Prolonged in-vivo half-life of factor VIIa by fusion to albumin

Thromb Haemost. 2008 Apr;99(4):659-67. doi: 10.1160/TH07-08-0525.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Base Sequence
  • Coagulants / pharmacokinetics
  • Coagulants / therapeutic use
  • DNA, Recombinant / genetics
  • Factor VIIa / genetics
  • Factor VIIa / pharmacokinetics*
  • Factor VIIa / therapeutic use
  • Half-Life
  • Hemophilia A / blood
  • Hemophilia A / drug therapy
  • Hemostasis / drug effects
  • Humans
  • In Vitro Techniques
  • Protein Binding
  • Protein Engineering
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / therapeutic use
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / therapeutic use
  • Serum Albumin / genetics
  • Serum Albumin / pharmacokinetics*
  • Serum Albumin / therapeutic use
  • Surface Plasmon Resonance
  • Thrombelastography
  • Thromboplastin / metabolism

Substances

  • Coagulants
  • DNA, Recombinant
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Serum Albumin
  • Thromboplastin
  • recombinant FVIIa
  • Factor VIIa