Journal
MOLECULAR PHARMACEUTICS
Volume 9, Issue 3, Pages 664-670Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp200347q
Keywords
human serum albumin fusion; long acting interferon; drug delivery
Funding
- Natural Science Foundation of China [31000550, 81172968]
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Human serum albumin (HSA) fusion (Albufusion) technology has evolved to be a general strategy to increase the in vivo half-lives of therapeutic proteins. However, because of the steric hindrance effect of HSA, conventional Albufusion technology improves the pharmacokinetics (PK) at the cost of pharmacodynamics (PD). To achieve balanced PK and PD of interferon-alpha 2b (IFN-alpha 2b) and HSA fusion protein, protease cleavage sites or disulfide linkage that enabled releasing of intact IFN-alpha 2b with full activity was introduced between these two moieties. Nonreleasable and releasable fusion proteins showed similar cell surface receptor binding affinities; however, releasable fusion proteins exhibited release efficiency proportional increase of in vitro antiviral and antiproliferative activities. The release rate also had a profound impact on the in vivo pharmaceutical properties of fusion proteins. Releasable fusion proteins with intermediate release rate had the most balanced PK and PD, which translated into improved therapeutic efficacy in the HT29 human colon cancer xenograft model. Releasable Albufusion (rAlbufusion) allows tailored design of the PK/PD profile and greatly extends the utility of conventional Albufusion technology.
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