Epidermal growth factor receptor downregulation by small heterodimeric binding proteins
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Wittrup_Epidermal growth.pdf
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407.13 KB
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Author(s)
Hackel, Benjamin J.
Neil, Jason Robert
White, Forest M.
Wittrup, Karl Dane
Date Issued
December 2011
Journal
Protein Engineering Design and Selection
Publisher
Oxford University Press
Citation
Hackel, B. J., J. R. Neil, F. M. White, and K. D. Wittrup. Epidermal Growth Factor Receptor Downregulation by Small Heterodimeric Binding Proteins. Protein Engineering Design and Selection 25, no. 2 (January 16, 2012): 47-57.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike 3.0
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DOI of Published Version
https://doi.org/10.1093/protein/gzr056
