Prolonged in-vivo half-life of factor VIIa by fusion to albumin.
For the treatment of haemophilia patients with inhibitors, recombinant factor VIIa (rFVIIa) is available as a therapeutic option to control bleeding episodes with a good balance of safety and efficacy. However, the short in-vivo half-life of approximately 2.5 hours makes multiple injections necessary, which is inconvenient for both physicians and patients. Here we describe the generation of a recombinant FVIIa molecule with an extended half-life based on genetic fusion to human albumin. The recombinant FVII albumin fusion protein (rVII-FP) was expressed in mammalian cells and upon activation displayed a FVII activity close to that of wild type FVIIa. Pharmacokinetic studies in rats demonstrated that the half-life of the activated recombinant FVII albumin fusion protein (rVIIa-FP) was extended six- to seven-fold compared with wild type rFVIIa. The in-vitro and in-vivo efficacy was evaluated and was found to be comparable to a commercially available rFVIIa (NovoSeven((R))). The results of this study demonstrate that it is feasible to develop a half-life extended FVIIa molecule with haemostatic properties very similar to the wild-type factor.
Weimer
Thomas
T
CSL Behring GmbH, Emil-von-Behring-Strasse 76, 35041 Marburg, Germany.
Wormsbächer
Wilfried
W
Kronthaler
Ulrich
U
Lang
Wiegand
W
Liebing
Uwe
U
Schulte
Stefan
S
D000818:Animals; D001483:Base Sequence; D003029:Coagulants / Q000493:pharmacokinetics / Q000627:therapeutic use; D004274:DNA, Recombinant / Q000235:genetics; D015942:Factor VIIa / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D015202:Protein Engineering; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D012709:Serum Albumin / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020349:Surface Plasmon Resonance; D013916:Thrombelastography; D013925:Thromboplastin / Q000378:metabolism
D003029:Coagulants; D004274:DNA, Recombinant; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012709:Serum Albumin; D013925:Thromboplastin; C103587:recombinant FVIIa; D015942:Factor VIIa