Oncotarget

Research Papers:

ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells

Arjan Kol, Anton Terwisscha van Scheltinga, Martin Pool, Christian Gerdes, Elisabeth de Vries and Steven de Jong _

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Oncotarget. 2017; 8:45432-45446. https://doi.org/10.18632/oncotarget.17139

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Abstract

Arjan Kol1, Anton Terwisscha van Scheltinga2, Martin Pool1, Christian Gerdes3, Elisabeth de Vries1, Steven de Jong1

1Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

2Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

3Roche Pharma Research & Early Development, Roche Innovation Center Zürich, Schlieren, Switzerland

Correspondence to:

Steven de Jong, email: [email protected]

Keywords: non-small cell lung cancer, EGFR, imgatuzumab, cetuximab, antibodies

Received: October 19, 2016    Accepted: March 30, 2017    Published: April 17, 2017

ABSTRACT

Imgatuzumab is a novel glycoengineered anti-epidermal growth factor receptor (EGFR) monoclonal antibody optimized to induce both antibody-dependent cellular cytotoxicity (ADCC) and EGFR signal transduction inhibition. We investigated anti-EGFR monoclonal antibodies imgatuzumab and cetuximab–induced internalization and membranous turnover of EGFR, and whether this affected imgatuzumab–mediated ADCC responses and growth inhibition of non-small cell lung cancer (NSCLC) cells.

In a panel of wild-type EGFR expressing human NSCLC cell lines, membranous and total EGFR levels were downregulated more effectively by imgatuzumab when compared with cetuximab. Imgatuzumab plus cetuximab enhanced EGFR internalization and reduced membranous turnover of EGFR, resulting in an even stronger downregulation of EGFR. Immunofluorescent analysis showed that combined treatment increased clustering of receptor-antibody complexes and directed internalized EGFR to lysosomes. The antibody combination potently inhibited intracellular signaling and epidermal growth factor (EGF)-dependent cell proliferation. More importantly, robust EGFR downregulation after 72 hours with the antibody combination did not impair ADCC responses.

In conclusion, imgatuzumab plus cetuximab leads to a strong downregulation of EGFR and superior cell growth inhibition in vitro without affecting antibody-induced ADCC responses. These findings support further clinical exploration of the antibody combination in EGFR wild-type NSCLC.


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