title: Reduction of complement factor H binding to CLL cells improves the induction of rituximab-mediated complement-dependent cytotoxicity.
abstract: A main effector mechanism of rituximab (RTX) is the induction of complement-dependent cytotoxicity (CDC). However, this effector function is limited, because CLL cells are protected from complement-induced damage by regulators of complement activation (RCAs). A prominent RCA in fluid phase is factor H (fH), which has not been investigated in this context yet. Here, we show that fH binds to CLL cells and that human recombinant fH-derived short-consensus repeat 18-20 (hSCR18-20) interferes with this binding. In complement-based lysis assays, CLL cells from therapy-naive patients were differently susceptible to RTX-induced CDC and were defined as CDC responder or CDC non-responder, respectively. In CDC responders, but notably also in non-responders, hSCR18-20 significantly boosted RTX-induced CDC. Killing of the cells was specific for CD20(+) cells, whereas CD20(-) cells were poorly affected. CDC resistance was independent of expression of the membrane-anchored RCAs CD55 and CD59, although blocking of these RCAs further boosted CDC. Thus, inhibition of fH binding by hSCR18-20 sensitizes CLL cells to CDC and may provide a novel strategy for improving RTX-containing immunochemotherapy of CLL patients.
authors.affiliation: Division of Virology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Hörl
authors.forename: Z
authors.initials: Z
authors.lastname: Bánki
authors.forename: G
authors.initials: G
authors.lastname: Huber
authors.forename: A
authors.initials: A
authors.lastname: Ejaz
authors.forename: D
authors.initials: D
authors.lastname: Windisch
authors.forename: B
authors.initials: B
authors.lastname: Muellauer
authors.forename: E
authors.initials: E
authors.lastname: Willenbacher
authors.forename: M
authors.initials: M
authors.lastname: Steurer
authors.forename: H
authors.initials: H
authors.lastname: Stoiber
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D003167:Complement Activation / Q000276:immunology*; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000069283:Rituximab; D014407:Tumor Cells, Cultured
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C493495:CFH protein, human; D011994:Recombinant Proteins; D000069283:Rituximab; D017242:Complement Factor H