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Inhibitory Fc receptors modulatein vivo cytoxicity against tumor targets
Nature Medicinevolume 6, pages443–446 (2000)Cite this article
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Abstract
Inhibitory receptors have been proposed to modulate thein vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways1. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcγRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicityin vivo, modulating the activity of FcγRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcγ receptors on effector cells is a dominant component of thein vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin®) and rituximab (Rituxan®), engaged both activation (FcγRIII) and inhibitory (FcγRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcγRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growthin vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB.
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Acknowledgements
We thank D. White for his technical expertise, C. Ritter for her administrative assistance and R. Steinman and M. Nussenzweig for their comments on the manuscript. These studies were supported by grants from the National Institutes of Health, Cancer Research Institute and Genentech.
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Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Ave, New York , 10021, New York, USA
Raphael A. Clynes, Terri L. Towers & Jeffrey V. Ravetch
Dept. of Immunology, Genentech, 1 DNA Way, South San Francisco, 94080 , California, USA
Leonard G. Presta
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Correspondence toJeffrey V. Ravetch.
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Clynes, R., Towers, T., Presta, L.et al. Inhibitory Fc receptors modulatein vivo cytoxicity against tumor targets.Nat Med6, 443–446 (2000). https://doi.org/10.1038/74704
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