Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs
Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs
复制标题
DOI：
10.1182/blood-2011-08-367813
复制
发表时间：
2012-03-29
期刊：
影响因子：
20.3
通讯作者：
Jiang, Haiyan
中科院分区：
文献类型：
--
作者：
Dumont, Jennifer A.;Liu, Tongyao;Jiang, Haiyan
尽管已证明有益，但血友病A的预防性治疗受到因子VIII半衰期短的阻碍。构建了重组因子VIII-Fc融合蛋白（rFVIIIFc），以确定降低给药频率的可能性。在血友病A（HemA）小鼠和犬中，rFVIIIFc的半衰期比rFVIII长2倍。rFVIIIFc半衰期的延长需要Fc与新生儿Fc受体（FcRn）相互作用。在FcRn基因敲除小鼠中，rFVIIIFc半衰期延长消失，在人FcRn转基因小鼠中恢复。Fc融合对FVIII特异性活性没有影响。rFVIIIFc在治疗HemA小鼠夹尾损伤方面的急性疗效与rFVIII相当，并在给药后立即完全纠正HemA犬的全血凝血时间（WBCT）。此外，与半衰期延长一致，rFVIIIFc在保护A型血友病小鼠免受给药后24-48小时诱导的尾静脉横断出血方面的预防性疗效延长2倍。在HemA犬中，rFVIIIFc维持WBCT部分校正的时间也比rFVIII长1.5- 2倍。rFVIIIFc在两个种属中均耐受良好。因此，通过Fc融合拯救FVIII以提供延长的保护，为FVIII催化剂提供了一种新的途径，值得进一步研究。（血。2012;119（13）：3024-3030）
Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an similar to 2-fold longer half-life than rFVIII in hemophiliaA (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. (Blood. 2012;119(13):3024-3030)