title: Anchoring interferon alpha to apolipoprotein A-I reduces hematological toxicity while enhancing immunostimulatory properties.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fioravanti
authors.forename: Iranzu
authors.initials: I
authors.lastname: González
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.forename: Esther
authors.initials: E
authors.lastname: Larrea
authors.forename: Nuria
authors.initials: N
authors.lastname: Ardaiz
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D007114:Immunization; D016898:Interferon-alpha / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism* / Q000821:virology*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020239:Receptor Cross-Talk / Q000502:physiology; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D053633:Receptor, Interferon alpha-beta