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ErbB receptor activation, cell morphology changes, and apoptosis induced by anti-Her2 monoclonal antibodies
1Department of Immunology, Amgen Inc., Amgen Center, Thousand Oaks, California 91320, USA.
Abstract:
A panel of mAbs were generated against the purified soluble form of erbB2/Her2 receptor, corresponding to the extracellular region of the receptor, and examined for their ability to mimic the receptor ligand. Some of the mAbs strongly induced tyrosine phosphorylation of 180-185 kDa proteins, including not only Her2 but also Her3 and Her4 receptors, when they were expressed on the surface of breast cancer cells. These mAbs do not cross-react with Her3 or Her4 as demonstrated by competition study. Receptor phosphorylation was also observed with the cell lines transfected with Her2 or a chimeric receptor consisting of the extracellular domain of Her2 and the transmembrane and cytoplasmic domains of epidermal growth factor receptor. Selected mAbs were tested for their ability to change cell morphology, and one specific mAb, mAb74, induced cell morphology changes and apoptosis.
Insights
Monoclonal antibodies (mAbs) targeting the Her2 receptor can activate Her2, Her3, and Her4, leading to breast cancer cell changes. One mAb, mAb74, induced apoptosis, suggesting therapeutic potential.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The human epidermal growth factor receptor 2 (Her2) is a key target in breast cancer therapy.
- Understanding how antibodies interact with and activate Her2 signaling is crucial for developing targeted treatments.
Purpose of the Study:
- To generate monoclonal antibodies (mAbs) against the extracellular domain of the Her2 receptor.
- To investigate the ability of these mAbs to mimic Her2 ligands and induce downstream signaling.
- To evaluate the effects of these mAbs on breast cancer cells, including morphology changes and apoptosis.
Main Methods:
- Generation of a panel of monoclonal antibodies (mAbs) against the soluble extracellular domain of Her2.
- Assessment of mAb-induced tyrosine phosphorylation of Her2, Her3, and Her4 in breast cancer cells.
- Competition studies to determine antibody cross-reactivity.
- Analysis of cell morphology changes and induction of apoptosis in response to specific mAbs.
Main Results:
- Several mAbs induced tyrosine phosphorylation of Her2, Her3, and Her4 in breast cancer cells expressing Her2.
- These mAbs did not cross-react with Her3 or Her4.
- Receptor phosphorylation was confirmed in cell lines transfected with Her2 or a Her2/EGFR chimeric receptor.
- A specific mAb, mAb74, induced significant changes in cell morphology and apoptosis.
Conclusions:
- Monoclonal antibodies targeting the Her2 extracellular domain can activate downstream signaling pathways, including those involving Her3 and Her4.
- The mAb74 demonstrates potential as a therapeutic agent by inducing apoptosis in cancer cells.