Commercialization Readiness Pilot for Amplifying Fibrinolysis in Ischemic Stroke

缺血性中风是全球第二大致死致残原因。组织纤溶酶原激活物 (TPA)，唯一批准的治疗缺血性中风，溶解罪魁祸首纤维蛋白血栓，以恢复血液 流动和缓解脑缺血。不幸的是，在长时间缺血后，TPA可以恢复全血流量 仅30%的患者，可能导致严重或致命的并发症;这限制了TPA的使用， 中风患者 对纤维蛋白血栓溶解（纤维蛋白溶解）的分子控制的新见解将核心作用分配给 α-2-抗纤溶酶（α 2 AP）在确定缺血性卒中后结局中的作用。高a2 AP水平与 增加缺血性中风和TPA失败的风险。临床前研究表明，a2 AP在- 以剂量依赖的方式增加脑损伤。相反，a2 AP缺乏或单克隆抗体无活性， a2 AP的表达显著减少脑损伤、细胞凋亡、出血和肿胀。即使经过长时间的 脑缺血时，a2 AP失活减少微血管血栓形成和MMP-9表达（ 急性炎症）。因此，a2 AP失活可预防缺血性卒中后的死亡和残疾。因此在 在临床前研究中，a2 AP灭活比TPA更安全、更有效，并且具有更长的治疗窗。 鉴于这种方法的巨大治疗潜力，我们开始开发一种新的治疗方法， 在NIH/NINDS的研究支持下，我们表现得很稳健， 严格的临床前研究，我们已经完成了关键的安全性毒理学研究， 生物标志物功效。在人体I期试验中，单次推注剂量的α 2AP失活抗体诱导了 剂量相关的α 2 AP中和和内源性纤维蛋白溶解，如D-二聚体水平升高所示。这 α 2AP灭活抗体耐受性良好，未引起出血或严重不良事件。在 与StrokeNet团队的主要成员合作，我们正在开发这种a2 AP的第二阶段试验 在缺血性卒中中灭活抗体，以检查安全性、生物标志物功效和概念验证。使 作为第二阶段试验，该提案寻求所需的资金，以支持这种a2 AP的cGMP生物制造， 灭活抗体。

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.