title: A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non-EGFR-Mediated Pathways.
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.
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rios-Doria
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Darrin
authors.initials: D
authors.lastname: Sabol
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Jon
authors.initials: J
authors.lastname: Chesebrough
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Dave
authors.initials: D
authors.lastname: Stewart
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Linda
authors.initials: L
authors.lastname: Xu
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Tammali
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Qun
authors.initials: Q
authors.lastname: Du
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schifferli
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Ray
authors.initials: R
authors.lastname: Rothstein
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Ching Ching
authors.initials: CC
authors.lastname: Leow
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Jenny
authors.initials: J
authors.lastname: Heidbrink-Thompson
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Jin
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Changshou
authors.initials: C
authors.lastname: Gao
authors.affiliation: Champions Oncology Inc., Baltimore, Maryland.
authors.forename: Jay
authors.initials: J
authors.lastname: Friedman
authors.affiliation: Champions Oncology Inc., Baltimore, Maryland.
authors.forename: Brandy
authors.initials: B
authors.lastname: Wilkinson
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Melissa
authors.initials: M
authors.lastname: Damschroder
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pierce
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hollingsworth
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, Maryland. michelottie@medimmune.com.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Michelotti
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D000068818:Cetuximab