title: Targeted antireceptor therapy with monoclonal antibodies leads to the formation of inactivated tetrameric forms of ErbB receptors.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, 36th Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Keiji
authors.initials: K
authors.lastname: Furuuchi
authors.forename: Alan
authors.initials: A
authors.lastname: Berezov
authors.forename: Toru
authors.initials: T
authors.lastname: Kumagai
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002384:Catalysis; D002460:Cell Line; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008970:Molecular Weight; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases