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Experimental Antibody Therapy of Liver Metastases Reveals Functional Redundancy between FcRI and FcRIV¹

Marielle A. Otten^*,, Gerben J. van der Bij^,, Sjef J. Verbeek, Falk Nimmerjahn^¶, Jeffrey V. Ravetch^||, Robert H. J. Beelen, Jan G. J. van de Winkel^*,# and Marjolein van Egmond^2,,

^* Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, Amsterdam, Department of Surgical Oncology, Vrije University Medical Center, Amsterdam, and Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; ^¶ Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nürnberg, Germany; ^|| Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065; and ^# Genmab, Utrecht, The Netherlands

Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery—although mandatory—paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR -chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory FcR was necessary for successful therapy. TA99-treatment was still effective in FcRI^–/–, FcRIII^–/–, FcRI/III^–/–, and FcRI/II/III^–/– mice, suggesting an important role for FcRIV. However, wild-type mice that were treated with TA99 Abs and an FcRIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both FcRI and FcRIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Dutch Cancer Society (UU2001-2431).

² Address correspondence and reprint requests to Dr. Marjolein van Egmond, Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail address: m.vanegmond{at}vumc.nl

³ Abbreviations used in this paper: ADCC, Ab-dependent cellular cytotoxicity; KO, knockout.