title: The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia-Microenvironment Interactions in Chronic Lymphocytic Leukemia.
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 twoin vivomodels.Results:Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCCin vitroand ADCP bothin vitroandin vivowhereas 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 demonstratedin vitroby its effect on CXCL12-induced migration andin vivoby 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.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Matas-Céspedes
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Vidal-Crespo
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Vanina
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Department of Hematology, Hospital Clínic, Barcelona, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Department of Hematology, Hospital Clínic, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Giné
authors.affiliation: Josep Carreras Leukaemia Research Institute, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
authors.forename: Heleia
authors.initials: H
authors.lastname: Roca-Ho
authors.affiliation: Josep Carreras Leukaemia Research Institute, Department of Biomedicine, University of Barcelona, Barcelona, Spain.|Institució Catalana de Recerca i Estadis Avançats (ICREA), Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menéndez
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Department of Hematology, Hospital Clínic, Barcelona, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.affiliation: Genmab, Utrecht, the Netherlands.|Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.|Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.affiliation: Janssen R&D, Spring House, Pennsylvania.
authors.forename: Parul
authors.initials: P
authors.lastname: Doshi
authors.affiliation: Genmab, Utrecht, the Netherlands.
authors.forename: Jeroen Lammerts
authors.initials: JL
authors.lastname: van Bueren
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. pperez@clinic.ub.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D057899:Cytophagocytosis / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C556306:daratumumab; D051997:ADP-ribosyl Cyclase 1; D020780:Matrix Metalloproteinase 9