶解的剂量相关中和，如D二二聚体水平上升所示。这 A2AP失活的抗体耐受良好，不会引起出血或严重的不良事件。在与Strokenet团队的主要成员合作，我们正在开发该A2AP的II阶段试验缺血性中风中灭活抗体，以检查安全性，生物标志物功效和概念证明。启用该提案是II阶段试验，寻求所需的资金来支持该A2AP-的CGMP生物制造灭活抗体。