Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications.
The type I interferon alpha family consists of small proteins that have clinically important anti-infective and anti-tumor activity. Interferon alpha-2b (Intron A) combination therapy with ribavirin is the current standard of care for the treatment of chronic hepatitis C virus infection. A drawback to the therapy however, is the short serum half-life and rapid clearance of the interferon alpha protein. Schering-Plough has developed a semi-synthetic form of Intron A by attaching a 12-kDa mono-methoxy polyethylene glycol to the protein (PEG Intron) which fulfills the requirements of a long-acting interferon alpha protein while providing significant clinical benefits. A detailed physicochemical and biological characterization of PEG Intron revealed its composition of pegylated positional isomers and the specific anti-viral activity associated with each of them. Though pegylation appeared to decrease the specific activity of the interferon alpha-2b protein, the potency of PEG Intron, independent of protein concentration, was comparable to the Intron A standard at both the molecular and cellular level. Importantly, PEG Intron has demonstrated an enhanced pharmacokinetic profile in both animal and human studies. Recently, PEG Intron in combination with ribavirin has been shown to be very effective in reducing hepatitis C viral load and maintaining effective sustained viral suppression in patients. Because of the improved clinical benefits, it is anticipated that the PEG Intron plus ribavirin combination therapy will become the new standard of care for the treatment of chronic hepatitis C.
Wang
Yu-Sen
YS
Structural Chemistry, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Youngster
Stephen
S
Grace
Michael
M
Bausch
James
J
Bordens
Ronald
R
Wyss
Daniel F
DF
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002942:Circular Dichroism; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D007536:Isomerism; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a