Antibodies specifically targeting a locally misfolded region of tumor associated EGFR
| Autor: | Webster K. Cavenee, Dane Wittrup, Ginger Chao, Anthony W Burgess, Gerd Ritter, Andrew M. Scott, Timothy E. Adams, Mezhen Lou, Bruno Catimel, Elisabeth Stockert, Thomas P. J. Garrett, Peter A. Hoyne, Rodney B. Luwor, Shenggen Yao, Francesca Walker, Edouard C. Nice, Lloyd J. Old, Jennifer R. Cochran, Julie Rothacker, Suzanne G Orchard, Trevor Huyton, W. Douglas Fairlie, Glenn A Cartwright, Andrew H. A. Clayton, Cindy S. Luo, Yibin Xu, Terrance Grant Johns, Hui K Gan |
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| Rok vydání: | 2009 |
| Předmět: |
Protein Denaturation
Antibodies Neoplasm Protein Conformation Mutant Mice Nude Antineoplastic Agents Antigen-Antibody Complex Crystallography X-Ray Epitope Epitopes Mice ErbB Receptors Epidermal growth factor Animals Humans Epidermal growth factor receptor Receptor Autocrine signalling Multidisciplinary biology Antibodies Monoclonal Biological Sciences Xenograft Model Antitumor Assays Molecular biology Neoplasm Proteins Cell biology biology.protein Antibody |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:5082-5087 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Epidermal Growth Factor Receptor (EGFR) is involved in stimulating the growth of many human tumors, but the success of therapeutic agents has been limited in part by interference from the EGFR on normal tissues. Previously, we reported an antibody (mab806) against a truncated form of EGFR found commonly in gliomas. Remarkably, it also recognizes full-length EGFR on tumor cells but not on normal cells. However, the mechanism for this activity was unclear. Crystallographic structures for Fab:EGFR 287–302 complexes of mAb806 (and a second, related antibody, mAb175) show that this peptide epitope adopts conformations similar to those found in the wtEGFR. However, in both conformations observed for wtEGFR, tethered and untethered, antibody binding would be prohibited by significant steric clashes with the CR1 domain. Thus, these antibodies must recognize a cryptic epitope in EGFR. Structurally, it appeared that breaking the disulfide bond preceding the epitope might allow the CR1 domain to open up sufficiently for antibody binding. The EGFR C271A/C283A mutant not only binds mAb806, but binds with 1:1 stoichiometry, which is significantly greater than wtEGFR binding. Although mAb806 and mAb175 decrease tumor growth in xenografts displaying mutant, overexpressed, or autocrine stimulated EGFR, neither antibody inhibits the in vitro growth of cells expressing wtEGFR. In contrast, mAb806 completely inhibits the ligand-associated stimulation of cells expressing EGFR C271A/C283A . Clearly, the binding of mAb806 and mAb175 to the wtEGFR requires the epitope to be exposed either during receptor activation, mutation, or overexpression. This mechanism suggests the possibility of generating antibodies to target other wild-type receptors on tumor cells. |
| Databáze: | OpenAIRE |
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