The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia-Microenvironment Interactions in Chronic Lymphocytic Leukemia.

Abstract

<b>Purpose:</b> To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38⁺ chronic lymphocytic leukemia (CLL) subtype.<b>Experimental Design:</b> The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP), or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two <i>in vivo</i> models.<b>Results:</b> Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC <i>in vitro</i> and ADCP both <i>in vitro</i> and <i>in vivo</i> whereas exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38⁺ MEC2 cell line and CLL patient-derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs, and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated <i>in vitro</i> by its effect on CXCL12-induced migration and <i>in vivo</i> by interfering with CLL cell homing to spleen in NSG mice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by downregulation of the matrix metalloproteinase MMP9.<b>Conclusions:</b> These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL. <i>Clin Cancer Res; 23(6); 1493-505. ©2016 AACR</i>.