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Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells

2019; Landes Bioscience; Volume: 8; Issue: 7 Linguagem: Inglês

10.1080/2162402x.2019.1599636

2162-402X

María C. Ochoa, Elisabeth Pérez-Ruíz, Luna Minute, Carmen Oñate, Guiomar Pérez, Inmaculada Rodríguez, Aintzane Zabaleta, Diego Alignani, Myriam Fernandez-Sendín, Ascensión López, Aura Muntasell, Miguel F. Sanmamed, Bruno Paiva, Miguel López‐Botet, Pedro Berraondo, Ignacio Melero,

T-cell and B-cell Immunology

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.