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.
Highlights
ADAM17/TACE (TNFa converting enzyme) is a protease originally identified as the major sheddase for TNFa [1, 2]
Cetuximab sensitivity is predicted by high EGFR ligand levels [31, 32], strongly suggesting that high ligand levels predict MEDI3622 sensitivity as well
MEDI3622 sensitive cell lines expressed high mRNA levels for at least one EGFR ligand, and no correlation was found between MEDI3622 sensitivity and mRNA levels of ADAM17, EGFR, HER2 or HER3 (Supplementary Fig. S13)
Summary
ADAM17/TACE (TNFa converting enzyme) is a protease originally identified as the major sheddase for TNFa [1, 2]. The phenotype of Adam knockout mice [3], closely aligns with those of EGFR and HBEGF knockout mice implicating ADAM17 in the shedding of ligands that transduce signals through EGFR family receptor tyrosine kinases [4, 5] and implying that it is the shed form of these ligands which are responsible for the majority of EGFR-driven signaling. Knockout of Adam in mouse embryo fibroblasts dramatically reduces the amount of shed EGFR ligands (amphiregulin, epiregulin, HBEGF, TGFa) as well as the major ligand for HER3 ADAM17 and its substrates within the HER pathways are important drivers of tumorigenesis and promote resistance to existing therapeutics. High expression of both ADAM17 and TGFa correlate with reduced survival in breast cancer as well as in other indications [7].
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