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

Autor:	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, Finch, D K, Buchanan, C L, Craggs, R I, Lowe, D C, Pattison, D V
Předmět:	INTERLEUKINS ANTI-antibodies BIOCHEMICAL mechanism of action LYMPHOCYTES CELL populations CELL proliferation INFLAMMATION CYTOKINES THERAPEUTIC use of monoclonal antibodies BINDING sites RESEARCH ANIMAL experimentation RESEARCH methodology CELL receptors MONOCLONAL antibodies IMMUNOLOGY technique CELL physiology MEDICAL cooperation EVALUATION research COMPARATIVE studies IMMUNITY T cells MICE CHEMICAL inhibitors
Zdroj:	British Journal of Pharmacology; Jan2011, Vol. 162 Issue 2, p480-490, 11p, 7 Graphs
Abstrakt:	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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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