Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells. (3rd July 2019)

• Record Type: Journal Article
• Authors: Ochoa, Maria C.; Perez-Ruiz, Elisabeth; Minute, Luna; Oñate, Carmen; Perez, Guiomar; Rodriguez, Inmaculada; Zabaleta, Aintzane; Alignani, Diego; Fernandez-Sendin, Myriam; Lopez, Ascension; Muntasell, Aura; Sanmamed, Miguel F.; Paiva, Bruno; Lopez-Botet, Miguel; Berraondo, Pedro; Melero, Ignacio
• Is Part Of: Oncoimmunology. Volume 8:Number 7(2019)
• Publication Date: 2019-07-03
• Subjects: NK cells -- ADCC -- multiple myeloma -- CD137 -- daratumumab; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2019.1599636
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: 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.