Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/9887
Title: The antitumor monoclonal antibody 806 recognizes a high-mannose form of the EGF receptor that reaches the cell surface when cells over-express the receptor.
Authors: Johns, Terrance G;Mellman, Ira;Cartwright, Glenn A;Ritter, Gerd;Old, Lloyd J;Burgess, Antony W;Scott, Andrew M
Affiliation: Ludwig Institute for Cancer Research, Tumour Targeting Program, Austin Hospital, Heidelberg, Australia. terry.johns@ludwig.edu.au
Issue Date: 17-Mar-2005
Citation: Faseb Journal : Official Publication of the Federation of American Societies For Experimental Biology 2005; 19(7): 780-2
Abstract: Overexpression of the EGFR is commonly caused by EGFR gene amplification and is sometimes associated with expression of a variant EGFR (de2-7 EGFR or EGFRvIII) bearing an internal deletion in its extracellular domain. mAb 806 is a novel EGFR antibody with significant antitumor activity that recognizes both the de2-7 EGFR and a subset of the wild-type (wt) EGFR when overexpressed, but does not bind the EGFR expressed in normal tissues. Recently, we demonstrated that the mAb 806 epitope is restricted to a short cysteine loop of the EGFR (amino acids 287-302) that is only available for antibody binding in a transitional form of the receptor, which occurs as the receptor changes from its inactive tethered conformation to a dimeric untethered form. The truncation associated with the de2-7 EGFR mutation renders this receptor constitutively untethered, leading to increased binding of mAb 806. We now show that mAb 806 preferentially binds the immature high-mannose wt and de2-7 EGFR precursors normally located in the endoplasmic reticulum, indicating that this form of the wt EGFR is also constitutively untethered. Using the unique specificity of mAb 806, we clearly demonstrated the presence of these high-mannose EGFR precursors on the cell surface. Given that the high-mannose forms of the wt EGFR must be untethered they may contribute to the spontaneous EGFR signaling reported in cells overexpressing the receptor. These precursor forms of the EGFR thus represent novel tumor targets and contribute to the exceptional selectivity of mAb 806 for EGFR when overexpressed in cancer cells. As our observations are likely to apply to other receptors overexpressed in cancer, they suggest a strategy for developing antitumor antibodies even when the target receptor is expressed in normal tissue.
Internal ID Number: 15774576
URI: http://ahro.austin.org.au/austinjspui/handle/1/9887
DOI: 10.1096/fj.04-1766fje
URL: http://www.ncbi.nlm.nih.gov/pubmed/15774576
Type: Journal Article
Subjects: Antibodies, Monoclonal.immunology
Antibody Specificity
Astrocytoma
Carcinoma, Squamous Cell
Cell Line, Tumor
Cell Membrane.chemistry
Dimerization
Endoplasmic Reticulum.chemistry
Epitopes.chemistry.immunology
Gene Amplification
Gene Expression
Glycosylation
Head and Neck Neoplasms
Humans
Immunosorbent Techniques
Mannose.analysis
Receptor, Epidermal Growth Factor.chemistry.genetics.immunology
Structure-Activity Relationship
Appears in Collections:Journal articles

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