Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C.
A 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.
Bailon
P
P
Hoffmann-La Roche Inc, Nutley, New Jersey 07110, USA. pascal.bailon@roche.com
Palleroni
A
A
Schaffer
C A
CA
Spence
C L
CL
Fung
W J
WJ
Porter
J E
JE
Ehrlich
G K
GK
Pan
W
W
Xu
Z X
ZX
Modi
M W
MW
Farid
A
A
Berthold
W
W
Graves
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D015151:Immunoblotting; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a