Abstract 2668: RG7116, a novel humanized anti-HER3 antibody with superior preclinical in vitro and in vivo efficacy in combination with, everolimus and other anti-cancer agents

Abstract

Abstract HER3 is a member of the Human Epidermal Growth Factor Receptor (HER) family. HER3 is a kinase dead receptor, but by forming heterodimers with other HER family receptors, HER3 works as amplifier for PI3 kinase driven tumorigenesis. It has been reported that tumors treated with EGFR-, HER2-, cMET-or mTOR targeted therapies can escape via HER3 activation or upregulation. HER3 is expressed in a large variety of tumors for example in non-small cell lung cancer (NSCLC), head and neck, colorectal, gastric, pancreatic, breast, ovarian, thyroid and prostate cancer. Anti-HER3 antibodies can work via various mechanisms including: (1) blocking ligand (HRGs) binding to the receptor, (2) blocking heterodimerization with other HER family members (HER1, 2 and 4), (3) downregulation of the receptor from the cell surface, and (4) engaging immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC). The first three mechanisms lead to inhibition of HER3 phosphorylation and downstream signaling thereby resulting in tumor cell growth inhibition, while ADCC is a mechanism of direct target cell killing triggered by cross-linking of Fc receptors on immune effector cells (e.g. NK cells, macrophages). RG7116 is a novel humanized and glycoengineered IgG1 antibody currently in clinical development, that binds to HER3 with high affinity. This antibody prevents ligand binding and receptor heterodimerization, thereby blocking receptor phosphorylation. In various tumor xenograft models monotherapy treatment with this antibody leads to substantial tumor growth inhibition. Only in a few cases monotherapy treatment resulted in complete tumor remission. Most of the models initially show convincing efficacy, but tumors regrow after a while. Combination therapy with other HER targeted therapies such as pertuzumab, cetuximab or erlotinib, lead to complete remission in preclinical models. The combination of RG7116 with downstream signaling inhibitors like: everolimus (mTOR) andand other anti-cancer agents leads to increased efficacy. Citation Format: Birgit Bossenmaier, Thomas Friess, Martin Weisser, Stefanie Lechner, Esther Abraham, Monika Hoch, Christian Mirschberger. RG7116, a novel humanized anti-HER3 antibody with superior preclinical in vitro and in vivo efficacy in combination with, everolimus and other anti-cancer agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2668. doi:10.1158/1538-7445.AM2014-2668