biostudies-literatureHackel BJNCI NIH HHS47-57https://www.ebi.ac.uk/biostudies/studies/S-EPMC3286197biostudies-literatureUnknown25(2)No single engineered protein has been shown previously to robustly downregulate epidermal growth factor receptor (EGFR), a validated cancer target. A panel of fibronectin-based domains was engineered to bind with picomolar to nanomolar affinity to multiple epitopes of EGFR. Monovalent and homo- and hetero-bivalent dimers of these domains were tested for EGFR downregulation. Selected orientations of non-competitive heterodimers decrease EGFR levels by up to 80% in multiple cell types, without activating receptor signaling. These heterodimers inhibit autophosphorylation, proliferation and migration, and are synergistic with the monoclonal antibody cetuximab in these activities. These small (25 kDa) heterodimers represent a novel modality for modulating surface receptor levels.Protein engineering, design & selection : PEDSEpidermal growth factor receptor downregulation by small heterodimeric binding proteins.PMC3286197CA96504R01 CA096504CA118705R01 CA118705Wittrup KDHackel BJWhite FMNeil JRfalseEpidermal growth factor receptor downregulation by small heterodimeric binding proteins.No single engineered protein has been shown previously to robustly downregulate epidermal growth factor receptor (EGFR), a validated cancer target. A panel of fibronectin-based domains was engineered to bind with picomolar to nanomolar affinity to multiple epitopes of EGFR. Monovalent and homo- and hetero-bivalent dimers of these domains were tested for EGFR downregulation. Selected orientations of non-competitive heterodimers decrease EGFR levels by up to 80% in multiple cell types, without activating receptor signaling. These heterodimers inhibit autophosphorylation, proliferation and migration, and are synergistic with the monoclonal antibody cetuximab in these activities. These small (25 kDa) heterodimers represent a novel modality for modulating surface receptor levels.2012-01-01T00:00:00Z2012 Feb2020-11-19T12:21:52Z2019-03-27T00:49:26ZS-EPMC32861972216086710.1093/protein/gzr056