Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Abstract

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 g/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 g/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 doserelated antiviral activity for Ն8 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 2Ј,5Ј-oligoadenylate synthetase mRNA relative to IFN-␣-or vehicle-treated animals were maintained for Ն10 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-␣.

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

“…Plasma half-lives for therapeutic proteins invariably increase with the size of the animal (Mordenti et al, 1991). Allometric scaling from our rat data, in light of experience with other albumin fusion proteins (Osborn et al, 2002), is compatible with a several-day half-life of Albu-CocH in humans, allowing infrequent dosing. Gene transfer represents an alternative mode of delivery that, if perfected, could provide continuous supply.…”

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

“…It was shown in vitro, that alb-IFN has the same anti-viral properties as IFN-a, and the induction of ISG is very similar to that of pegIFN-a2a and 2b (Liu et al, 2007). In vivo studies in cynomolgus monkeys revealed a prolonged halflife of alb-IFN in comparison with IFN-a (Osborn et al, 2002). The efficacy of alb-IFN was evaluated in clinical phase IIb studies with IFN-naive patients chronically infected with HCV, in which it was administered every 2 or 4 weeks (Zeuzem et al, 2008).…”

Inhibition of the ubiquitin ligase activity improves the production of biologically active fusion protein HSA-HGF in Chinese hamster ovary cells

“…16 Compared to their native proteins, the lower binding affinity and biological potency (about 10 percent or less) in vitro assay had shown in most HSA fusion product. [23][24][25] It was surmised that the increase in molecular size after small parent molecules fused with albumin possibly reduced the numbers of receptors occupied, HSA maybe influenced the binding of receptor but could not affect signal transduction.…”