Pharmacology Department, Ablynx NV, Zwijnaarde, Belgium.
Blood. 2011 Jul 21;118(3):757-65. doi: 10.1182/blood-2010-11-317859. Epub 2011 May 16.
Neutralizing the interaction of the platelet receptor gpIb with VWF is an attractive strategy to treat and prevent thrombotic complications. ALX-0081 is a bivalent Nanobody which specifically targets the gpIb-binding site of VWF and interacts avidly with VWF. Nanobodies are therapeutic proteins derived from naturally occurring heavy-chain-only Abs and combine a small molecular size with a high inherent stability. ALX-0081 exerts potent activity in vitro and in vivo. Perfusion experiments with blood from patients with acute coronary syndrome on standard antithrombotics demonstrated complete inhibition of platelet adhesion after addition of ALX-0081, while in the absence of ALX-0081 residual adhesion was observed. In a baboon efficacy and safety model measuring acute thrombosis and surgical bleeding, ALX-0081 showed a superior therapeutic window compared with marketed antithrombotics. Pharmacokinetic and biodistribution experiments demonstrated target-mediated clearance of ALX-0081, which leads to a self-regulating disposition behavior. In conclusion, these preclinical data demonstrate that ALX-0081 combines a high efficacy with an improved safety profile compared with currently marketed antithrombotics. ALX-0081 has entered clinical development.
中和血小板受体 gpIb 与 VWF 的相互作用是治疗和预防血栓并发症的一种有吸引力的策略。ALX-0081 是一种双价纳米抗体，专门针对 VWF 的 gpIb 结合位点，并与 VWF 强烈相互作用。纳米抗体是从天然存在的重链抗体中衍生的治疗性蛋白，结合了小分子大小和高固有稳定性。ALX-0081 在体外和体内均具有强大的活性。在用标准抗血栓药物治疗的急性冠状动脉综合征患者的血液进行的灌注实验中，添加 ALX-0081 后完全抑制了血小板黏附，而在没有 ALX-0081 的情况下观察到残留黏附。在一项测量急性血栓形成和手术出血的食蟹猴功效和安全性模型中，与市售抗血栓药物相比，ALX-0081 显示出更好的治疗窗口。药代动力学和生物分布实验表明，ALX-0081 具有靶向介导的清除作用，导致自我调节的处置行为。总之，这些临床前数据表明，与目前市售的抗血栓药物相比，ALX-0081 具有更高的疗效和改善的安全性。ALX-0081 已进入临床开发阶段。
