Interferon-α2b secretion by adenovirus-mediated gene delivery in rat, rabbit, and chimpanzee results in similar pharmacokinetic profiles

G. William Demers, Barry J. Sugarman, Josefina C. Beltran, Louis N. Westreich, C. M. Iqbal Ahmed, Johnson Y. Lau, Zhi Hong, Robert E. Lanford, Daniel C. Maneval

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    17 Scopus citations

    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-α (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-α2b 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 (∼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 limiting the persistence of transgene expression was highlighted by the persistence of serum IFN concentrations for over 200 days in beige/SCID immunodeficient mice. These studies suggest that serum concentration of secreted transgene products after gene delivery in small animal models may be highly predictive for larger species and will help define dosing strategies in human patients.

    Original languageEnglish (US)
    Pages (from-to)36-42
    Number of pages7
    JournalToxicology and Applied Pharmacology
    Volume180
    Issue number1
    DOIs
    Publication statusPublished - Apr 1 2002

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    Keywords

    • Chimpanzee
    • Gene therapy
    • Interferon-alpha
    • Pharmacokinetics
    • Rabbit
    • Rat

    ASJC Scopus subject areas

    • Toxicology
    • Pharmacology

    Cite this

    Demers, G. W., Sugarman, B. J., Beltran, J. C., Westreich, L. N., Iqbal Ahmed, C. M., Lau, J. Y., ... Maneval, D. C. (2002). Interferon-α2b secretion by adenovirus-mediated gene delivery in rat, rabbit, and chimpanzee results in similar pharmacokinetic profiles. Toxicology and Applied Pharmacology, 180(1), 36-42. https://doi.org/10.1006/taap.2002.9372