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Vol. 303, Issue 2, 540-548, November 2002
Fusion Protein in Cynomolgus Monkeys
Human Genome Sciences, Inc., Rockville, Maryland
Interferon-
(IFN-) is indicated for the treatment of certain
viral infections including hepatitis B and C, and cancers such as
melanoma. The short circulating half-life of unmodified IFN- makes
frequent dosing (daily or three times weekly) over an extended period
(6-12 months or more) necessary. To improve the pharmacokinetics of
IFN- and decrease dosing frequency, IFN- was fused to human serum
albumin producing a new protein, Albuferon. In vitro comparisons of
Albuferon and IFN- showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than
IFN-. Pharmacokinetic and pharmacodynamic properties of the fusion
protein were enhanced in monkeys. After a single intravenous injection
(30 µg/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 µg/kg subcutaneous injection,
apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was
64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN- given by the
subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated dose-related antiviral activity for 
8 days based
on an in vitro bioassay, whereas antiviral activity from IFN--treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2',5'-oligoadenylate synthetase mRNA
relative to IFN-- or vehicle-treated animals were maintained for
10 days after subcutaneous dosing. The improved pharmacokinetics of
Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-.
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