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

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.

• Authors: Arjan Kol, Anton Terwisscha van Scheltinga, Martin Pool, Christian Gerdes, Elisabeth de Vries, Steven de Jong
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 28 Pg. 45432-45446 (Jul 11 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28467975 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Immunological
• ErbB Receptors
• Cetuximab

Topics

• Antibody-Dependent Cell Cytotoxicity (drug effects, immunology)
• Antineoplastic Agents, Immunological (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, immunology, metabolism, pathology)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Proliferation (drug effects)
• Cetuximab (pharmacology)
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Gene Expression
• Humans
• Lung Neoplasms (drug therapy, immunology, metabolism, pathology)
• Lysosomes (metabolism)
• Protein Binding
• Protein Transport
• Proteolysis
• Signal Transduction (drug effects)