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Blood ; 121(11): 2108-16, 2013 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-23335368

RESUMEN

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.


Asunto(s)
Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Animales , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Factor VIII/administración & dosificación , Factor VIII/metabolismo , Femenino , Glicosilación , Hemofilia A/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/metabolismo , Conejos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Resultado del Tratamiento
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