Kinetic modeling of protein PEGylation. (1st December 2015)

• Record Type: Journal Article
• Authors: Pfister, David; Bourgeaux, Eric; Morbidelli, Massimo
• Is Part Of: Chemical engineering science. Volume 137(2015)
• Page Start: 816
• Page End: 827
• Publication Date: 2015-12-01
• Subjects: PEGylation -- Kinetic modeling -- Positional isomers -- Isoforms distribution; Chemical engineering -- Periodicals; Génie chimique -- Périodiques; Chemical engineering; Periodicals; Electronic journals; 660
• DOI: 10.1016/j.ces.2015.07.031
• Languages: English
• ISSNs: 0009-2509

Abstract

Abstract: PEGylation is currently the technique of choice to extend the in-vivo circulation half-life of therapeutic proteins. Nevertheless, the PEGylation reaction is not yet fully described, particularly concerning the development of a proper kinetic model. In this work, we propose a detailed model which describes the rate of protein amine PEGylation with functionalized PEG esters by accounting for the specific reactivity of the various residues and for the shielding effect generated by the already conjugated PEG chains. The proposed kinetic rate constants are derived so as to explicitly include diffusion limitations, heterogeneous reactivities and the steric hindrance caused by the polymer layer surrounding the PEGylated proteins. With illustrative purposes, this new model has been applied to the simulation of lysozyme PEGylation at the lysine residues with PEG esters of various molecular weights and with various PEG to protein molar ratios. Highlights: The amine PEGylation of lysozyme is investigated with various polymer sizes. A detailed kinetic model for protein PEGylation is described. Multiple reactive sites at the protein surface are accounted for. Diffusion-limited reactions and shielding effect are implemented. A limiting case assuming iso-reactivity of the sites is derived.