Potential Monoclonal Antibody Therapy for the Treatment of Ovarian Cancer

IntroductionAlthough ovarian cancer is the fifth most common cancer among women, it causes more death than any other type of female reproductive cancer (Mørch et al., 2009).Besides difficulties in early detection, limited options for the treatment of ovarian cancer at late stages have been the major cause of high mortality rate (Jemal et al., 2003).About 76% of women with ovarian cancer survive 1 year after diagnosis, but only about 45% will live 5 years after diagnosis (Choi et al., 2008).Therefore, it may be desirable to look for alternative means of treating this type of cancer rather than the conventional ones including chemo-or radiotherapy.During the last two decades, target-oriented antibody-based anti-cancer drugs have become the main stream choices for cancer treatments in humans.Although the efficacy of cancer treatments varies greatly with individual cases, overall improvements of patients' care and survival are significant, when compared to those of the conventional ones.Besides those approved by the FDA of the United States of America for the clinical treatments of cancer, numerous antibody-drug candidates are still at various stages of clinical trials and pending for the final approval by the FDA (Waldmann, 2003).Generally speaking, the majority of antibody-based anti-cancer drugs are target-oriented and the adverse side effects upon infusion of the antibody drugs are relatively mild as compared to those of the traditional ones.Therefore, selections of suitable targets against the tumor cells have become an essential step for the long term antibody drug development.In general, the ideal tumor target for the antibody drugs can be selected based on its accessibility, high abundance and surface homogeneity.Moreover, it should not be highly expressed on normal cells or tissues, especially the vital organs in humans (McGuire et al., 1996).Recently, two monoclonal antibodies were identified and selected based on these criteria for ovarian cancer.One is RP215 which recognizes a carbohydrate-associated epitope found preferentially in cancer cell-expressed immunoglobulin superfamily proteins, designated in general as CA215.The other is GHR106 which was shown to react with the extracellular domain of human GnRH receptor.Both CA215 and GnRH receptor are widely expressed among cancer cells of different tissue origins, especially those of the human ovary with positive rates ranging from 60-80% (Lee et al., 2008(Lee et al., , 2009;; Lee & Ge, www.intechopen.comOvarian Cancer -Basic Science Perspective 386 2010a).The binding of either of these two monoclonal antibodies was found to inhibit the growth of ovarian cancer cells in vitro and in vivo through studies of induced apoptosis and complement-dependent cytotoxicity.Therefore, additional preclinical studies were performed to elucidate the mechanisms of action of these monoclonal antibodies as anticancer drugs for the treatment of ovarian cancer.These studies should represent our efforts to demonstrate the potential use of these monoclonal antibodies as the anti-ovarian cancer drugs in the future. Results and discussionIn this study, two monoclonal antibodies, RP215 and GHR106, were evaluated to see if they are suitable drug candidates for the potential treatment of ovarian cancer.Several in vitro and in vivo experiments were performed including (1) immunohistochemical staining and Western blot assay to reveal the relative abundance of target antigens, CA215 and GnRH receptor, respectively, each of which appears on the surface of cancer cells of the ovary, (2) apoptosis and complement-dependent cytotoxicity assays to demonstrate the respective anti-cancer efficacy of these two monoclonal antibodies, (3) elucidation of respective molecular mechanisms of action of RP215 and GHR106 as anti-cancer drugs through gene expression/regulation studies, (4) nude mouse experiments to reveal the dose-dependent inhibition of the growth of tumor cells and (5) construction of chimeric forms of RP215 and GHR106 monoclonal antibodies for future preclinical and clinical studies, (6) clinical evaluations of CA215 levels from serum specimens of cancer patients by using the established enzyme immunoassay kits, and (7) glycoanalysis to elucidate the proposed structure of carbohydrate-associated epitope(s) recognized by RP215 in CA215. Immunohistochemical studies and Western blot assayRP215 and GHR106 monoclonal antibodies were found to react with antigens localized on the surface of a variety of cancer cells including that of the ovary.By indirect immunohistochemical studies, it can be shown that three of the selected ovarian cancer cell lines, including OC-3-VGH, OVCAR-3, and SKOV-3, were strongly stained with RP215 and GHR106, respectively, whereas normal mouse IgG as the negative control gave little or no colour staining.The results of such an analysis are presented in Figure 1A (Lee et al., 1992(Lee et al., , 2008(Lee et al., , 2009;; Lee & Ge, 2010a).The immunohistochemical studies of selected cancerous tissue sections of the human ovary were also performed with RP215 as the primary antibody probe.The results are presented in Figure 1B for comparisons.In a separate study, GHR106 was used as a probe to carry out immunohistochemical staining of cancerous tissue sections of the ovary from patients at four various stages of ovarian cancer (Chien et al., 2004).From the results of this analysis, it was generally concluded that the positive staining rates of ovarian cancer tissue sections increase with the stages of this disease (37.5% at stage I to 100% at stage IV) (Chien et al., 2004).In contrast, the immunohistochemical staining of tissue sections of the normal ovary showed negative staining results.The results of such analysis are summarized in Figure 1C.The antigens recognized by RP215 and GHR106 in the cell extract of ovarian cancer cells were also determined by Western blot assay (Lee et al., 2008(Lee et al., , 2009;; Lee & Ge, 2010a).In the case of RP215, the corresponding antigen, CA215, was found to have a molecular size ranging from 50 to 75 kDa for the cell extract from either of the three ovarian cancer cell www.intechopen.com How to referenceIn order to correctly reference this scholarly work, feel free to

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