Interferon-alpha2b secretion by adenovirus-mediated gene delivery in rat, rabbit, and chimpanzee results in similar pharmacokinetic profiles.
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 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.
Demers
G William
GW
Canji, Inc., San Diego, California 92121, USA.
Sugarman
Barry J
BJ
Beltran
Josefina C
JC
Westreich
Louis N
LN
Ahmed
C M Iqbal
CM
Lau
Johnson Y
JY
Hong
Zhi
Z
Lanford
Robert E
RE
Maneval
Daniel C
DC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016867:Immunocompromised Host; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics*; D051379:Mice; D016513:Mice, SCID; D002679:Pan troglodytes / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011915:Rats, Inbred BUF; D011994:Recombinant Proteins; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins