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posted on 2023-03-31, 18:26 authored by Alba Matas-Céspedes, Anna Vidal-Crespo, Vanina Rodriguez, Neus Villamor, Julio Delgado, Eva Giné, Heleia Roca-Ho, Pablo Menéndez, Elías Campo, Armando López-Guillermo, Dolors Colomer, Gaël Roué, Adrian Wiestner, Paul W.H.I. Parren, Parul Doshi, Jeroen Lammerts van Bueren, Patricia Pérez-Galán Figure S1. Effect of CRPs blockade on daratumumab-induced CDC. Daudi and CLL cells were labeled with Calcein-AM (1μM) and challenged to CDC induction by daratumumab (DARA), rituximab (RITUX), ofatumumab (OFA) or isotype control, all of them at 10μg/mL, in the presence of 10% Normal Human Serum (NHS).
Funding
Genmab and Janssen pharmaceuticals
Spanish Ministry of Economy and Competitivity
Instituto de Salud Carlos III
Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF)
History
ARTICLE ABSTRACT
Purpose: 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.Experimental Design: 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 in vivo models.Results: Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo 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 in vitro by its effect on CXCL12-induced migration and in vivo 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.Conclusions: These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL. Clin Cancer Res; 23(6); 1493–505. ©2016 AACR.
