The resistance of retroviral vectors produced from human cells to serum inactivation in vivo and in vitro is primate species dependent.
The ability to deliver genes as therapeutics requires an understanding of the vector pharmacokinetics similar to that required for conventional drugs. A first question is the half-life of the vector in the bloodstream. Retroviral vectors produced in certain human cell lines differ from vectors produced in nonhuman cell lines in being substantially resistant to inactivation in vitro by human serum complement (F. L. Cosset, Y. Takeuchi, J. L. Battini, R. A. Weiss, and M. K. Collins, J. Virol. 69:7430-7436, 1995). Thus, use of human packaging cell lines (PCL) may produce vectors with longer half-lives, resulting in more-efficacious in vivo gene therapy. However, survival of human PCL-produced vectors in vivo following systemic administration has not been explored. In this investigation, the half-lives of retroviral vectors packaged by either canine D17 or human HT1080 PCL were measured in the bloodstreams of macaques and chimpanzees. Human PCL-produced vectors exhibited significantly higher concentrations of circulating biologically active vector at the earliest time points measured (>1, 000-fold in chimpanzees), as well as substantially extended half-lives, compared to canine PCL-produced vectors. In addition, the circulation half-life of human PCL-produced vector was longer in chimpanzees than in macaques. This was consistent with in vitro findings which demonstrated that primate serum inactivation of vector produced from human PCL increased with increasing phylogenetic distance from humans. These results establish that in vivo retroviral vector half-life correlates with in vitro resistance to complement. Furthermore, these findings should influence the choice of animal models used to evaluate retroviral-vector-based therapies.
DePolo
N J
NJ
Vector Technologies Group, Center for Gene Therapy, Chiron Technologies, San Diego, California 92121, USA. nick_depolo@cc.chiron.com
Harkleroad
C E
CE
Bodner
M
M
Watt
A T
AT
Anderson
C G
CG
Greengard
J S
JS
Murthy
K K
KK
Dubensky
T W
TW
Jolly
D J
DJ
D000818:Animals; D004285:Dogs; D005260:Female; D005822:Genetic Vectors / Q000502:physiology*; D006801:Humans; D008251:Macaca; D008253:Macaca mulatta; D008297:Male; D002679:Pan troglodytes; D010215:Papio; D012190:Retroviridae / Q000502:physiology*; D013045:Species Specificity; D014407:Tumor Cells, Cultured