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Thromb Haemost 2002; 87(05): 836-839
DOI: 10.1055/s-0037-1613093
Review Article
Schattauer GmbH

Evaluation of Potential Antigenicity of Active-Site-Inhibited Recombinant Human FVIIa (FFR-rFVIIa) in an Immune-Tolerant Rat Model

Else Marie Nicolaisen
3   NovoSeven Research, Novo Nordisk A/S, Måløv, Denmark
,
Hanne Kristensen
1   Leo Pharmaceutical Products, Ballerup, Denmark
,
Annemarie Kristensen
2   The Royal Veterinary and Agricultural University, Frederiksberg, Denmark
,
Ulla Hedner
3   NovoSeven Research, Novo Nordisk A/S, Måløv, Denmark
› Author Affiliations
Further Information

Publication History

Received 08 October 2001

Accepted after revision 22 January 2002

Publication Date:
11 December 2017 (online)

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Summary

Recombinant human FVIIa (rFVIIa) was inactivated by coupling Phe-Phe-Arg-CO- (FFR) covalently to the active site of the enzyme. To test the chemically-modified human protein for potential antigenicity prior to clinical trial an immune-tolerant rat model was established. Intraperitoneal injection of the parent compound, human rFVIIa, within 30 h after birth, followed by repeated subcutaneous challenge with rFVIIa in Freunds incomplete adjuvant resulted in 79% non-responding rats at day 32. Monthly subcutaneous challenge showed that the induced tolerance was stable over the 3 months study period in 80% of the rats. The clinically relevant route, intravenous administration, was used for evaluating the potential antigenicity of FFR-rFVIIa. Repeated intravenous administration of different dosages of FFR-rFVIIa did not break tolerance, indicating that FFR-rFVIIa might not be antigenic, for a limited number of intravenous administrations in a clinical setting.

Keywords

Immune tolerance - active-site-inhibited FVIIa - FFR-rFVIIa - antigenicity - antithrombotic
 

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