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

Int J Cancer. 1997 Dec 10;73(6):875-9. doi: 10.1002/(sici)1097-0215(19971210)73:6<875::aid-ijc19>3.0.co;2-3.

Abstract

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.

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity
  • Breast / cytology
  • Breast / immunology
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Cell Division
  • Cells, Cultured
  • Culture Media, Conditioned
  • Female
  • Humans
  • Immunotherapy
  • Receptor, ErbB-2 / analysis
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / physiology*
  • Solubility
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Culture Media, Conditioned
  • Receptor, ErbB-2