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

• 批准号: 10010350
• 负责人: Guy L Reed
• 金额: $ 164.61万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 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/10010350
• 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

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.

缺血性中风是全球第二大致死和致残原因。组织纤溶酶原激活剂 (TPA)是唯一被批准的治疗缺血性中风的药物，它溶解了罪魁祸首纤维蛋白血栓以恢复血液 血液流动，减轻大脑的缺血。不幸的是，在长时间的缺血后，TPA恢复了充分的血流量 仅在30%的患者中出现，并可能导致严重或致命的并发症；这限制了TPA的使用仅限于少数 中风患者。 对纤维蛋白血栓溶解(纤溶)的分子控制的新见解赋予了 α-2-抗纤溶酶(A2AP)在判断缺血性卒中预后中的作用。高a2AP水平与 增加缺血性中风和TPA失败的风险。临床前研究表明，a2AP在- 以剂量依赖的方式增加脑损伤。相反，a2AP缺乏或单抗失活- A2AP的治疗可显著减少脑损伤、细胞凋亡、出血和肿胀。即使是在长时间 脑缺血，a2AP失活减少微血管血栓形成和基质金属蛋白酶-9的表达(一种 急性炎症)。因此，A2AP失活可以防止缺血性中风后的死亡和残疾。因此，在 临床前研究表明，与TPA相比，A2AP灭活更安全、更有效，治疗窗口更长。 考虑到这种方法的巨大治疗潜力，我们开始了一种新的治疗方法的开发 用于灭活a2AP的抗体，由NIH/NINDS提供研究支持。我们表现强劲， 严格的临床前研究，我们已经完成了关键的安全-毒理学研究，表明安全和 生物标记物功效。在人类的I期试验中，单次注射a2AP灭活抗体可诱导 剂量相关的a2AP中和和内源性纤溶，如D-二聚体水平升高所示。这 A2AP灭活抗体耐受性良好，未引起出血或严重不良事件。在……里面 与StrokeNet团队的主要成员合作，我们正在开发这一a2ap的第二阶段试验 在缺血性中风中灭活抗体以检查安全性、生物标记物有效性和概念验证。要启用 作为第二阶段的试验，这项提案寻求所需的资金，以支持cGMP生物制造这种a2AP- 灭活抗体。