替奈普酶治疗急性缺血性卒中：从分子生物工程到III期关键性试验。
完整摘要 · 中文译文
阿替普酶静脉溶栓是急性缺血性卒中的主要再灌注治疗手段，但其临床应用受到半衰期短、需持续输注以及对纤溶酶原激活物抑制剂-1易感等限制。替奈普酶是阿替普酶的一种生物工程改造变体，旨在通过延长半衰期、提高纤维蛋白特异性以及增强对纤溶酶原激活物抑制剂-1的抵抗性来克服这些局限。这些结构修饰使其能够单次推注给药，并减少全身性纤溶紊乱。在本综述中，我们探讨了替奈普酶的靶向分子修饰如何塑造了其在急性缺血性卒中中的逐步转化研发历程。我们首先详述了阿替普酶的局限性，正是这些局限性推动了向替代药物的转变，随后阐述了替奈普酶的分子设计依据及其临床前证据。此外，我们综合分析了确立0.25 mg/kg为最佳疗效与安全性平衡剂量的II期剂量探索试验，并将其与0.4 mg/kg剂量下观察到的颅内出血过多相区别。最后，我们回顾了在不同人群中开展的关键III期试验，这些试验表明替奈普酶0.25 mg/kg不劣于阿替普酶，是一种切实可行、有证据支持的替代方案，尤其是在单次推注给药可能便利工作流程或转运行血管内血栓切除术的情况下。从这一分子到临床的框架来看，替奈普酶的研发历程展示了靶向蛋白质工程如何能够转化—— 转化为卒中再灌注治疗中的药理学、操作流程和临床优势。
完整摘要 · 英文原文
Intravenous thrombolysis with alteplase is a primary reperfusion therapy for acute ischemic stroke, yet its clinical utility is constrained by a short half-life, continuous infusion requirements, and susceptibility to plasminogen activator inhibitor-1. Tenecteplase, a bioengineered variant of alteplase, was developed to address these limitations through a prolonged half-life, increased fibrin specificity, and enhanced resistance to plasminogen activator inhibitor-1. These structural modifications enable single-bolus administration and reduce systemic fibrinolytic disturbance. In this review, we examine how the targeted molecular modifications of tenecteplase shaped its stepwise translational development in acute ischemic stroke. We first detail the limitations of alteplase, which motivated the transition to alternative agents, the molecular rationale for tenecteplase, and its preclinical evidence. Furthermore, we synthesize the phase II dose-finding trials that established 0.25 mg/kg as providing the optimal efficacy and safety balance, distinguishing it from the excess intracranial hemorrhage observed with the 0.4 mg/kg dose. Finally, we review the pivotal phase III trials across diverse populations demonstrating that tenecteplase 0.25 mg/kg is non-inferior to alteplase and represents a practical, evidence-based alternative, particularly where single-bolus administration may facilitate workflow or transfer for endovascular thrombectomy. Viewed through this molecular-to-clinical framework, the development of tenecteplase illustrates how targeted protein engineering can translate into pharmacological, operational, and clinical advantages in stroke reperfusion therapy.