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- Title
Epidermal growth factor receptor downregulation by small heterodimeric binding proteins.
- Authors
Hackel, Benjamin J; Neil, Jason R; White, Forest M; Wittrup, K Dane
- Abstract
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.
- Publication
Protein engineering, design & selection : PEDS, 2012, Vol 25, Issue 2, p47
- ISSN
1741-0134
- Publication type
Journal Article
- DOI
10.1093/protein/gzr056