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Nimotuzumab, an Antitumor Antibody that Targets the Epidermal Growth Factor Receptor, Blocks Ligand Binding while Permitting the Active Receptor Conformation

¹ Center of Molecular Immunology, Havana, Cuba; ² Department of Chemistry, University of Oslo, Oslo, Norway; and ³ Center for Molecular and Behavioral Neuroscience, Institute of Medical Microbiology, University of Oslo, Rikshospitalet HF, Oslo, Norway; ⁴ Department of Chemistry, University of York, Heslington, York, United Kingdom; and ⁵ Center for Genetic Engineering and Biotechnology, Havana, Cuba

Requests for reprints: Ute Krengel, University of Oslo, Department of Chemistry, P.O. Box 1033 Blindern, Oslo, NO-0315, Norway. E-mail: ute.krengel{at}kjemi.uio.no and Ernesto Moreno, Center of Molecular Immunology, P.O. Box 16040, Playa, Havana, 11600 Cuba. Phone: 53-7-2717933; Fax: 53-7-2720644; E-mail: emoreno{at}cim.sld.cu.

Key Words: Nimotuzumab/h-R3 • EGFR • antitumor antibody • X-ray crystal structure • protein-protein docking • molecular dynamics

Overexpression of the epidermal growth factor (EGF) receptor (EGFR) in cancer cells correlates with tumor malignancy and poor prognosis for cancer patients. For this reason, the EGFR has become one of the main targets of anticancer therapies. Structural data obtained in the last few years have revealed the molecular mechanism for ligand-induced EGFR dimerization and subsequent signal transduction, and also how this signal is blocked by either monoclonal antibodies or small molecules. Nimotuzumab (also known as h-R3) is a humanized antibody that targets the EGFR and has been successful in the clinics. In this work, we report the crystal structure of the Fab fragment of Nimotuzumab, revealing some unique structural features in the heavy variable domain. Furthermore, competition assays show that Nimotuzumab binds to domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by Cetuximab (another anti-EGFR antibody) and the binding site for EGF. A computer model of the Nimotuzumab-EGFR complex, constructed by docking and molecular dynamics simulations and supported by mutagenesis studies, unveils a novel mechanism of action, with Nimotuzumab blocking EGF binding while still allowing the receptor to adopt its active conformation, hence warranting a basal level of signaling. [Cancer Res 2009;69(14):5851–9]

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				Correction: Article on Nimotuzumab Blocks the EGFR by a Novel Mechanism Cancer Res., August 15, 2009; 69(16): 6758 - 6758. [Full Text] [PDF]