Abstract 1228: AV-203, a fully humanized ERBB3 inhibitory antibody, reverses ERBB3-induced resistance to targeted therapies.

Abstract

Abstract Targeted therapies have changed the treatment paradigm of cancer. Specifically, the use of tyrosine kinase inhibitors (TKIs) has improved therapeutic responses in a number of tumor types. However, initial response to TKIs is often followed by rapid relapse due to the acquisition of molecular features that lead to resistance. ERBB3, a receptor of the epidermal growth factor receptor (EGFR/ERBB1) family, has been linked to the development of resistance to multiple ERBB targeting TKIs. A proposed potential mechanism is the recruitment and activation of ERBB3 as a bypass mechanism to activate PI3K dependent pro-survival pathways. We investigated whether the inhibition of ERBB3 could reverse TKI resistance linked to ERBB3 activation. AV-203 is a humanized IgG1 antibody directed against ERBB3. AV-203 potently inhibits both ligand dependent and ligand independent activation of ERBB3. AV-203 was shown to inhibit the binding of NRG1 to ERBB3 and promote ERBB3 degradation. The tumor growth inhibitory activity of AV-203 was demonstrated in numerous xenograft models representing major human carcinomas (breast, lung, ovarian, kidney and pancreas). Here, we investigated the ability of AV-203 to restore TKI sensitivity in models with activated ERBB3. First, we demonstrated that ligand mediated (NRG1) activation of ERBB3 leads to acquired resistance to the EGFR TKI erlotinib in a lung cancer model bearing EGFR TKI sensitizing mutation, to the ERBB2/HER2 inhibitor lapatinib in a HER2 amplified breast cancer model, and to the EGFR inhibitory antibody cetuximab in head and neck cancer models. AV-203 was able to restore sensitivity to these RTK inhibitors. This data suggest that the combination of AV-203, with EGFR/HER2 targeted therapies could potentially extend the efficacy of these agents by preventing the emergence of ERBB3 mediated resistance. This hypothesis will be tested in future clinical trials. AV-203 is currently in Phase I development for the treatment of solid tumors. Citation Format: Steven M. Tyler, Sylvie Vincent, Christina Fleet, Steve Bottega, Donna McIntosh, Kristan Meetze, Jeno Gyuris. AV-203, a fully humanized ERBB3 inhibitory antibody, reverses ERBB3-induced resistance to targeted therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2013-1228