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Identification of a potent anti‐IL‐15 antibody with opposing mechanisms of action in vitro and in vivo
Author(s) -
Finch DK,
Midha A,
Buchanan CL,
Cochrane D,
Craggs RI,
Cruwys S,
Grahames C,
Kolbeck R,
Lowe DC,
Maltby J,
Pattison DV,
Vousden KA,
Ward A,
Sleeman MA,
Mallinder PR
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01061.x
Subject(s) - interleukin 15 , in vivo , cytokine , biology , monoclonal antibody , interleukin , receptor , interleukin 2 , cell culture , cd8 , cell growth , immunology , microbiology and biotechnology , antibody , chemistry , immune system , biochemistry , genetics
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 α (IL‐15Rα) 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‐15Rα, 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‐15Rα and also potently inhibits IL‐15 dependent proliferation of cells expressing IL‐15Rα, shared interleukin 2/ interleukin 15 receptor β chain (IL‐15Rβ) and common gamma chain (γ c ). DISC0280 also inhibited the IL‐15 dependent proliferation of M‐07e cells that only express IL‐15Rβ/γ 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‐15Rα. CONCLUSIONS AND IMPLICATIONS The ability of DISC0280 to bind to the IL‐15Rα‐binding site on IL‐15 allows trans‐presentation of IL‐15 by DISC0280 in vivo, similar to the trans‐presentation by soluble IL‐15Rα. DISC0280 may be therefore suitable as a clinical substitute for IL‐15.