Herceptin was the first therapeutic monoclonal antibody that was approved by the US FDA for the treatment of solid tumours in 1998 (Bell, 2002; Freebairn et al., 2001). Unlike Rituxan, Herceptin is a humanized antibody, which is directed against the external domain of the human epidermal growth factor receptor-2 (HER-2). It has been approved for the treatment of patients with metastatic breast cancer whose tumours overexpress HER-2 receptors.
HER-2 is a non-mutated, tumour-associated, cell surface antigen and a member of the type I growth factor receptor family (Rubin and Yarden, 2001). Overexpression of HER-2 has been shown in 20-30% of patients with breast cancer and in a number of other epithelial tumours (Walker, 2000). In addition, high levels of expression of HER-2 have often been associated with more aggressive disease, poor response to the conventional form of therapy, increased risk of metastasis and poor survival in patients with breast cancer (Cook et al., 2001). As HER-2 overexpression plays an important role in the clinical behaviour of human tumours and is responsible for a poor response to conventional forms of therapy, such antigens form an ideal target for mAb-based therapy (Green et al., 2000; Rubin and Yarden, 2001).
In the past 15 years, a panel of mouse and rat mAbs have been generated against the external domain of HER-2 for both diagnostic and therapeutic applications in oncology (Sliwkowski et al., 1999; Baselga and Albanell, 2001). HER-2 blockade by mAbs has been shown to inhibit the proliferation of the HER-2 overexpressing tumours both in vitro and in animal models (Baselga and Albanell, 2001). Of the anti-HER-2 antibodies studied, the mouse anti-HER-2 mAb 4D5, which showed potent anti-tumour activity and specificity in preclinical studies, was selected for humanization, by the American Biotech Company Genentech (Carter et al., 1992). The humanized form of mouse anti-HER-2 mAb 4D5 (i.e. Herceptin) was generated by transferring the CDR from mAb 4D5 into a human IgG1 framework (Carter et al., 1992). Preclinical studies with Herceptin have shown that it can induce anti-tumour activity against HER-2-overexpressing tumours by several mechanisms, including downregulation of HER-2 from the cell surface and its subsequent mitogenic signal, cell-cycle arrest, induction of apoptosis, inhibition of angiogenesis, activation of complement and mediation of ADCC at tumour sites by binding to effector cells such as NK cells (Sliwkowski et al., 1999; Harries and Smith, 2002). In addition, Herceptin has been shown to increase the anti-tumour activity of cytotoxic drugs against HER-2-overexpressing human breast tumour cell lines in preclinical settings (Baselga et al., 1998; Baselga and Abanell, 2001; Sliwkowski et al., 1999).
Clinical trials with Herceptin in breast cancer patients, both as single agent and in combination with cytotoxic drugs such as pacli-taxel, have shown that it improves survival in such patients (Harries and Smith, 2002). In particular, the benefit of therapy with Herceptin was more evident in patients whose tumours expressed the highest level of HER-2 (3+). The results of clinical studies have also indicated that, although Herceptin is well tolerated in the great majority of such patients, cardiac toxicity is seen in a minority of patients (about 2%) treated with Herceptin alone. This was greater in patients who received Herceptin in combination with an anthracycline regimen (26-28%). Further studies, using Herceptin in combination with a newer generation of cytotoxic drugs and/or other biological agents, are currently under way which could in turn lead to the development of more effective therapeutic regimens for these highly aggressive, HER-2-overexpressing, metastatic breast cancers (Bell, 2002; Ligibel and Winer, 2002). In addition, recent studies have indicated that some cancer patients, whose tumours are HER-2 positive, may also shed some HER-2 antigen into their sera (Hait, 2001). Such shed antigens in turn may trap some of the administered Herceptin, thereby reducing the effective dose reaching tumour sites. In such cases the dose of Herceptin administered to patients should be increased to compensate for the antibodies trapped by shed antigens.
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