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BACKGROUND AND PURPOSE ) 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 APPROACHDISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor a (IL-15Ra) 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-15Ra, with or without DISC0280, and assessing changes in lymphocytic cell populations and serum cytokines was utilized. KEY RESULTSDISC0280 inhibited the binding of IL-15 to IL-15Ra and also potently inhibits IL-15 dependent proliferation of cells expressing IL-15Ra, shared interleukin 2/ interleukin 15 receptor b chain (IL-15Rb) and common gamma chain (gc). DISC0280 also inhibited the IL-15 dependent proliferation of M-07e cells that only express IL-15Rb/gc 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-15Ra. CONCLUSIONS AND IMPLICATIONSThe ability of DISC0280 to bind to the IL-15Ra-binding site on IL-15 allows trans-presentation of IL-15 by DISC0280 in vivo, similar to the trans-presentation by soluble IL-15Ra. DISC0280 may be therefore suitable as a clinical substitute for IL-15. Abbreviationsgc, common g chain; hIL-15, human IL-15; hIL-15/sIL-15Ra, pre-associated complex of human IL-15 and soluble IL-15Ra; IL-2, interleukin 2; (s)IL-15Ra, (soluble)interleukin 15 receptor a; IL-15Rb, shared interleukin 2/ interleukin 15 receptor b chain

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