Abstract 2509: AV-203, a humanized ERBB3 inhibitory antibody inhibits ligand-dependent and ligand-independent ERBB3 signaling in vitro and in vivo
Authors: Vincent Sylvie , Fleet Christina , Bottega Steven , McIntosh Donna , Winston William , Chen Ting , Tyler Steven , Meetze Kristan , Weiler Solly , Gyuris Jeno 
Published: August 2012

Abstract
ERBB3 is a member of the EGFR receptor tyrosine kinase (RTK) family. Agents targeting the family of EGFR RTKs have become widely used for the treatment of lung, colon, breast, gastric, and head and neck cancers. Among EGFR family members, ERBB3 is of special interest because of its ability to activate the survival pathway driven by PI3K, its essential role in HER2 mediated cancers, and its involvement in tumor progression and drug resistance. The ERBB3 receptor is expressed on cells from cancers of the head and neck, lung, breast, ovaries, prostate, colon, pancreas, and gastrointestinal tract. Its expression is often linked to poor prognosis. In addition, it has been implicated in the development of resistance to current anti-cancer agents including receptor-targeted tyrosine kinase inhibitors (TKI). ERBB3 lacks detectable tyrosine kinase activity and its activation requires the heterodimerization of ERBB3 with RTK partners, i.e., HER2, EGFR or MET. ERBB3 recruitment in heterodimer complexes takes place when RTKs are overexpressed or amplified or stimulated by ligands, i.e. Neuregulin-1 (NRG1) or epidermal growth factor (EGF). Because of the lack of ERBB3 kinase activity, antibody therapies directed against the extracellular domain of ERBB3 seem to be the most effective method to disrupt the function of ERBB3. Herein, characterization of AV-203, a humanized ERBB3 inhibitory antibody, is presented. AV-203 is a humanized immunoglobulin G1/kappa antibody that targets the ERBB3 RTK. AV-203 binds to human ERBB3 with high affinity (KD = 76 pM at 37°C) characterized by fast association and slow dissociation rates. AV-203 also binds to cynomolgus monkey ERBB3 but not to mouse ERBB3, allowing toxicological assessment of the antibody in this species. AV-203 is a potent inhibitor of ERBB3 activation and its downstream signaling molecule AKT in response to both ligands, NRG1 and EGF. In ligand-independent settings, AV-203 inhibits the steady state activation of ERBB3/AKT which depends on the presence of an overexpressed RTK such as HER2. AV-203 can prevent the ERBB3/HER2 heterodimer formation and completely inhibit the proliferation in response to NRG1 ligand in human breast cancer cell line, MCF7. AV-203 down regulates ERBB3 receptor in vitro and in vivo. Finally, AV-203 inhibits tumor growth in a broad spectrum of xenograft models in which ERRB3 is activated by its ligand NRG1 or by HER2 overexpression such as the pancreatic cancer BxPC3 or the HER2 amplified breast cancer MDA-MB-453 xenograft models, respectively. In conclusion, AV-203 demonstrated high affinity binding to ERBB3, potent inhibition of NRG1 binding and of ERBB3 activation in ligand-dependent and ligand-independent manners both in vitro and in vivo. First in human trial of AV-203 in cancer patients is planned for 2012.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2509. doi:1538-7445.AM2012-2509