Soluble HER‐2/neu neutralizes biologic effects of anti‐HER‐2/neu antibody on breast cancer cells in vitro

• Published in: International journal of cancer 1997-12, Vol.73 (6), p.875-879
• Main Authors: Brodowicz, Thomas, Wiltschke, Christoph, Budinsky, Alexandra C., Krainer, Michael, Steger, Günther G., Zielinski, Christoph C.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibody-Dependent Cell Cytotoxicity; Antineoplastic agents; Biological and medical sciences; Breast - cytology; Breast - immunology; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cell Division; Cells, Cultured; Culture Media, Conditioned; Female; Humans; Immunotherapy; Medical sciences; Pharmacology. Drug treatments; Receptor, ErbB-2 - analysis; Receptor, ErbB-2 - immunology; Receptor, ErbB-2 - physiology; Solubility; Tumor Cells, Cultured
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19971210)73:6<875::AID-IJC19>3.0.CO;2-3

Amplification and over‐expression of the HER‐2/neu proto‐oncogene are associated with poor prognosis in women with both node‐positive and node‐negative breast cancer. Therefore, the encoded surface glycoprotein represents an attractive target for cancer immunotherapies. Furthermore, the extracellular domain of HER‐2/neu is released from the cell surface by proteolytic cleavage. In the present experiments, we investigated the potential biologic effects of soluble HER‐2/neu with particular emphasis on its interaction with anti‐HER‐2/neu antibodies. A monoclonal antibody specific for the extracellular domain of HER‐2/neu dose dependently inhibited the proliferation of highly HER‐2/neu‐expressing SK‐BR‐3 and BT‐474 breast cancer cells but had no effect on the proliferation of weakly to moderately HER‐2/neu‐expressing MCF‐7, HBL‐100 and ZR‐75‐1 breast cells. Addition of SK‐BR‐3 or BT‐474 cell supernatants with high concentrations of soluble HER‐2/neu led to a neutralization of anti‐HER‐2/neu antibody–mediated inhibition of proliferation due to a binding of soluble HER‐2/neu by the antibody, which could be demonstrated by immunoprecipitation. Furthermore, the ability of anti‐HER‐2/neu antibodies to mediate antibody‐dependent cellular cytotoxicity (ADCC) by lymphokine‐activated killer cells was assessed. Cytolysis of SK‐BR‐3 tumor cells was increased significantly in the presence of anti‐HER‐2/neu antibodies. Similar to the proliferation inhibition, ADCC was neutralized by addition of soluble HER‐2/neu‐containing supernatants. Our data suggest that tumors rich in HER‐2/neu might thus escape certain steps of immunologic control by neutralizing biologic activities of anti HER‐2/neu antibodies due to the presence of soluble HER‐2/neu. Int. J. Cancer 73:875–879, 1997. © 1997 Wiley‐Liss, Inc.