Derivatization of
protein-based
therapeutics with
polyethylene glycol (pegylation) can often improve pharmacokinetic and pharmacodynamic properties of the
proteins and thereby, improve efficacy and minimize dosing frequency. This review will provide an overview of pegylation technology and pegylated
protein-based drugs being used or investigated clinically. The novel therapeutic,
PEG Intron(R), formed by attaching a 12-kDa mono-methoxy
polyethylene glycol (PEG) to the
interferon alpha-2b
protein, will be discussed in detail in terms of its structure,
biological activities, pharmacokinetic properties, and clinical efficacy for the treatment of
chronic hepatitis C. Detailed physicochemical and
biological characterization studies of
PEG Intron revealed its composition of pegylated positional isomers and the specific anti-viral activity associated with each of them. Pegylation of Intron A at pH 6.5 results in a mixture of > or = 95% mono-pegylated
isoforms with the predominant species (approximately 50%) derivatized to the His(34) residue with the remaining positional isomers pegylated at various lysines, the N-terminal
cysteine, as well as
serine,
tyrosine, and another
histidine residue. The anti-viral activity for each pegylated isomer showed that the highest specific activity (37%) was associated with the His(34)-pegylated isomer. Though pegylation decreases the specific activity of the
interferon alpha-2b
protein in vitro, the potency of
PEG Intron was comparable to the Intron A standard at both the molecular and cellular level. The substituted IFN had an enhanced pharmacokinetic profile in both animal and human studies, and, when combined with
ribavirin, was very effective in reducing
hepatitis C viral load and maintaining sustained viral suppression in patients.