title: Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing.
abstract: Efficacy of anticancer monoclonal antibodies (mAb) is limited by the exhaustion of effector mechanisms. IgG mAbs mediate cellular effector functions through FcγRs expressed on effector cells. IgA mAbs can also induce efficient tumor killing both in vitro and in vivo. IgA mAbs recruit FcαRI-expressing effector cells and therefore initiate different effector mechanisms in vivo compared with IgG. Here, we studied killing of tumor cells coexpressing EGFR and HER2 by the IgG mAbs cetuximab and trastuzumab and their IgA variants. In the presence of a heterogeneous population of effector cells (leukocytes), the combination of IgG and IgA mAbs to two different tumor targets (EGFR and HER2) led to enhanced cytotoxicity compared with each isotype alone. Combination of two IgGs or two IgAs or IgG and IgA against the same target did not enhance cytotoxicity. Increased cytotoxicity relied on the presence of both the peripheral blood mononuclear cell and the polymorphonuclear (PMN) fraction. Purified natural killer cells were only cytotoxic with IgG, whereas cytotoxicity induced by PMNs was strong with IgA and poor with IgG. Monocytes, which coexpress FcγRs and FcαRI, also displayed increased cytotoxicity by the combination of IgG and IgA in an overnight killing assay. Coinjection of cetuximab and IgA2-HER2 resulted in increased antitumor effects compared with either mAb alone in a xenograft model with A431-luc2-HER2 cells. Thus, the combination of IgG and IgA isotypes optimally mobilizes cellular effectors for cytotoxicity, representing a promising novel strategy to improve mAb therapy.
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Arianne M
authors.initials: AM
authors.lastname: Brandsma
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Toine
authors.initials: T
authors.lastname: Ten Broeke
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Nederend
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Laura A P M
authors.initials: LA
authors.lastname: Meulenbroek
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: van Tetering
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: J H Marco
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: M Alejandra
authors.initials: MA
authors.lastname: Beltrán Buitrago
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, the Netherlands.
authors.forename: Sietse Q
authors.initials: SQ
authors.lastname: Nagelkerke
authors.affiliation: Developmental Drug Metabolism and Pharmacokinetics, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Németh
authors.affiliation: Synthon Biopharmaceuticals B.V., Nijmegen, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Ubink
authors.affiliation: Synthon Biopharmaceuticals B.V., Nijmegen, the Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Rouwendal
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lohse
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands. jleusen@umcutrecht.nl.
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000276:immunology / Q000494:pharmacology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D011961:Receptors, Fc / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D000068878:Trastuzumab / Q000276:immunology / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D017452:Receptors, IgG; D000068878:Trastuzumab; C036832:Fc(alpha) receptor; C512478:EGFR protein, human; C508053:ERBB2 protein, human