Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth

Abstract

Summary Four monoclonal antibodies (MAbs) specific for the extracellular domain of the human erbB-2/ HER2 protein (FRP5, FSP16, FWP51 and FSP77) have been isolated (Harwerth et al., J. Biol. Chem., 267, 15160-15167, 1992). In this paper we describe the effects of erbB-2 specific MAb administration on the tumorigenic growth of human erbB-2 transformed NIH3T3 cells implanted into The erbB-2 protein is a member of the receptor tyrosine kinase family and is closely related to the epidermal growth factor (EGF) receptor (Schechter et al., 1984;Coussens et al., 1985;Yamamoto et al., 1986). The oncogenic potential of the erbB-2 receptor has been shown to be released through different mechanisms involving point mutation (Segatto et al., 1988;Suda et al., 1990) and overexpression. Amplification of the c-erbB-2 gene, leading to overexpression of the protein, has been observed in a high percentage of human breast and ovarian tumour cells (Slamon et al., 1987;Kraus et al., 1987;van de Vijver et al., 1987;Slamon et al., 1989). It is likely that the elevated levels of the erbB-2 protein contribute to the malignancy process. Overexpression of erbB-2 in cultured cells has been found to induce the malignant phenotype in fibroblasts (Di Fiore et al., 1987) as well as in mammary epithelial cells (Pierce et al., 1991). Overexpression of erbB-2 in breast and ovarian carcinomas has been correlated with an unfavourable patient prognosis (Slamon et al., 1987; Varley et al., 1987;Berger et al., 1988;Slamon et al., 1989;Wright et al., 1989).The use of monoclonal antibodies (MAbs) in diagnosis and treatment of cancer has many promising aspects. The tumour enriched expression and extracellular accessibility of the erbB-2 receptor make it a potential target for immunotherapy. We have recently described several MAbs which bind to the extracellular domain of the human erbB-2 protein (Harwerth et al., 1992). These MAbs are able to affect erbB-2 receptor phosphorylation and turnover, as well as the anchorage-dependent growth properties of erbB-2-expressing tumour cells. In this paper we describe the effect of these anti-erbB-2 monoclonal antibodies, alone and in combination, on the tumorigenic growth of erbB-2 expressing cells in athymic nude mice. Two of the MAbs, FWP51 and FSP77, inhibited the onset of tumour growth. In a parallel experiment the antitumour activity of a singleCorrespondence: N. Hynes.

Characterization of DNA vaccines encoding the domains of calreticulin for their ability to elicit tumor-specific immunity and antiangiogenesis

“…Even though antibody-mediated responses have not been shown to play an important role in controlling HPV-associated malignancies, antigen-specific Abs are significant in other tumor models, such as the breast cancer model with the HER-2/neu antigen. The chimeric NCRT or CRT vaccine strategy may be used to generate HER-2/neuspecific Ab's to induce growth arrest in cells expressing high levels of HER-2/neu on the cell surface [36].…”

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…In addition, anti-HER2 mAbs downregulate mutationally activated HER2 much more effectively than wild-type HER2, reproducing the effects seen with anti-Neu mAbs in the NeuT model (van Leeuween et al, 1990). Adding complexity to the picture is that even growth inhibition in vitro does not correlate with tumor growth inhibition in vivo such that some mAbs are growth stimulatory in cell-culture models yet inhibit tumor growth in mice (Stancovski et al, 1991;Harwerth et al, 1993). The mechanistic principles underlying the diversity of findings from anti-HER2mAbs remain unclear to this day.…”

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

“…Many groups have developed growth-inhibitor monoclonal antibodies that target the receptor tyrosine kinase (RTK) ErbB2 (Drebin et al, 1985;Hudziak et al, 1989;Harwerth et al, 1993;Lewis et al, 1996). In September 1998, a major clinical milestone in the field of targeted therapeutics was reached when the humanised 4D5 antibody, known as trastuzumab (Herceptin), was approved by the Food and Drug Administration for the treatment of breast cancer (Baselga et al, 1996;Slamon and Pegram, 2001).…”