Molecular Cancer Therapeutics 2015-07-01

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non-EGFR-Mediated Pathways.

Jonathan Rios-Doria, Darrin Sabol, Jon Chesebrough, Dave Stewart, Linda Xu, Ravinder Tammali, Li Cheng, Qun Du, Kevin Schifferli, Ray Rothstein, Ching Ching Leow, Jenny Heidbrink-Thompson, Xiaofang Jin, Changshou Gao, Jay Friedman, Brandy Wilkinson, Melissa Damschroder, Andrew J Pierce, Robert E Hollingsworth, David A Tice, Emil F Michelotti

Index: Mol. Cancer Ther. 14 , 1637-49, (2015)

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Abstract

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 in as a focused set of head and neck patient-derived xenograft models. The antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in the OE21 esophageal model and the COLO205 colorectal model 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 that function outside of the HER pathways and may contribute toward the antitumor activity of the monoclonal antibody.©2015 American Association for Cancer Research.