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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Valerius, T. Articles by G.J. van de Winkel, J. Search for Related Content PubMed PubMed Citation Articles by Valerius, T. Articles by G.J. van de Winkel, J. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  FcRI (CD89) as a Novel Trigger Molecule for Bispecific Antibody Therapy Thomas Valerius, Bernhard Stockmeyer, Annemiek B. van Spriel, Robert F. Graziano, Ingrid E. van den Herik-Oudijk, Roland Repp, Yashwant M. Deo, John Lund, Joachim R. Kalden, Martin Gramatzki, and Jan G.J. van de Winkel From the Department of Medicine III, University of Erlangen, Nürnberg, Germany; Medarex, Annandale, NJ; Medarex Europe, Utrecht, The Netherlands; the Department of Immunology, University of Birmingham, Birmingham, UK; and the Department of Immunology, University Hospital Utrecht, Utrecht, The Netherlands. Promising results from clinical trials with unconjugated antibodies stimulated renewed interest in immune effector mechanisms of monoclonal antibodies (MoAbs). We investigated the potential of IgA as antibody isotype for cell- or complement-mediated tumor cell lysis and assessed the potential of its myeloid Fc receptor, FcRI (CD89), as trigger molecule for bispecific antibody (BsAb)-mediated immunotherapy. Comparing hapten-directed antibodies of human IgA2 with IgG1 or IgG3 isotypes, we found all three to mediate effective killing of sensitized tumor target cells in whole blood assays. Analysis of effector mechanisms showed IgG-mediated lysis to be predominantly complement-dependent, whereas IgA-dependent killing was primarily effector cell-mediated. A comparison of effector cell populations in antibody-dependent cell-mediated cytotoxicity (ADCC) showed neutrophils to be most important for IgA-dependent tumor cell killing, involving FcRI as shown with Fc receptor blocking antibodies. Reverse ADCC experiments against target cells sensitized with Fc receptor antibodies, or assays with FcRI-directed bispecific antibodies confirmed FcRI as effective trigger molecule in polymorphonuclear neutrophil (PMN)-mediated lysis. During granulocyte colony-stimulating factor (G-CSF ) therapy, (FcRI × HER-2/neu) bispecific antibodies induced enhanced killing of HER-2/neu positive SK-BR-3 breast cancer cells in whole blood assays. This enhanced cytotoxicity was paralleled by increased PMN counts, which lead to higher effector to target cell ratios in G-CSF-primed blood. Furthermore, bispecific antibodies, directed to FcRI and Candida albicans, enhanced neutrophils' phagocytosis of fungi. In summary, these results identify IgA as an effective antibody isotype for immunotherapy, working primarily via FcRI on neutrophils. They suggest FcRI-directed bispecific antibodies and G-CSF to be an attractive combination for malignant or infectious diseases. Blood, Vol. 90 No. 11 (December 1), 1997: pp. 4485-4492 © 1997 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Dechant, T. Beyer, T. Schneider-Merck, W. Weisner, M. Peipp, J. G. J. van de Winkel, and T. Valerius Effector Mechanisms of Recombinant IgA Antibodies against Epidermal Growth Factor Receptor J. Immunol., September 1, 2007; 179(5): 2936 - 2943. [Abstract] [Full Text] [PDF] H. Horner, C. Frank, C. Dechant, R. Repp, M. Glennie, M. Herrmann, and B. 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