(The FASEB Journal. 2008;22:lb429)
© 2008 FASEB
Improved expression and delivery of IL-15 DNA vectors in combination with IL-15 receptor alpha in mice and macaques provide a potent growth signal for NK and T cells
Cristina Bergamaschi1,
Antonio Valentin1,
Rashmi Jalah1,
Margherita Rosati1,
Viraj Kulkarni1,
Candido Alicea1,
Vainav Patel1,
Gen-Mu Zhang1,
Rune Kjeken2,
Barbara K Felber1 and
George N Pavlakis1
1 Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD,
2 Inovio, Inc., San Diego, CA
ABSTRACT
Optimized DNA vectors expressing IL-15 and IL-15 Receptor alpha (IL-15Ra) were generated by optimizing mRNA expression and protein trafficking. Co-expression of IL-15 with IL-15Ra allowed for the intracellular interaction of the two proteins, resulting in increased stability and secretion of both molecules (Bergamaschi et al, JBC, 2007). Mutual stabilization of IL-15 and IL-15Ra leads to remarkable increase in production of bioactive IL-15 in vivo. Co-injection of IL-15 and IL-15Ra DNAs into mice resulted in about 1000-fold increase of IL-15 serum levels, compared to the wild type IL-15 alone. This high concentration of systemic IL-15 in mice was biologically active, as demonstrated by the increased frequency of NK and effector memory T cells in lung, liver and spleen. Rhesus macaques receiving these vectors by intramuscular in vivo electroporation also express high levels of plasma IL-15, which peaks at day 4. As a result of DNA injection, the frequency of NK and T cells in blood decreased between day 0 and day 5 after injection (p=0.002), suggesting their mobilization to the periphery, where they mediate surveillance and effectors functions. These results indicate that the most potent form of IL-15 is as part of a complex with IL-15Ra. The high level of expression of bioactive cytokine, achieved by the optimized vectors in primates, suggest that they will be useful in DNA-based vaccines or immunotherapy protocols.
