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* Division of Nephrology, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany;
Section for Stem Cell Transplantation and Immunotherapy, University Schleswig-Holstein, Campus Kiel, Kiel, Germany;
Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, The Netherlands; and
Genmab, Utrecht, The Netherlands
IgA is the most abundantly produced Ab isotype in humans, but its potential as immunotherapeutic reagent has hardly been explored. In this study, we describe anti-tumor mechanisms of mouse/human chimeric IgA Abs against the epidermal growth factor receptor (EGF-R). EGF-R Abs of IgG isotype are currently approved for the treatment of colon or head and neck cancers. As expected, the human IgG1, IgA1, and IgA2 variants of the 225 Ab demonstrated similar binding to EGF-R. Furthermore, IgA Abs were as effective as IgG in mediating direct effector mechanisms such as blockade of EGF binding, inhibition of EGF-R phosphorylation, and induction of growth inhibition. None of the three variants induced complement-mediated lysis. Human IgG1 effectively recruited MNC for ADCC, but activated PMN only weakly, whereas both IgA isoforms proved to be effective in triggering neutrophils. Interestingly, the IgA2 isoform was significantly superior to its IgA1 counterpart in recruiting PMN as effector cells. Because neutrophils constitute the most abundant effector cell population in human blood, this enhanced neutrophil recruitment lead to increased killing of EGF-R expressing tumor cells in whole blood assays. This killing was further enhanced when blood from G-CSF-primed donors was compared with healthy donor blood. Together, these data suggest EGF-R Abs of human IgA isotype to bear promise for therapeutic use in cancer.
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 grants from the Deutsche Forschungsgemeinschaft (Va124/6–3 and De1478/1–1) and by intramural grants from the University of Schleswig-Holstein, Campus Kiel (Kiel, Germany).
2 M.D. and T.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Thomas Valerius, Division of Nephrology, University of Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, Kiel, Germany. E-mail address: valerius{at}nephro.uni-kiel.de
4 Abbreviations used in this paper used in this paper: EGF-R, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; CDC, complement-dependent cell lysis; PMN, polymorphonuclear cell; ADCC, Ab-dependent cellular cytotoxicity; mIL-3, murine IL-3; MNC, mononuclear cells; RFI, relative fluorescence intensity; E:T, effector-to-target; CI, confidence interval.
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