Anchoring interferon alpha to apolipoprotein A-I reduces hematological toxicity while enhancing immunostimulatory properties§

Authors

  • Jessica Fioravanti,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • Iranzu González,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • José Medina-Echeverz,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • Esther Larrea,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • Nuria Ardaiz,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • Gloria González-Aseguinolaza,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • Jesús Prieto,

    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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  • Pedro Berraondo

    Corresponding author
    1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
    • Prof. Jesús Prieto Division of Hepatology and Gene Therapy, Center for Applied Medical Research University of Navarra, Pamplona, Navarra, Spain
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    • These authors share senior authorship.

    • fax: +34948194717.


  • Potential conflict of interest: Nothing to report.

  • Supported by the agreement between FIMA and the “UTE project CIMA,” Fundación Pedro Barrié de la Maza and Condesa de Fenosa and Red de Inmunoterapia INMUNONET-SOE1/P1/E014. J.F. and J.M-E. were supported by a fellowship of Spanish Fondo de Investigación Sanitaria. P.B. was supported by a Juan de la Cierva contract from Ministerio de Educación y Ciencia and a Miguel Servet contract from Instituto de Salud Carlos III, FIS.

Abstract

Interferon alpha (IFNα) is widely used for the treatment of viral hepatitis but substantial toxicity hampers its clinical use. In this work, we aimed at improving the efficacy of IFNα therapy by increasing the IFNα half-life and providing liver tropism. We selected apolipoprotein A-I (ApoA-I) as the stabilizing and targeting moiety. We generated plasmids encoding IFNα, albumin bound to IFNα (ALF), or IFNα linked to ApoA-I (IA) and mice were treated either by hydrodynamic administration of the plasmids or by injection of the corresponding recombinant proteins or high-density lipoproteins containing IA. The plasma half-life of IA was intermediate between IFNα and ALF. IA was targeted to the liver and induced higher hepatic expression of interferon-stimulated genes than IFNα or even ALF. IA exhibits stronger in vivo antiviral activity than IFNα and the hematologic cytopenic effects of IA are milder than those observed when using IFNα or ALF. In contrast to IFNα, IA does not cause activation-dependent cell death of lymphocytes in vitro. Accordingly, in vivo studies showed that IA boosts T-cell immune responses more efficiently than IFNα or ALF. The difference in immunostimulatory activity between IFNα and IA disappears in scavenger receptor class B type I (SR-BI) knockout mice, suggesting that crosstalk between SR-BI and IFNα receptor is essential for enhanced induction of cytotoxic T cells by IA. Conclusion: Anchoring IFNα to ApoA-I prolongs the half-life of IFNα and promotes targeting to the liver. Importantly, the fusion protein shows increased immunostimulatory properties and lower hematological toxicity. (HEPATOLOGY 2011;)

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