Formation of human IFN-beta complex with the soluble type I interferon receptor IFNAR-2 leads to enhanced IFN stability, pharmacokinetics, and antitumor activity in xenografted SCID mice.

Abstract

Interferon-beta (IFN-beta) is biologically unstable under physiologic conditions in vitro and is cleared rapidly from the bloodstream on administration in vivo. In the present study, we demonstrate that a soluble recombinant form of the type I IFN receptor subunit, sIFNAR-2, can neutralize the bioactivity of type I IFNs at high concentrations and, at lower concentrations, causes an enhancement of IFN-beta-mediated antiviral activity. The in vitro enhancement is due to the specific interaction of IFN-beta with sIFNAR-2, followed by dissociation of IFN-beta from the complex over time in culture. In vivo, the serum half-life of IFN-beta is extended from minutes to hours when administered intravenously in mice as a sIFNAR-2-associated complex. Moreover, the antitumor effect of IFN-beta is increased by between 9-fold and 27-fold when injected as an sIFNAR-2-associated complex, as demonstrated by an increase in the mean survival time of immunodeficient mice challenged with human Burkitt lymphoma cell (Daudi) xenografts (sIFNAR-2-complexed vs. free IFN-beta treatment). These results show that on association with sIFNAR-2, IFN-beta is more stable in vitro and exhibits increased efficacy when administered in vivo. Administration as a complex with sIFNAR-2 may, therefore, provide a method of enhancing the delivery and effectiveness of type I IFNs.

• Authors: Sean D McKenna, Kristin Vergilis, Antonio R N Arulanandam, Weishui Y Weiser, Roustem Nabioullin, Mark A Tepper
• Journal: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research (J Interferon Cytokine Res) Vol. 24 Issue 2 Pg. 119-29 (Feb 2004) ISSN: 1079-9907 [Print] United States
• PMID: 14980076 (Publication Type: Journal Article)

Chemical References

• IFNAR1 protein, human
• Ifnar2 protein, mouse
• Interferon Type I
• Membrane Proteins
• Receptors, Interferon
• Recombinant Proteins
• Receptor, Interferon alpha-beta
• Interferon-beta

Topics

• Animals
• Burkitt Lymphoma (immunology)
• CHO Cells
• Cell Line, Tumor
• Cricetinae
• Female
• Half-Life
• Humans
• Immunotherapy
• Injections, Intravenous
• Interferon Type I (pharmacokinetics, pharmacology, therapeutic use)
• Interferon-beta (pharmacokinetics, pharmacology, therapeutic use)
• Membrane Proteins
• Mice
• Mice, Inbred Strains
• Mice, SCID
• Neoplasm Transplantation (immunology)
• Receptor, Interferon alpha-beta
• Receptors, Interferon (therapeutic use)
• Recombinant Proteins (pharmacokinetics, pharmacology, therapeutic use)
• Transplantation, Heterologous (immunology)