<i>In vivo</i> Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling

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  • Simone de Haij
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • J.H. Marco Jansen
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Peter Boross
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Frank J. Beurskens
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Jantine E. Bakema
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Desiree L. Bos
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Anton Martens
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • J. Sjef Verbeek
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Paul W.H.I. Parren
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Jan G.J. van de Winkel
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • Jeanette H.W. Leusen
    Authors' Affiliations: 1Genmab; 2Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands and 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

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<jats:title>Abstract</jats:title> <jats:p>Antibody–Fc receptor (FcR) interactions play an important role in the mechanism of action of most therapeutic antibodies against cancer. Effector cell activation through FcR triggering may induce tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking of antibody may lead to the induction of apoptotic signaling in tumor cells. The relative importance of these bisecting pathways to in vivo antibody activity is unknown. To unravel these roles, we developed a novel mouse model with normal FcR expression but in which FcR signaling was inactivated by mutation of the associated γ-chain. Transgenic mice showed similar immune complex binding compared with wild-type mice. In contrast, ADCC of cells expressing frequently used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and rituximab, we show that FcR cross-linking of antibody-antigen immune complexes in the absence of γ-chain signaling is insufficient for their therapeutic activity in vivo. ADCC therefore represents an essential mechanism of action for immunotherapy of lymphoid tumors. Cancer Res; 70(8); 3209–17. ©2010 AACR.</jats:p>

Journal

  • Cancer Research

    Cancer Research 70 (8), 3209-3217, 2010-04-14

    American Association for Cancer Research (AACR)

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