title: Complement-dependent cytotoxicity induced by therapeutic antibodies in B-cell acute lymphoblastic leukemia is dictated by target antigen expression levels and augmented by loss of membrane-bound complement inhibitors.
abstract: To optimally utilize therapeutic monoclonal antibodies in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) understanding their mechanisms of action and the factors influencing these mechanisms is required. We show strong correlations between target antigen expression levels and sensitivity to complement-dependent cytotoxicity (CDC) induced by rituximab, ofatumumab, or alemtuzumab in a panel of cell lines derived from primary B-ALL cells and in primary B-ALL samples. Simultaneous loss of expression of membrane-bound complement regulatory proteins (mCRP) CD55 and CD59 due to glycophosphatidylinositol-anchor deficiency, significantly increased sensitivity to CDC. Accordingly, induced increase in CD55 or CD59 expression protected cells against CDC. The extent of protection co-depended on antigen expression and antibody concentration. In contrast, natural variation in mCRP expression could not be used as a single factor to predict sensitivity to CDC. In conclusion, sensitivity of B-ALL cells to CDC was predominantly determined by antibody concentration and target antigen expression.
authors.affiliation: a Department of Hematology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Floris C
authors.initials: FC
authors.lastname: Loeff
authors.affiliation: a Department of Hematology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: H M Esther
authors.initials: HME
authors.lastname: van Egmond
authors.affiliation: a Department of Hematology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Nijmeijer
authors.affiliation: a Department of Hematology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: J H Frederik
authors.initials: JHF
authors.lastname: Falkenburg
authors.affiliation: a Department of Hematology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Constantijn J
authors.initials: CJ
authors.lastname: Halkes
authors.affiliation: a Department of Hematology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D015415:Biomarkers; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015415:Biomarkers; D018958:CD55 Antigens; D018957:CD59 Antigens; D003165:Complement System Proteins
keywords: B-cell acute lymphoblastic leukemia; CD55; CD59; Complement-dependent cytotoxicity; antibody therapy; membrane-bound complement regulatory proteins