Abstract
Abstract One important manifestation of the plasticity of cancer is the rapid escape from the effect of anti-cancer agents following initial therapeutic response. ERBB3, a kinase inactive member of the epidermal growth factor (EGFR) receptor family, which also includes EGFR, HER-2 and ERBB-4, has been linked to the development of resistance to multiple cancer therapies. The reactivation of ERBB3 following treatments with EGFR or HER-2 inhibitors has been observed in multiple tumor types following initial responses. The reactivation of ERBB3 signaling is thought to be the consequence of the formation of kinase active heterodimers of ERBB3 with EGFR, HER-2 and c-Met. ERBB3 heterodimer formation is consequence of a conformational change in the ErbB3 ECD (extracellular domain) in response to increased presence of the ERBB3 ligand NRG (neuregulin) or increased membrane concentrations of ERBB3 partners or ERBB3 itself which is often due overexpression or increased membrane localization. To understand the role of NRG dependent and independent ERBB3 activation mechanisms in the development of resistance to EGFR and/or HER-2 inhibitors, we set out to identify a diverse set of ERBB3 specific inhibitory monoclonal antibodies with different mechanisms of action. Immunizations with a mixture of tethered and opened ERBB3 ECD antigens allowed us to identify a large variety of potent ERBB3 inhibitors. Competition binding experiments have identified at least 5 independent binding sites for these antibodies on ERBB3. Some of these antibodies inhibited NRG binding (ligand neutralizers) while others did not interfere with ligand binding. Since a few of these antibodies bound to the dimerization domain (domain II) of ERBB3, we have inferred that they most likely inhibit the formation of ERBB3 heterodimers (dimerization inhibitors). In vivo activity of these antibodies was tested in tumor models driven by ligand independent and dependent activation of ERBB3 to identify the most promising candidate for the development of a highly potent ERBB3 therapeutic antibody with superior activity against both ligand dependent and independent ERBB3 heterodimers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 628. doi:10.1158/1538-7445.AM2011-628
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