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Protein Eng Des Sel. 2012 Feb;25(2):47-57. doi: 10.1093/protein/gzr056. Epub 2011 Dec 9.

Epidermal growth factor receptor downregulation by small heterodimeric binding proteins.

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  • 1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.

PMID:
22160867
[PubMed - indexed for MEDLINE]
PMCID:
PMC3286197
Free PMC Article

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