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Targeted Antireceptor Therapy with Monoclonal Antibodies Leads to the Formation of Inactivated Tetrameric Forms of ErbB Receptors¹

Keiji Furuuchi^*, Alan Berezov^*, Toru Kumagai^*, and Mark I. Greene^2,*

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, PA 19104; and Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

mAbs capable of disabling heterodimeric kinase complexes of the epidermal growth factor receptor (EGFR) and human EGFR type 2/neu have therapeutic relevance to various human cancers. In this study, we demonstrate that in addition to the dimer, EGFR and human EGFR type 2 can associate as homo- and heterotetramers. EGF-induced phosphorylation of the tetramers was significantly lower than that of the dimers, indicating that the tetrameric receptor complexes have impaired signaling activity. Targeting v-erb-b2 erythroblastic leukemia viral oncogene homolog (erbB) receptors with mAbs promoted erbB tetrameric assembly, suggesting that a component of the antitumor activity may be mediated by the ability of Abs to shift the equilibrium from active dimeric to impaired tetrameric receptor complex states. This study suggests a novel therapeutic approach to disable signaling of erbB and potentially other receptors in tumors by biologic agents capable of inducing receptor tetramerization.

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 National Cancer Institute, the Susan Komen Foundation, the U.S. Army, and the Abramson Family Cancer Center (to M.I.G.).

² Address correspondence and reprint requests to Dr. Mark I. Greene, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, 36th Hamilton Walk, John Morgan Building, Room 252, Philadelphia, PA 19104. E-mail address: greene{at}reo.med.upenn.edu

³ Abbreviations used in this paper: erbB, v-erb-b2 erythroblastic leukemia viral oncogene homolog; EGFR, epidermal growth factor receptor; HER2, human EGFR type 2; VSVG, vesticular stomatitis virus glycoprotein; IB, immunoblotting; IP, immunoprecipitation; AHNP, anti-HER2 peptide; Sbd, subdomain.

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