Abstract
ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classified epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory effect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Klapper, L., Vaisman, N., Hurwitz, E. et al. A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors. Oncogene 14, 2099–2109 (1997). https://doi.org/10.1038/sj.onc.1201029
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1201029
Keywords
This article is cited by
-
Multi-level model for the investigation of oncoantigen-driven vaccination effect
BMC Bioinformatics (2013)
-
The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity
Investigational New Drugs (2012)
-
Combining epitope-distinct antibodies to HER2: cooperative inhibitory effects on invasive growth
Oncogene (2011)
-
Emerging therapeutic targets in schwannomas and other merlin-deficient tumors
Nature Reviews Neurology (2011)
-
Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer
Histochemistry and Cell Biology (2008)