Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo

BACKGROUND AND PURPOSE Interleukin-15 (IL-15) is important in the activation and proliferation of lymphocytic cell populations and is implicated in inflammatory disease. We report the characterization of a novel monoclonal antibody DISC0280 which is specific for human IL-15. EXPERIMENTAL APPROACH DISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor alpha (IL-15R alpha) and by its ability to alter IL-15 mediated proliferation of a range of cell lines (cytotoxic T lymphocyte line-2, M-07e, KIT225). A pharmacodynamic model injecting male C57/BL6 mice with IL-15 or IL-15/IL-15R alpha, with or without DISC0280, and assessing changes in lymphocytic cell populations and serum cytokines was utilized. KEY RESULTS DISC0280 inhibited the binding of IL-15 to IL-15R alpha and also potently inhibits IL-15 dependent proliferation of cells expressing IL-15R alpha, shared interleukin 2/ interleukin 15 receptor beta chain (IL-15R beta) and common gamma chain (gamma(c)). DISC0280 also inhibited the IL-15 dependent proliferation of M-07e cells that only express IL-15R beta/gamma(c) subunits. Human IL-15 injected into mice caused an increase in NK1.1+ and CD3+ cells in the spleen and peripheral blood and these effects were unexpectedly potentiated by giving DISC0280 with human IL-15. This increase in cells caused by DISC0280/IL-15 co-administration was greater than that observed when IL-15 was administered complexed with soluble IL-15R alpha. CONCLUSIONS AND IMPLICATIONS The ability of DISC0280 to bind to the IL-15R alpha-binding site on IL-15 allows trans-presentation of IL-15 by DISC0280 in vivo, similar to the trans-presentation by soluble IL-15R alpha. DISC0280 may be therefore suitable as a clinical substitute for IL-15.