IgA EGFR antibodies mediate tumour killing in vivo

EMBO Molecular Medicine

Peter Boross¹  Stefan Lohse³  Maaike Nederend¹  Johannes Hendrik Marco Jansen¹  Geert van Tetering¹  Michael Dechant²  Matthias Peipp³  Louise Royle⁷  Li Phing Liew⁷  Louis Boon⁶  Nico van Rooijen⁴  Wim K. Bleeker⁵  Paul W. H. I. Parren⁵  Jan G. J. van de Winkel¹  Thomas Valerius³ 

[1] Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands;Department of Internal Medicine IV, Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany;Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University, Kiel, Germany;Department of Molecular Cell Biology, Vrije University Medical Center, Amsterdam, The Netherlands;Genmab, Utrecht, The Netherlands;Bioceros, Utrecht, The Netherlands;Ludger Ltd, Oxfordshire, United Kingdom

关键词: antibody therapy;    EGFR;    Fcalpha receptor I;    IgA;    tumour immunology;   

DOI  :  10.1002/emmm.201201929

来源: Wiley

【 摘 要 】

Abstract

Currently all approved anti-cancer therapeutic monoclonal antibodies (mAbs) are of the IgG isotype, which rely on Fcgamma receptors (FcγRs) to recruit cellular effector functions. In vitro studies showed that targeting of FcαRI (CD89) by bispecific antibodies (bsAbs) or recombinant IgA resulted in more effective elimination of tumour cells by myeloid effector cells than targeting of FcγR. Here we studied the in vivo anti-tumour activity of IgA EGFR antibodies generated using the variable sequences of the chimeric EGFR antibody cetuximab. Using FcαRI transgenic mice, we demonstrated significant in vivo anti-tumour activity of IgA2 EGFR against A431 cells in peritoneal and lung xenograft models, as well as against B16F10-EGFR cells in a lung metastasis model in immunocompetent mice. IgA2 EGFR was more effective than cetuximab in a short-term syngeneic peritoneal model using EGFR-transfected Ba/F3 target cells. The in vivo cytotoxic activity of IgA2 EGFR was mediated by macrophages and was significantly decreased in the absence of FcαRI. These results support the potential of targeting FcαRI for effective antibody therapy of cancer.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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