Medi3622, A Monoclonal Antibody To Adam17, Inhibits Tumor Growth By Inhibiting Egfr- And Non-Egfr-Mediated Pathways

ADAM17 is the primary sheddase for HER pathway ligands. We report the discovery of a potent and specific ADAM17 inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent tumor models. The inhibitory activity of MEDI3622 correlated with EGFR activity both in a series of tumor models across several indications as well as in a focused set of head and neck patient derived xenograft models. Cynomolgus monkey and rat PK/PD assays showed MEDI3622 inhibited TNFα shedding. Toxicity observed in cynomolgus monkey and rat was similar to EGFR inhibitor-induced rash. However, the antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in OE21 head and neck and COLO205 colorectal xenograft models suggesting additional activity outside of the EGFR pathway. Combination of MEDI3622 and cetuximab in the OE21 model was additive and eradicated tumors. Proteomics analysis revealed novel ADAM17 substrates which function outside of the HER pathways and may contribute towards the antitumor activity of the monoclonal antibody. Citation Format: Darrin Sabol, Jonathan RiosDoria, Jon Chesebrough, David Stewart, Kevin Schifferli, Raymond Rothstein, Ching Ching Leow, Jenny Heidbrink-Thompson, Li Cheng, Qun Du, Linda Xu, Xiaofang Jin, Ravinder Tammali, Chanshou Gao, Jay Friedman, Brandy Wilkinson, Melissa Damschroder, Andrew Pierce, MunMun Patnaik, Rong Zeng, Yuling Wu, Susan Spitz, Gabriel Robbie, Lorin Roskos, Robert Hollingsworth, David Tice, Emil Michelotti. Medi3622, a monoclonal antibody to ADAM17, inhibits tumor growth by inhibiting EGFR- and non-EGFR-mediated pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 30. doi:10.1158/1538-7445.AM2015-30