Pestel Sabine, Beltz Hans-Wilhelm, Claar Philipp, Lind Holger, Mischnik Marcel, Raquet Elmar, Andrews Arna, Simmonds Jason, Tomasetig Vesna, Dower Steven K, Tjärnlund-Wolf Anna, Schulte Stefan, Schmidt Peter M, Weimer Thomas
Research and Development, CSL Behring GmbH, Marburg, Germany.
Research and Development, CSL Limited, BIO21 Institute, Parkville, VIC, Australia.
Blood Adv. 2020 May 12;4(9):1870-1880. doi: 10.1182/bloodadvances.2019000999.
A novel mechanism for extending the circulatory half-life of coagulation factor VIII (FVIII) has been established and evaluated preclinically. The FVIII binding domain of von Willebrand factor (D'D3) fused to human albumin (rD'D3-FP) dose dependently improved pharmacokinetics parameters of coadministered FVIII in all animal species tested, from mouse to cynomolgus monkey, after IV injection. At higher doses, the half-life of recombinant FVIII (rVIII-SingleChain) was calculated to be increased 2.6-fold to fivefold compared with rVIII-SingleChain administered alone in rats, rabbits, and cynomolgus monkeys, and it was increased 3.1-fold to 9.1-fold in mice. Sustained pharmacodynamics effects were observed (ie, activated partial thromboplastin time and thrombin generation measured ex vivo). No increased risk of thrombosis was observed with coadministration of rVIII-SingleChain and rD'D3-FP compared with rVIII-SingleChain alone. At concentrations beyond the anticipated therapeutic range, rD'D3-FP reduced the hemostatic efficacy of coadministered rVIII-SingleChain. This finding might be due to scavenging of activated FVIII by the excessive amount of rD'D3-FP which, in turn, might result in a reduced probability of the formation of the tenase complex. This observation underlines the importance of a fine-tuned balance between FVIII and its binding partner, von Willebrand factor, for hemostasis in general.
一种延长凝血因子VIII（FVIII）循环半衰期的新机制已被确立并进行了临床前评估。血管性血友病因子的FVIII结合域（D'D3）与人白蛋白融合（rD'D3-FP），在静脉注射后，能剂量依赖性地改善所共给药的FVIII在所有受试动物物种（从小鼠到食蟹猴）中的药代动力学参数。在较高剂量下，重组FVIII（rVIII-单链）的半衰期在大鼠、兔子和食蟹猴中经计算比单独给药的rVIII-单链增加了2.6倍至5倍，在小鼠中增加了3.1倍至9.1倍。观察到了持续的药效学效应（即体外测量的活化部分凝血活酶时间和凝血酶生成）。与单独使用rVIII-单链相比，联合使用rVIII-单链和rD'D3-FP未观察到血栓形成风险增加。在超过预期治疗范围的浓度下，rD'D3-FP降低了所共给药的rVIII-单链的止血效果。这一发现可能是由于过量的rD'D3-FP清除了活化的FVIII，这反过来可能导致形成凝血酶原酶复合物的概率降低。这一观察结果强调了FVIII与其结合伴侣血管性血友病因子之间精确平衡对于一般止血的重要性。
