Abstract 2718: REGN1400, a fully-human ERBB3 antibody, potently inhibits tumor growth in preclinical models, both as a monotherapy and in combination with EGFR or HER2 blockers

Abstract

Abstract ERBB3 is a member of the ERBB family of receptor tyrosine kinases, that includes EGFR and HER2, well-established drivers of tumorigenesis. Recent preclinical studies indicate that both EGFR and HER2 cooperate with ERBB3 to activate the phosphatidylinositol-3 kinase/Akt survival pathway and to promote tumor cell survival. Furthermore, ERBB3 activation has been demonstrated to mediate resistance to EGFR inhibitors in non-small cell lung cancer cell lines and to HER2 inhibitors in breast cancer cell lines. Consistent with these findings, anti-ERBB3 monoclonal antibodies have been shown to inhibit the growth of human tumor xenografts, demonstrating the importance of ERBB3 for tumor growth in vivo. REGN1400 is a fully-human anti-ERBB3 monoclonal antibody that binds human ERBB3 with high affinity (KD ∼50pM) and potently inhibits binding of the ERBB3 ligand neuregulin 1 (IC50 ∼30pM). REGN1400 inhibited phosphorylation of ERBB3 and Akt in multiple human tumor cell lines in vitro, including A431 (epidermoid carcinoma), MDA-MB-175-VII (breast cancer) and FaDu (head and neck cancer). In addition, REGN1400 strongly inhibited the growth of these cell lines in vitro. Consistent with its potent effects on tumor cell growth in vitro, REGN1400 strongly inhibited the growth of A431 and FaDu tumor xenografts in a dose-dependent manner, providing 70% and 97% tumor growth inhibition, respectively. Inhibition of FaDu tumor growth by REGN1400 was accompanied by a significant decrease in tumor ERBB3 phosphorylation, as assessed by both western blot and immunohistochemistry, confirming target inhibition in vivo. While treatment of FaDu tumors with single agent REGN1400 provided almost complete tumor growth inhibition, but not regression, the combination of REGN1400 plus anti-EGFR antibody caused significant tumor regression. Furthermore, combination treatment with REGN1400 plus the anti-HER2 antibody trastuzumab inhibited the growth of BT474 breast tumor xenografts more potently than either single agent. These findings indicate that ERBB3-directed therapies might be more effective when combined with agents that inhibit other ERBB family members. Finally, gene profiling studies in REGN1400-treated tumor cells revealed upregulation of several genes that could promote resistance to REGN1400, e.g., ERBB3 itself and ERBB4. Further analysis of tumor gene expression changes induced by REGN1400 could provide insight into potentially useful combination regimens. In summary, REGN1400, a novel anti-ERBB3 antibody, exhibits significant antitumor activity in preclinical models, suggesting the possibility that it could provide benefit to patients with multiple types of cancer, either as a single agent or when combined with therapies targeting other ERBB family members. 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 2718. doi:1538-7445.AM2012-2718