Molecular and Cell Biology, Biogen Idec Hemophilia, 9 Fourth Ave, Waltham, MA 02451, USA.
Blood. 2010 Mar 11;115(10):2057-64. doi: 10.1182/blood-2009-08-239665. Epub 2010 Jan 7.
Treatment of hemophilia B requires frequent infusions of factor IX (FIX) to prophylax against bleeding episodes. Hemophilia B management would benefit from a FIX protein with an extended half-life. A recombinant fusion protein (rFIXFc) containing a single FIX molecule attached to the Fc region of immunoglobulin G was administered intravenously and found to have an extended half-life, compared with recombinant FIX (rFIX) in normal mice, rats, monkeys, and FIX-deficient mice and dogs. Recombinant FIXFc protein concentration was determined in all species, and rFIXFc activity was measured in FIX-deficient animals. The half-life of rFIXFc was approximately 3- to 4-fold longer than that of rFIX in all species. In contrast, in mice in which the neonatal Fc receptor (FcRn) was deleted, the half-life of rFIXFc was similar to rFIX, confirming the increased circulatory time was due to protection of the rFIXFc via the Fc/FcRn interaction. Whole blood clotting time in FIX-deficient mice was corrected through 144 hours for rFIXFc, compared with 72 hours for rFIX; similar results were observed in FIX-deficient dogs. Taken together, these studies show the enhanced pharmacodynamic and pharmacokinetic properties of the rFIXFc fusion protein and provide the basis for evaluating rFIXFc in patients with hemophilia B.
治疗乙型血友病需要频繁输注凝血因子 IX（FIX）以预防出血发作。乙型血友病的管理将受益于具有延长半衰期的 FIX 蛋白。一种包含单个 FIX 分子连接到免疫球蛋白 G 的 Fc 区的重组融合蛋白（rFIXFc），与正常小鼠、大鼠、猴子和 FIX 缺乏的小鼠和狗中的重组 FIX（rFIX）相比，静脉内给药后发现其半衰期延长。在所有物种中均测定了重组 FIXFc 蛋白浓度，并在 FIX 缺乏的动物中测定了 rFIXFc 活性。rFIXFc 的半衰期比所有物种中的 rFIX 长约 3-4 倍。相比之下，在新生 Fc 受体（FcRn）缺失的小鼠中，rFIXFc 的半衰期与 rFIX 相似，证实循环时间的延长是由于 rFIXFc 通过 Fc/FcRn 相互作用得到保护。rFIXFc 可使 FIX 缺乏的小鼠的全血凝固时间延长至 144 小时，而 rFIX 为 72 小时；在 FIX 缺乏的狗中也观察到类似的结果。总之，这些研究表明 rFIXFc 融合蛋白具有增强的药效学和药代动力学特性，并为评估乙型血友病患者的 rFIXFc 提供了基础。
