In vivo Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling
| Autor: | Jantine E. Bakema, Paul W. H. I. Parren, Peter Boross, Frank J. Beurskens, J. H. Marco Jansen, Jeanette H. W. Leusen, Jan G. J. van de Winkel, Simone de Haij, Anton C.M. Martens, J. Sjef Verbeek, Desiree L Bos |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
medicine.drug_class medicine.medical_treatment Amino Acid Motifs Molecular Sequence Data Melanoma Experimental Fc receptor Apoptosis Mice Transgenic chemical and pharmacologic phenomena Receptors Fc Antibodies Monoclonal Humanized Monoclonal antibody Antibodies Antibodies Monoclonal Murine-Derived Mice medicine Animals Humans Amino Acid Sequence Epidermal growth factor receptor Antibody-dependent cell-mediated cytotoxicity Sequence Homology Amino Acid biology Antibodies Monoclonal Immunotherapy Antigens CD20 Immune complex ErbB Receptors Oncology Mutation Immunology biology.protein Cancer research Signal transduction Antibody Rituximab Signal Transduction |
| Zdroj: | Cancer Research. 70:3209-3217 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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