Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling
Due to its common dysregulation in epithelial-based cancers and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) is a highly validated target for anticancer therapies. There has been particular interest in the development of monoclonal antibodies (mAbs)...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2011
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| Online Access: | http://hdl.handle.net/1721.1/66709 https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0003-2398-5896 |
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| author | Spangler, Jamie Berta Neil, Jason Robert Abramovitch, Sivan Yarden, Yosef White, Forest M. Lauffenburger, Douglas A. Wittrup, Karl Dane |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Spangler, Jamie Berta Neil, Jason Robert Abramovitch, Sivan Yarden, Yosef White, Forest M. Lauffenburger, Douglas A. Wittrup, Karl Dane |
| author_sort | Spangler, Jamie Berta |
| collection | MIT |
| description | Due to its common dysregulation in epithelial-based cancers and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) is a highly validated target for anticancer therapies. There has been particular interest in the development of monoclonal antibodies (mAbs) targeting EGFR, resulting in two approved mAb-based drugs and several others in clinical trials. It has recently been reported that treatment with combinations of noncompetitive mAbs can induce receptor clustering, leading to synergistic receptor down-regulation. We elucidate three key aspects of this phenomenon. First, we show that highly potent combinations consisting of two noncompetitive mAbs that target EGFR domain 3 reduce surface receptor levels by up to 80% with a halftime of 0.5–5 h in both normal and transformed human cell lines to an extent inversely proportional to receptor density. Second, we find the mechanism underlying down-regulation to be consistent with recycling inhibition. Third, in contrast to the agonism associated with ligand-induced down-regulation, we demonstrate that mAb-induced down-regulation does not activate EGFR or its downstream effectors and it leads to synergistic reduction in migration and proliferation of cells that secrete autocrine ligand. These new insights will aid in ongoing rational design of EGFR-targeted antibody therapeutics. |
| first_indexed | 2024-09-23T13:00:25Z |
| format | Article |
| id | mit-1721.1/66709 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:00:25Z |
| publishDate | 2011 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/667092022-10-01T12:26:58Z Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling Spangler, Jamie Berta Neil, Jason Robert Abramovitch, Sivan Yarden, Yosef White, Forest M. Lauffenburger, Douglas A. Wittrup, Karl Dane Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering White, Forest M. White, Forest M. Spangler, Jamie Berta Neil, Jason Robert Wittrup, Karl Dane Due to its common dysregulation in epithelial-based cancers and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) is a highly validated target for anticancer therapies. There has been particular interest in the development of monoclonal antibodies (mAbs) targeting EGFR, resulting in two approved mAb-based drugs and several others in clinical trials. It has recently been reported that treatment with combinations of noncompetitive mAbs can induce receptor clustering, leading to synergistic receptor down-regulation. We elucidate three key aspects of this phenomenon. First, we show that highly potent combinations consisting of two noncompetitive mAbs that target EGFR domain 3 reduce surface receptor levels by up to 80% with a halftime of 0.5–5 h in both normal and transformed human cell lines to an extent inversely proportional to receptor density. Second, we find the mechanism underlying down-regulation to be consistent with recycling inhibition. Third, in contrast to the agonism associated with ligand-induced down-regulation, we demonstrate that mAb-induced down-regulation does not activate EGFR or its downstream effectors and it leads to synergistic reduction in migration and proliferation of cells that secrete autocrine ligand. These new insights will aid in ongoing rational design of EGFR-targeted antibody therapeutics. National Institutes of Health (U.S.) (Grant CA96504) National Defense Science and Engineering Graduate Fellowship 2011-11-01T18:14:22Z 2011-11-01T18:14:22Z 2010-07 2009-11 Article http://purl.org/eprint/type/JournalArticle 1091-6490 http://hdl.handle.net/1721.1/66709 Spangler, J. B. et al. “Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling.” Proceedings of the National Academy of Sciences 107 (2010): 13252-13257. ©2010 by the National Academy of Sciences. https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0003-2398-5896 en_US http://dx.doi.org/10.1073/pnas.0913476107 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Spangler, Jamie Berta Neil, Jason Robert Abramovitch, Sivan Yarden, Yosef White, Forest M. Lauffenburger, Douglas A. Wittrup, Karl Dane Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| title | Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| title_full | Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| title_fullStr | Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| title_full_unstemmed | Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| title_short | Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| title_sort | combination antibody treatment down regulates epidermal growth factor receptor by inhibiting endosomal recycling |
| url | http://hdl.handle.net/1721.1/66709 https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0003-2398-5896 |
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