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.The study reveals that IgA antibodies directed against EGFR and engaging Fcalpha receptor (FcαRI) on effector cells, have in vivo anti-cancer activity. These data support the development of novel immunotherapeutic strategies based on targeting FcαRI.
Highlights
Therapeutic monoclonal antibodies are successfully used in the clinic to treat various malignancies
IgA epidermal growth factor receptor (EGFR) antibodies mediate tumour cell killing by mouse effector cells ex vivo To assess the anti‐tumour activity of IgA antibodies we previously generated IgA1 and IgA2 variants of the human IgG1 EGFR antibody cetuximab (c225; Dechant et al, 2007; Lohse et al, 2011)
Isolated CD14‐positive monocytes did not induce tumour lysis in a 4 h assay (Supporting Information Fig S1B). These results show that polymorphonuclear granulocytes (PMNs) are the only blood‐resident effector cells that mediate IgA EGFR activity in 4 h assays
Summary
Therapeutic monoclonal antibodies (mAbs) are successfully used in the clinic to treat various malignancies. Cetuximab and panitumumab are antibodies that target the epidermal growth factor receptor (EGFR) and are currently part of standard regimens against metastatic colorectal cancer with wild‐type (WT) K‐Ras. Cetuximab is approved by the FDA against head and neck cancer (Kim, 2009). Cetuximab (1) Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands (2) Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University, Kiel, Germany (3) Department of Internal Medicine IV, Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany (4) Ludger Ltd, Oxfordshire, United Kingdom (5) Bioceros, Utrecht, The Netherlands (6) Department of Molecular Cell Biology, Vrije University Medical Center, Currently, all antibodies approved for human treatment are of the IgG isotype, owing to their long half‐life in serum and ß 2013 The Authors.
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