Prolonged circulation half-life of interferon γ activity by gene delivery of interferon γ-serum albumin fusion protein in mice.
Gene delivery of mouse interferon (IFN) γ has been shown to inhibit metastatic tumor growth and onset of atopic dermatitis in mouse models. In this study, we tried to increase the circulation half-life of IFNγ after its gene delivery by designing a novel fusion protein of IFNγ with mouse serum albumin (MSA). Western blot analysis confirmed that IFNγ-MSA was expressed as a fusion protein, but hardly formed dimer as IFNγ did. The biological activity of IFNγ-MSA, which was examined using a plasmid expressing luciferase under the control of gamma-activated sequence elements, was about 200-fold lower than the activity of IFNγ. Intravenous injection of the proteins into mice confirmed that the circulation half-life of IFNγ was significantly prolonged by the modification. A hydrodynamic injection of a plasmid expressing IFNγ-MSA resulted in a sustained concentration in mouse serum; it resulted in about sixfold greater area under the concentration-time curve and about threefold longer mean residence time of IFNγ activity than those of IFNγ. Gene delivery of IFNγ-MSA inhibited tumor metastasis to a similar level to that of IFNγ despite the reduced activity of IFNγ-MSA. These results indicate that gene delivery of IFNγ-MSA is a promising approach to prolong the circulation half-life of IFNγ activity.
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Noriko
N
Miyakawa
Makiya
M
Nishikawa
Yuki
Y
Takahashi
Mitsuru
M
Ando
Masayuki
M
Misaka
Yoshihiko
Y
Watanabe
Yoshinobu
Y
Takakura
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006207:Half-Life; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000097:blood* / Q000235:genetics / Q000627:therapeutic use; D049409:Luciferases, Firefly / Q000235:genetics; D008175:Lung Neoplasms / Q000097:blood / Q000517:prevention & control / Q000556:secondary; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000097:blood* / Q000235:genetics / Q000627:therapeutic use; D012709:Serum Albumin / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014162:Transfection
D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D007371:Interferon-gamma; D004247:DNA; D049409:Luciferases, Firefly