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• W2016876962 startingPage "93" @default.
• W2016876962 abstract "Albumin fusion/conjugation (albumination) has been an effective method to prolong in vivo half-life of therapeutic proteins. However, its broader application to proteins with complex folding pathway or multi-subunit is restricted by incorrect folding, poor expression, heterogeneity, and loss of native activity of the proteins linked to albumin. We hypothesized that the site-specific conjugation of albumin to a permissive site of a target protein will expand the utilities of albumin as a therapeutic activity extender to proteins with a complex structure. We show here the genetic incorporation of a non-natural amino acid (NNAA) followed by chemoselective albumin conjugation to prolong therapeutic activity in vivo. Urate oxidase (Uox), a therapeutic enzyme for treatment of hyperuricemia, is a homotetramer with multiple surface lysines, limiting conventional approaches for albumination. Incorporation of p-azido-l-phenylalanine into two predetermined positions of Uox allowed site-specific linkage of dibenzocyclooctyne-derivatized human serum albumin (HSA) through strain-promoted azide-alkyne cycloaddition (SPAAC). The bio-orthogonality of SPAAC resulted in the production of a chemically well-defined conjugate, Uox-HSA, with a retained enzymatic activity. Uox-HSA had a half-life of 8.8 h in mice, while wild-type Uox had a half-life of 1.3 h. The AUC increased 5.5-fold (1657 vs. 303 mU/mL x h). These results clearly demonstrated that site-specific albumination led to the prolonged enzymatic activity of Uox in vivo. Site-specific albumination enabled by NNAA incorporation and orthogonal chemistry demonstrates its promise for the development of long-acting protein therapeutics with high potency and safety." @default.
• W2016876962 created "2016-06-24" @default.
• W2016876962 creator A5014572075 @default.
• W2016876962 creator A5029721024 @default.
• W2016876962 creator A5075596188 @default.
• W2016876962 date "2015-06-01" @default.
• W2016876962 modified "2023-10-18" @default.
• W2016876962 title "Site-specific albumination of a therapeutic protein with multi-subunit to prolong activity in vivo" @default.
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• W2016876962 doi "https://doi.org/10.1016/j.jconrel.2015.04.004" @default.
• W2016876962 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4430413" @default.
• W2016876962 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25862515" @default.
• W2016876962 hasPublicationYear "2015" @default.
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