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Stennicke, Henning R.; Kjalke, Marianne; Karpf, Ditte M.; Balling, Kristoffer W.; Johansen, Peter B.; Elm, Torben; Øvlisen, Kristine; Möller, Flemming; Holmberg, Heidi L.; Gudme, Charlotte N.; Persson, Egon; Hilden, Ida; Pelzer, Hermann; Rahbek-Nielsen, Henrik; Jespersgaard, Christina; Bogsnes, Are; Pedersen, Anette A.; Kristensen, Anne K.; Peschke, Bernd; Kappers, Wendy; Rode, Frederik; Thim, Lars; Tranholm, Mikael; Ezban, Mirella; Olsen, Eva H.N.; Bjørn, Søren E.
Blood, 03/2013, Letnik: 121, Številka: 11Journal Article
Frequent infusions of intravenous factor VIII (FVIII) are required to prevent bleeding associated with hemophilia A. To reduce the treatment burden, recombinant FVIII with a longer half-life was developed without changing the protein structure. FVIII–polyethylene glycol (PEG) conjugates were prepared using an enzymatic process coupling PEG (ranging from 10 to 80 kDa) selectively to a unique O-linked glycan in the FVIII B-domain. Binding to von Willebrand factor (VWF) was maintained for all conjugates. Upon cleavage by thrombin, the B-domain and the associated PEG were released, generating activated FVIII (FVIIIa) with the same primary structure and specific activity as native FVIIIa. In both FVIII- and VWF-deficient mice, the half-life was found to increase with the size of PEG. In vivo potency and efficacy of FVIII conjugated with a 40-kDa PEG (N8-GP) and unmodified FVIII were not different. N8-GP had a longer duration of effect in FVIII-deficient mouse models, approximately a twofold prolonged half-life in mice, rabbits, and cynomolgus monkeys; however, the prolongation was less pronounced in rats. Binding capacity of N8-GP on human monocyte-derived dendritic cells was reduced compared with unmodified FVIII, resulting in several-fold reduced cellular uptake. In conclusion, N8-GP has the potential to offer efficacious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency. •GlycoPEGylated FVIII (N8-GP) demonstrates the same efficacy and prolonged effect in animal models as native FVIII.•Circulatory half-life of glycoPEGylated FVIII (N8-GP) is prolonged by approximately twofold in several species.
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