IL-15 is a member of the γ-chain family of cytokine important for the proliferation and function of NK and T cells. IL-15 acts on the surface of the cell in complex with IL-15Rα to engage IL-15Rβγ complex in nearby cells. We recently showed that in both murine and human sera IL-15 is in complex with soluble IL-15Rα (sIL-15Rα), suggesting that IL-15/IL-15Rα heterodimer is responsible for IL-15 bioactivity in vivo. We have generated stable cell lines secreting high levels of fully processed human IL-15/sIL-15Rα cytokine. We also prepared an additional form of human glycosylated IL-15 heterodimer in which the C-terminus of sIL-15Rα is fused to the Fc region of human IgG1. The biochemical properties and bioactivity of these IL-15 heterodimers were tested in mice and macaques. IL-15/IL-15RαFc was characterized by an increased bioactivity that reflected its superior plasma half-life in mice, in comparison to IL-15/sIL-15Rα. However, delivery of these two IL-15 heterodimers in macaques failed to reveal any major differences in their pharmacokinetic and pharmacodynamic profile. In macaques, both IL-15 heterodimeric forms resulted in similar levels of plasma IL-15 and induced similar proliferation of NK, γδ and CD8+ T cells. Also, both IL-15 heterodimers were effective in reducing tumor burden in a colon carcinoma mouse model. These results provide important insights for the choice of IL-15 for clinical use, and suggest caution when interpreting data using IL-15/IL-15RαFc in mice.
- Copyright © 2013 by The American Association of Immunologists, Inc.