Interferon-alpha2b secretion by adenovirus-mediated gene delivery in rat, rabbit, and chimpanzee results in similar pharmacokinetic profiles

Toxicology and Applied Pharmacology
G W DemersDaniel C Maneval

Abstract

Gene delivery, with subsequent protein synthesis and secretion, in vivo has been proposed as an alternative way to deliver a therapeutic protein to the systemic circulation. Interferon-alpha (IFN) protein is effective in the treatment of viral and malignant diseases but has short serum half-life that requires frequent administration. An E1 region-deleted adenovirus vector encoding human IFN-alpha2b gene driven by the cytomegalovirus immediate early promoter (rAd-IFN) was generated to assess the serum concentration-time profiles of expressed IFN protein in animal models. Intravenous administration of rAd-IFN, normalized for body weight, resulted in dose-dependent serum IFN concentrations that persisted 8-40 days with similar concentration-time profiles in rats and rabbits. We sought to determine if serum concentration-time profiles in the rat and rabbit animal models would be predictive for a larger animal and would therefore be relevant models for potential dosing of human patients. Two chimpanzees (approximately 70 kg) dosed with rAd-IFN by intravenous administration normalized to body weight achieved serum IFN concentration-time profiles similar to those observed in rats and rabbits. The role of the immune response in limitin...Continue Reading

Citations

Jun 7, 2011·American Journal of Respiratory and Critical Care Medicine·Daniel H StermanSteven M Albelda
Oct 14, 2006·The Journal of Clinical Investigation·Eui-Cheol ShinBarbara Rehermann
Apr 22, 2006·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Robert E LanfordCatherine B Bigger
Aug 3, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Robert E LanfordKathleen M Brasky
Sep 18, 2007·Advanced Drug Delivery Reviews·Stéphane Chevaliez, Jean-Michel Pawlotsky

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