Muntasell, A. (Aura)

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    Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocytedeficient mice reconstituted with human NK cells
    (Informa UK Limited, 2019) Berraondo, P. (Pedro); Zabaleta, A. (Aintzane); Fernández-Sendín, M. (Myriam); López-Botet, M. (Miguel); Perez-Ruiz, E. (Elisabeth); Rodriguez, I. (Inmaculada); Muntasell, A. (Aura); Oñate, C. (Carmen); Lopez, A. (Ascensión); Ochoa, M.C. (María Carmen); Alignani, D. (Diego); Melero, I. (Ignacio); Paiva, B. (Bruno); Perez, G. (Guiomar); Minute, L. (Luna); Fernandez-Sanmamed, M. (Miguel)
    Daratumumab is an anti-CD38 fully human IgG1 mAb approved for multiple myeloma treatment. One of the proposed mechanisms of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells. NK cells acquire surface CD137 expression in the presence of solid-phase-attached daratumumab and when encountering a daratumumab-coated CD38+ tumor cell line. In this setting, addition of the agonist anti-CD137 mAb urelumab enhances NK-cell activation increasing CD25 expression and IFNɣ production. However, in vitro ADCC is not increased by the addition of urelumab both in 4h or 24h lasting experiments. To study urelumab-increased daratumumab-mediated ADCC activity in vivo, we set up a mouse model based on the intravenous administration of a luciferase-transfected multiple myeloma cell line of human origin, human NK cells and daratumumab to immuno-deficient NSG mice. In this model, intravenous administration of urelumab 24h after daratumumab delayed tumor growth and prolonged mice survival.