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.
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.
Serano Reproductive Biology Institute, Rockland, MA 02370, USA. sean.mckenna@serono.com
Sean D
SD
McKenna
Kristin
K
Vergilis
Antonio R N
AR
Arulanandam
Weishui Y
WY
Weiser
Roustem
R
Nabioullin
Mark A
MA
Tepper
D000818:Animals; D002051:Burkitt Lymphoma / Q000276:immunology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D005260:Female; D006207:Half-Life; D006801:Humans; D007167:Immunotherapy; D007275:Injections, Intravenous; D007370:Interferon Type I / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016899:Interferon-beta / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000276:immunology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous / Q000276:immunology
C507964:IFNAR1 protein, human; C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D008565:Membrane Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta