title: Pulmonary administration of interferon Beta-1a-fc fusion protein in non-human primates using an immunoglobulin transport pathway.
abstract: Currently, products containing interferon beta (IFNβ) are injected either intramuscularly or subcutaneously. To avoid the necessity of injection, we developed a novel monomeric Fc fusion protein of IFNβ (IFNβFc) that is absorbed via an immunoglobulin transport system present in the upper and central airways upon administration of the drug as an inhaled aerosol. The systemic absorption of IFNβFc through the lung in non-human primates, at deposited doses of 1, 3, and 10 μg/kg, was compared to the absorption of a single 3 μg/kg dose of IFNβ-1a (Avonex®) subcutaneously administered. IFNβFc was well absorbed through the lung, displaying dose proportional increases in serum concentrations, and was biologically active, as shown by increases in plasma neopterin levels. The circulating half-life of IFNβFc was ∼3 times longer (∼30 h) than that of IFNβ-1a, (8-9 h). At approximately equimolar doses of IFNβFc (10 μg/kg) and IFNβ-1a (3 μg/kg), the stimulation of neopterin over background levels was approximately equivalent, demonstrating that the longer half-life of IFNβFc compensated for the lower relative specific antiviral activity of IFNβFc measured in vitro. In conclusion, IFNβFc was efficiently absorbed after pulmonary delivery in non-human primates, retained its biological activity, and may offer a convenient alternative to injectable IFNβ.
authors.affiliation: Biogen Idec Hemophilia, Waltham, Massachusetts 02451, USA. sebastien.vallee@biogenidec.com
authors.forename: Sebastien
authors.initials: S
authors.lastname: Vallee
authors.forename: Swapnil
authors.initials: S
authors.lastname: Rakhe
authors.forename: Thomas
authors.initials: T
authors.lastname: Reidy
authors.forename: Sandra
authors.initials: S
authors.lastname: Walker
authors.forename: Qi
authors.initials: Q
authors.lastname: Lu
authors.forename: Paul
authors.initials: P
authors.lastname: Sakorafas
authors.forename: Susan
authors.initials: S
authors.lastname: Low
authors.forename: Alan
authors.initials: A
authors.lastname: Bitonti
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002850:Chromatography, Gel; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000096:biosynthesis / Q000494:pharmacology*; D007136:Immunoglobulins / Q000378:metabolism*; D007279:Injections, Subcutaneous; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage* / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology*; D008252:Macaca fascicularis / Q000097:blood; D008297:Male; D019798:Neopterin / Q000097:blood; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D007141:Immunoglobulin Fc Fragments; D007136:Immunoglobulins; D011993:Recombinant Fusion Proteins; C575428:interferon beta-1a-Fc fusion protein; D019798:Neopterin; D016899:Interferon-beta; D000068556:Interferon beta-1a