Factor XI Inhibition for the Treatment of Ischemic Stroke

描述(申请人提供)：急性缺血性中风(AIS)的潜在原因之一是脑血管血栓形成-血栓栓塞性闭塞。早期使用组织型纤溶酶原激活剂(tPA，激活酶(R))，目前是FDA批准的唯一治疗AIS的方法，可以通过溶栓促进再通。然而，tPA治疗存在致命性颅内出血的高风险，这是一个安全问题，限制了接受tPA治疗并实现再通的中风患者的数量。此外，在接受tPA治疗的AIS患者中，三分之一会发生再闭塞，并伴随着最初改善后的临床恶化。因此，开发一种安全有效的抗血栓治疗方法，适用于AIS患者，无论是单独使用还是在 与tPA联合应用。我们认为理想的治疗策略是阻断凝血因子XI(FXI)的血栓前激活。在人类中，FXI水平升高是AIS的独立危险因素，而在人类和小鼠中，FXI缺乏与AIS的保护有关。我们的初步研究表明，使用我们的候选产品抗哺乳动物FXI抗体14E11来抑制由接触因子XIIa(FXIIa)激活的血栓前FXI将保护小鼠免受AIS的影响。由于FXII缺乏不会导致出血，我们推测14E11不会抑制止血FXI的激活，在安全治疗AIS方面具有巨大的潜力。此外，我们假设14E11可以通过增强tPA的疗效和减少再闭塞的发生率来增加tPA的长期疗效。我们的研究目的是利用AIS的小鼠模型来确定14E11治疗AIS的潜力。因此，这一阶段应用的具体目的是：1)确定14E11改善实验性AIS结果的有效性；2)确定14E11与纤溶tPA联合应用改善实验性AIS结果的有效性；3)确定14E11单独及与tPA联合应用的止血安全性。如果成功，这个第一阶段的项目将提供证据，证明抑制FXI是对抗血栓性AIS的一种安全和有前途的治疗策略。达到我们的里程碑将推动我们的项目进入第二阶段，目的是启动14E11的正式临床前开发，用于AIS患者的安全治疗。 与公共卫生相关：使用“凝血酶抑制剂”药物tPA(激活酶(R))治疗急性缺血性中风有严重的出血并发症，这限制了不到10%的患者使用它。这项拟议的研究评估了我们独特的治疗性抗体(14E11)，它可以阻断病理性凝块促进凝血因子XI(FXI)的激活，作为治疗中风的新药候选，中风仍然是导致死亡和慢性残疾的主要原因。由于14E11预计不会产生出血副作用，这种方法有可能为其他更危险的抗血栓治疗提供一种安全的替代或补充。

DESCRIPTION (provided by applicant): One of the underlying causes of acute ischemic stroke (AIS) is the thrombotic-thromboembolic occlusion of cerebral blood vessels. Early use of tissue-type plasminogen activator (tPA, Activase(R)), currently the only FDA-approved treatment for AIS, can promote reperfusion via thrombolysis. However, tPA treatment carries a high risk of fatal intracranial hemorrhage, which is a safety concern that limits the number of stroke victims who receive tPA treatment and achieve reperfusion. In addition, re-occlusion occurs in one third of tPA-treated AIS patients, alongside clinical deterioration following the initial improvement. Thus, there is a major unmet medical need for the development of a safe and effective antithrombotic treatment that is suitable for use in AIS patients, either alone or in combination with tPA. We propose that the ideal therapeutic strategy is to block the prothrombotic activation of coagulation factor XI (FXI). In humans, elevated FXI levels are an independent risk factor for AIS, while FXI deficiency is associated with protection from AIS both in humans and in mice. Our preliminary studies suggest that using our product candidate, anti-mammalian FXI antibody 14E11, to inhibit prothrombotic FXI activation by the contact factor XIIa (FXIIa) will protect mice from AIS. Since FXII deficiency does not cause bleeding, we hypothesize that 14E11, which does not inhibit hemostatic FXI activation, has great potential for the safe treatment of AIS. In addition, we hypothesize that 14E11 can increase the long-term efficacy of tPA by enhancing its efficacy and reducing the incidence of re-occlusion. Our research objective is to determine the therapeutic potential of 14E11 to treat AIS using a mouse model of AIS. Thus, the Specific Aims for this Phase I application are to: 1) Determine the efficacy of 14E11 for improving the outcome of experimental AIS; 2) Determine the efficacy of 14E11 in combination with fibrinolytic tPA to improve the outcome of experimental AIS; and 3) Determine the hemostatic safety of 14E11 alone and in combination with tPA. If successful, this Phase I project will provide evidence that the inhibition of FXI is a safe and promising therapeutic strategy to combat thrombotic AIS. Reaching our milestones will propel our project into Phase II, with the intent to initiate formal preclinical development of 14E11 for the safe treatment of AIS patients. PUBLIC HEALTH RELEVANCE: Treatment of acute ischemic stroke with the "clotbuster" drug tPA (Activase(R)) has serious bleeding complications, which limits its usage to less than 10% of patients. The proposed research evaluates our unique therapeutic antibody (14E11) that blocks pathological clot-promoting activation of coagulation factor XI (FXI) as a novel drug candidate for the treatment of stroke, which remains a leading cause of death and chronic disability. Since 14E11 is not expected to produce bleeding side-effects, this approach has the potential to provide a safe alternative or addition to other more dangerous antithrombotic treatments.