Monoclonal Antibodies That Are Currently Used In Cancer Therapy

There are currently nine mAbs commercially available that have been approved for the treatment of haematological cancers and breast, colorectal and head and neck cancers (see Table 10.1). The characteristic features of these antibodies, together with the antigens recognized by them, are discussed below.

RITUXIMAB

Rituximab was the first monoclonal antibody to be approved by the US FDA for the treatment of cancer, in 1997. Rituximab is a chimeric mAb (34% mouse protein and 66% human protein) and is directed against B-lymphocyte-restricted differentiation antigen CD20. It has been developed by transferring the entire Fab domain of mouse anti-CD20 antibody to the human IgG1 framework (Hainsworth, 2000). CD-20 antigen is expressed on the surface of more than 90% of B-cell non-Hodgkin's lymphomas (NHLs), on pre-B-lymphocytes and on mature lymphocytes, but not on stem cells, plasma cells or other normal tissues. B-cell lymphoma accounts for 95% of all lymphomas. Rituximab is jointly marketed by two American companies (IDEC Pharmaceutical and Genentech, California) for short-course outpatient treatment of relapsed or refractory CD20-positive, low-grade or follicular B-cell NHL. Rituximab is a less toxic alternative to chemotherapy and can induce anticancer activity by binding to CD20-positive cells, inducing apoptosis, recruiting immune effector functions (i.e. mediating ADCC) and activating complement (Scott, 1998; Hainsworth, 2000). As a single agent, rituximab has been shown to produce a response rate of 50% in patients with relapsed low-grade and follicular NHL. When added to standard chemotherapy in patients with diffuse, large B-cell NHL, it has been shown to prolong survival (Dearden, 2002). Treatment-related toxicity, which occurs most often with the first infusion of the antibody, is generally mild. Infusion-related reactions included rigors, nausea, urticaria, fatigue and headache (Dillman, 2002). One advantage of rituximab therapy is that, as it induces minimal adverse effects, it can be given to patients as short-course, outpatient therapy (375 mg/m2 weekly for 4-8 weeks).

The mAbs epratuzumab and apolizumab, which are directed against two different antigens, CD22 and HLD-DR respectively, are also under clinical investigation for use in NHL (Leonard and Link, 2002). Simultaneous targeting of CD20, CD22 and HLA-DR antigens by antibodies in patients with NHL may produce a better therapeutic benefit, compared with treatment by one antibody. Further clinical trials in patients with NHL, with a combination of rituximab, epratuzumab and apolizumab, should unravel the full potential of such strategies (Sharkey and Goldenberg, 2006).

TRASTUZUMAB (HERCEPTIN)

Trastuzumab was the first therapeutic monoclonal antibody that was approved by the US FDA for the treatment of solid tumours, in 1998 (Freebairn, Last and Illidge, 2001; Bell, 2002). Unlike rituximab, trastuzumab is a humanized antibody. It 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). 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, it forms an ideal target for mAb-based therapy (Green, Murray and Hortobagi, 2000; Rubin and Yarden, 2001).

In the past 18 years, a panel of mouse and rat mAbs has 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). 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. trastuzumab) was generated by transferring the CDR from mAb 4D5 into a human IgG1 framework (Carter et al., 1992). Preclin-ical studies with trastuzumab have shown that it can induce anti-tumour activity against HER-2-overexpressing tumours by several mechanisms, including down-regulation 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, trastuzumab 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; Sliwkowski et al., 1999; Baselga and Albanell, 2001). Clinical trials with trastuzumab, both as a single agent and in combination with cytotoxic drugs such as paclitaxel, have shown that it improves survival in breast cancer patients (Harries and Smith, 2002). The benefit was most evident in patients whose tumours expressed the highest level of HER-2 (3+). The results of clinical studies have also indicated that, although trastuzumab is well tolerated in the great majority of patients, cardiac toxicity is seen in a minority (about 2%) of those treated with trastuzumab alone, and in 26-28% of those who received trastuzumab in combination with an anthracycline regimen. In addition, recent studies have indicated that some cancer patients whose tumours are HER-2 positive may shed some HER-2 antigen into their sera (Hait, 2001). Such shed antigens may trap some of the administered trastuzumab, reducing the effective dose reaching the tumour sites. In such cases, the dose of trastuzumab administered to patients should be increased to compensate for the antibodies trapped by shed antigens.

More recently, in some studies Herceptin was also found to improve disease-free survival among women with HER-2 positive breast cancer in the adjuvant setting (i.e. after excision of early-breast cancer) (Norum, 2006). On 16 November 2006, the FDA expanded the use of trastuzumab, in combination with other drugs, for the treatment of early-stage HER-2-positive breast cancer after surgery (www.fda.gov/).

