Functional characteristics of N8, a new recombinant FVIII

The aim of this study was to evaluate the in vitro function of the new recombinant factor VIII (FVIII) compound, N8. The specific activity of N8 as measured in a FVIII:C one‐stage clot assay was 9300 ± 400 IU mg−1 based on the analysis of seven individual batches. The ratio between the FVIII:C activ...

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Published in:	Haemophilia : the official journal of the World Federation of Hemophilia Vol. 16; no. 6; pp. 878 - 887
Main Authors:	CHRISTIANSEN, M. L. S., BALLING, K. W., PERSSON, E., HILDEN, I., BAGGER-SØRENSEN, A., SØRENSEN, B. B., VIUFF, D., SEGEL, S., KLAUSEN, N. K., EZBAN, M., LETHAGEN, S., STEENSTRUP, T. D., KJALKE, M.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-11-2010 Wiley
Subjects:	Blood Coagulation - drug effects Enzyme-Linked Immunosorbent Assay factor VIII Factor VIII - analysis Factor VIIIa - analysis Factor VIIIa - pharmacokinetics FVIII FVIII:C haemophilia A Hemophilia A - blood Hemophilia A - drug therapy Humans Recombinant Proteins Thrombelastography Thrombin - biosynthesis thromboelastography von Willebrand Factor - metabolism Medicine
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Summary:	The aim of this study was to evaluate the in vitro function of the new recombinant factor VIII (FVIII) compound, N8. The specific activity of N8 as measured in a FVIII:C one‐stage clot assay was 9300 ± 400 IU mg−1 based on the analysis of seven individual batches. The ratio between the FVIII:C activity measured in clot and chromogenic assays was 1.00 (95% confidence interval 0.97–1.03). N8 bound to von Willebrand factor with Kd values of 0.2 nm when measured by ELISA and by surface plasmon resonance. FVIIIa cofactor activity was determined from the kinetic parameters of factor IXa‐catalysed factor X (FX) activation. The rate of activation of N8 by thrombin as well as Km and kcat for FX activation was in the same range as those observed for Advate®. The rate of activated protein C (APC)‐catalysed inactivation was similar for activated N8 and Advate®. N8 improved thrombin generation in a dose‐dependent manner and induced similar rates of thrombin generation as Advate® and the plasma‐derived FVIII product Haemate®. Using thromboelastography (TEG®), N8 was shown to improve the clot formation and clot stability in whole blood from haemophilia A patients. Comparable potency and efficacy of N8 and Advate® was found based on TEG® parameters. Finally, similar binding profiles to immobilized lipoprotein receptor‐related protein (LRP) of N8 and Advate® were observed. The study demonstrated that N8 is fully functional in a variety of assays measuring FVIII activity. No functional differences were found between N8 and comparator compounds.
Bibliography:	ArticleID:HAE2333 istex:A6939D03CAF12F74F7D2F9B47DFCF3A8C533FF59 ark:/67375/WNG-LSNNJQ70-Z ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1351-8216 1365-2516
DOI:	10.1111/j.1365-2516.2010.02333.x