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ImmunotoxinsIn recent years, antibodies have been considered potential 'magic bullets' in treating cancer. A large variety of monoclonal antibodies (MAbs) have been identified that bind to antigens on cancer cells, offering a means to specifically target tumour cells. A number of 'naked' (unconjugated) antibodies have been approved for treating various forms of cancer. There are several different ways in which naked antibodies can affect tumour growth; some mark the cancer cell for destruction by the immune system, whereas others attach to cell surface receptors and block the ability of growth factors to stimulate proliferation. Although naked antibodies have shown some utility for treating cancer, greater efficiacy can be achieved by using the antibody to deliver a toxic payload to the cancer cell. Tumor-specific antibodies have been used to deliver a variety of toxic compounds, including potent cytotoxic drugs, radioactive isotopes and peptide toxins (poisonous substances from plants or bacteria). Various immunotoxins have been made by attaching monoclonal antibodies to bacterial toxins such as diphtherial toxin (DT), pseudomonal exotoxin (PE40), or to plant toxins such as ricin A or saporin.HER2 is a growth factor receptor, frequently found overexpressed on a number of tumour types including breast, ovarian, gastric, NSCLC, mesenchymal, bladder, oesophageal and salivary gland cancers. Herceptin (Trastuzumab), a naked MAb approved for use against advanced breast cancer, works by blocking the HER2 receptor on cancer cells. However, the response rate in HER2 patients is only 30% and furthermore, patients who initially respond, eventually develop resistance. Although little is known about the mechanisms by which cancer cells become resistant to Herceptin, it does not appear to be via down-regulation of HER2 expression on the cell surface. Herceptin still binds effectively to HER2 on the cell surface of Herceptin-resistant cell lines, implying that the resistance is due to changes in the downstream signaling pathways. Herceptin-resistant HER2 cells should therefore remain sensitive to an immunotoxin which combines an anti-HER2 antibody with a toxic payload. TopoTarget is developing Zemab®, an immunotoxin which combines an antibody derived specific recognition domain against HER2 with an additional cell killing domain in the form of pseudomonal exotoxin. Zemab® therefore has potential utility in a variety of different HER2 tumour types, including those which have become resistant to Herceptin. Useful links :
Pipeline
- Zemab®
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