Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation
Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation
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DOI：
10.1111/jth.12474
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发表时间：
2014-02-01
影响因子：
10.4
通讯作者：
Hattori, K.
中科院分区：
文献类型：
--
作者：
Muto, A.;Yoshihashi, K.;Hattori, K.
背景我们先前报道了人源化抗凝血因子IX α/X双特异性抗体hBS 23，即使在存在FVIII抑制剂的情况下也能模拟FVIII的功能，并且在获得性血友病A的动物模型中对出血具有预防性止血活性。经过进一步的分子工程hBS 23，我们最近确定了一个改进的人源化双特异性抗体，ACE 910，用于临床研究。方法用抗人血友病A抗体建立非人灵长类获得性血友病A动物模型，并测定其药代动力学参数，探讨其预防作用。灵长类FVIII中和抗体。当在人工出血诱导程序后出现出血时，静脉内给予ACE 910或重组猪FVIII（rpoFVIII）。在接下来的2天中，每天两次额外施用rpoFVIII。监测出血症状3天。ACE 910的药代动力学研究和多次给药模拟也performed.ResultsA单次推注1或3 mgkg（-1）ACE 910显示止血活性与10 Ukg（-1）（每日两次）rpoFVIII对持续出血的止血活性相当。测定的ACE 910药代动力学参数包括长半衰期（3周）和高皮下生物利用度（接近100%）。基于药代动力学参数的模拟结果表明，每周一次皮下注射ACE 910可维持上述止血水平，提示ACE 910可能具有更有效的止血效果。结论ACE 910可为血友病A患者提供一种替代的按需治疗选择，同时也是一种用户友好和积极的常规补充治疗。
BackgroundWe previously reported that a humanized anti-factorIXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophiliaA. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation.ObjectivesTo elucidate the invivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use.MethodsA non-human primate model of acquired hemophiliaA was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2days. Bleeding symptoms were monitored for 3days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed.ResultsA single bolus of 1 or 3mgkg(-1) ACE910 showed hemostatic activity comparable to that of 10Ukg(-1) (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis.ConclusionsACE910 may offer an alternative on-demand treatment option for patients with hemophiliaA, as well as user-friendly and aggressive routine supplementation.