Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells
Maria C Ochoa, Elisabeth Perez-Ruiz, Luna Minute, Carmen Oñate, Guiomar Perez, Inmaculada Rodriguez, Aintzane Zabaleta, Diego Alignani, Myriam Fernandez-Sendin, Ascension Lopez, Aura Muntasell, Miguel F Sanmamed, Bruno Paiva, Miguel Lopez-Botet, Pedro Berraondo, Ignacio Melero
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.
CITATION Oncoimmunology. 2019 Apr 13;8(7):1599636. doi: 10.1080/2162402X.2019.1599636. eCollection 2019.