Rational Design of a Potent, Long-Lasting Form of Interferon: A 40 kDa Branched Polyethylene Glycol-Conjugated Interferon α-2a for the Treatment of Hepatitis C
2001; American Chemical Society; Volume: 12; Issue: 2 Linguagem: Inglês
10.1021/bc000082g
ISSN1520-4812
AutoresPascal Bailon, Alicia V. Palleroni, Carol Ann Schaffer, Cheryl Spence, Wen-Jian Fung, Jill E. Porter, George K. Ehrlich, Wen Pan, Zhixin Xu, Marlene Modi, Adrienne Farid, W. Berthold, Mary C. Graves,
Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoA potent, long-lasting form of interferon alpha-2a mono-pegylated with a 40 kilodalton branched poly(ethylene glycol) was designed, synthesized, and characterized. Mono-pegylated interferon alpha-2a was comprised of four major positional isomers involving Lys31, Lys121, Lys131, and Lys134 of interferon. The in vitro anti-viral activity of pegylated interferon alpha-2a was found to be only 7% of the original activity. In contrast, the in vivo antitumor activity was severalfold enhanced compared to interferon alpha-2a. Pegylated interferon alpha-2a showed no immunogenicity in mice. After subcutaneous injection of pegylated interferon alpha-2a, a 70-fold increase in serum half-life and a 50-fold increase in mean plasma residence time concomitant with sustained serum concentrations were observed relative to interferon alpha-2a. These preclinical results suggest a significantly enhanced human pharmacological profile for pegylated interferon alpha-2a. Results of Phase II/III hepatitis C clinical trials in humans confirmed the superior efficacy of pegylated interferon alpha-2a compared to unmodified interferon alpha-2a.
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