A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non-EGFR-Mediated Pathways
| Autor: | Jenny Heidbrink-Thompson, Darrin Sabol, Kevin Schifferli, Jonathan Rios-Doria, Robert E. Hollingsworth, Emil Michelotti, Jon Chesebrough, Brandy Wilkinson, Xiaofang Jin, Ray Rothstein, David A. Tice, Li Cheng, Dave Stewart, Linda Xu, Jay Friedman, Changshou Gao, Ching Ching Leow, Melissa Damschroder, Andrew J. Pierce, Qun Du, Ravinder Tammali |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
medicine.drug_class Blotting Western Cetuximab Mice Nude Pharmacology ADAM17 Protein Monoclonal antibody Proteomics Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Cell Proliferation biology Dose-Response Relationship Drug Antibodies Monoclonal Drug Synergism Sheddase HCT116 Cells Xenograft Model Antitumor Assays Blot ErbB Receptors ADAM Proteins Treatment Outcome Oncology Cell culture Mice Inbred DBA biology.protein Female Antibody HT29 Cells medicine.drug Signal Transduction |
| Zdroj: | Molecular cancer therapeutics. 14(7) |
| ISSN: | 1538-8514 |
| Popis: | 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. Mol Cancer Ther; 14(7); 1637–49. ©2015 AACR. |
| Databáze: | OpenAIRE |
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