title: Gene delivery of albumin binding peptide-interferon-gamma fusion protein with improved pharmacokinetic properties and sustained biological activity.
abstract: We have demonstrated that gene delivery of a fusion protein of mouse interferon (IFN) γ with mouse serum albumin (IFNγ-MSA) was effective in prolonging the circulation half-life of IFNγ in mice. However, the fusion to MSA greatly reduced the biological activity of IFNγ to less than 1%. In this study, we designed IFNγ fusion proteins with a 20 amino-acid long albumin-binding peptide (ABP) to prolong the in vivo half-life of IFNγ without reducing its biological activity. IFNγ-ABP and ABP-IFNγ, two fusion proteins with the ABP being fused to the C- or N-terminal of IFNγ, retained 40%-50% biological activities determined using a gamma-activated sequence-dependent luciferase assay. These fusion proteins exhibited the ability to bind to MSA. Gene delivery of IFNγ-ABP or ABP-IFNγ to mice using the hydrodynamic injection method resulted in a sustained concentration of IFNγ in the serum compared with gene delivery of IFNγ. In addition, the growth of mouse colon carcinoma CT-26 cells in the lung was efficiently inhibited by gene delivery of the IFNγ fusion proteins. These results indicate that the fusion of ABP is a useful approach to achieving prolonged retention in the blood circulation through binding to serum albumin and retaining biological activity.
authors: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto 606-8501, Japan.
authors: Noriko
authors: N
authors: Miyakawa
authors: Makiya
authors: M
authors: Nishikawa
authors: Yuki
authors: Y
authors: Takahashi
authors: Mitsuru
authors: M
authors: Ando
authors: Masayuki
authors: M
authors: Misaka
authors: Yoshihiko
authors: Y
authors: Watanabe
authors: Yoshinobu
authors: Y
authors: Takakura
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D018014:Gene Transfer Techniques; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D010455:Peptides; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D007371:Interferon-gamma
keywords: albumin; albumin-binding peptide; biological activity; clearance; fusion protein; gene delivery; hydrodynamic injection; moment analysis; pharmacokinetics; plasmid DNA