ALEMTUZUMAB

Alemtuzumab is a humanized mAb that is directed against the CD52 antigen (Waldman, 2002). The CD52 antigen is present on the surface of normal T-lymphocytes, B-lymphocytes and a high proportion of lymphoid cancers, but absent on haematopoietic stem cells. The original rat monoclonal antibody against CD52 was generated in Cambridge, in the United Kingdom, in 1980, and the humanized version of this antibody was approved by the FDA for the treatment of B-cell chronic lymphocytic leukaemia (CLL) in patients who have failed fludarabine therapy (Waldman, 2002). This antibody is able to 'kill' CD52-positive target cells by activating complement and by mediating ADCC (Dearden, 2002; Foran, 2002; Waldman, 2002; Ferrajoli, Faderi and Keating, 2006). However, this antibody induces immunosuppression, as a result of depletion of normal B- and T-lymphocytes, causing an increased risk of opportunistic infections (Pangalis et al., 2001; Rai et al., 2002).

CETUXIMAB AND PANITUMUMAB

Cetuximab is a chimeric, and panitumumab a fully human monoclonal antibody directed against the external domain of human epidermal growth factor receptor

(EGFR), which were approved by the FDA for the treatment of colorectal cancer (www.fda.gov/). The EGFR transmits the mitogenic action of the EGF family of growth factors, such as EGF, transforming growth factor TGFa, HB-EGF (heparin-binding epidermal growth factor), BTC (betacellulin) and epiregulin (Modjtahedi and Dean, 1994; Mendelsohn, 2001). From histological examination of human tumour biopsies, it has become evident that overexpression of EGFR, accompanied by co-production of one or more of its ligands, is a common feature of human tumours of epithelial origin (Modjtahedi and Dean, 1994). Overexpression of EGFR has been detected in cancer of the bladder, breast, lung, brain, stomach, prostate, ovary, pancreas and head and neck. It has been associated with a poor prognosis, as well as resistance to chemotherapy and/or radiotherapy, in many patients with these cancers (Modjtahedi and Dean, 1994; Nicholson, Gee and Harper, 2001). Consequently, several laboratories have generated a panel of mAbs against the external domain of EGFR, which blocks the binding of the ligands to EGFR and inhibits the growth in vitro and in vivo of a wide range of human tumours that overexpress EGFR (Modjtahedi et al., 1996; Mendelsohn, 2001; Yang et al., 2001; Needle, 2002). The anti-tumour activities of anti-EGFR antibodies have been shown to be mediated via several mechanisms, including down-regulation of the EGFR from the tumour cell surface, induction of G1 arrest, promotion of apoptosis, inhibition of angiogenesis and immune activation, such as ADCC and CDC. On the basis of these findings, the anti-EGFR mAb cetuximab was approved by the US FDA for the treatment of metastatic colorectal cancer in combination with chemotherapy (February 2004) and in combination with radiotherapy for the treatment of head and neck cancer (March 2006). The improved response rate and survival benefit does, however, come at a price. An estimated cost of treatment with cetuximab, with a loading dose of 450 mg/m2 in the first week and followed by weekly dose of 250 mg/m2 per patient for an eight week duration, is around $20 300 (Schrag, 2004). A further challenge in the routine use of anti-EGFR antibodies in the treatment of cancer patients is the identification of more specific tumour markers that can be used not only in the selection of a more specific subpopultaion of EGFR-positive patients who benefit from therapy with anti-EGFR antibodies, but also in discovering those factors that are responsible for the poor response or the development of resistance to therapy with anti-EGFR antibodies.

In September 2006, the FDA approved the fully human anti-EGFR antibody panitumumab for the treatment of patients with EGFR expressing non-curable metastatic colorectal carcinoma (Gibson, Ranganathan and Grothey, 2006). As panitumumab is a fully human anti-EGFR monoclonal antibody, patients receiving this antibody will run a reduced risk of developing an allergic reaction, compared to those receiving the chimeric anti-EGFR antibody cetuximab.

BEVACIZUMAB

Angiogenesis, the formation of new blood vessels, has been shown to be essential for the local growth of tumour cells (Folkman, 1992). High levels of angiogenesis have been associated with a poor prognosis in many patients with epithelial tumours.

Bevacizumab is a humanized monoclonal antibody, and was the first angiogenesis inhibitor to be approved by the FDA as the first line treatment for patients with metastatic colorectal cancer, in combination with standard chemotherapy (Culy, 2005). In combination with cytotoxic agents, bevacizumab increased overall survival by 5 months and median progression-free survival by 4 months, compared to cyto-toxic drugs alone. Bevacizumab inhibits tumour growth by blocking the function of vascular endothelial growth factor (VEGF), a potent mitogen, and survival factor for endothelial cells. Recent studies suggest that bevacizumab may also have potential in treatment of other cancers, such as renal cell cancer and ovarian, lung and breast cancers (Ellis, 2005). The two most common side effects reported with this drug are hypertension and blood clots. There were also rare reports of bowel perforation.

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