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Gene delivery of albumin binding peptide-interferon-gamma fusion protein with improved pharmacokinetic properties and sustained biological activity.


J Pharm Sci. 2013 Mar 5;


Authors: Miyakawa N, Nishikawa M, Takahashi Y, Ando M, Misaka M, Watanabe Y, Takakura Y


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. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

PMID: 23463584 [PubMed - as supplied by publisher]