New strategy for pancreatic cancer. immunotargeting therapy by chimeric monoclonal antibody

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Chimeric Nd2 (c-Nd2) is a monoclonal antibody produced against pancreatic cancer mucin and its recognizing antigen epitope is supposed to be a core peptide of MUC5AC including cancer-associated carbohydrates. Chimeric Nd2 has been known to demonstrate almost no reaction to normal tissues, but specific reaction to pancreatic cancer by immunostaining study. In the present study, we investigated whether it can induce an antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) which are known to be an important for functioning effect in the use for immunotherapy of antibody. By in vitro investigation, c-Nd2 demonstrated the ability inducing ADCC during co-culture with targeting cells, pancreatic cancer cells (SW1990) and effector cells which were obtained from peripheral blood of healthy volunteers. The effector cells inducing ADCC by c-Nd2 were clarified not only mononuclear cells (monocytes and NK cells) but also polymorphonuclear neutrophils. The … More ADCC activity was enhanced by pretreatment of neutrophils with G-CSF. Furthermore, CDC could be found to be induced by c-Nd2 during target cells incubation with complement. Consequently, we investigated whether the in vivo anti-tumor effect can be induced by treatment of pancreatic cancer transplanted nude mice with c-Nd2. C-Nd2 demonstrated the growth inhibition of xenografted tumor by intra-peritoneal injection (i.p.) and enlonged the survival of nude mice which had orthotopic transplanted tumor. It could also inhibit liver metastasis induced by injecting cancer cells into spleen. When G-CSF were administered to xenografted nude mice, anti-tumor effect was enhanced by activating neutrophils corresponding to the in vitro results. According to the present results, c-Nd2 is suggested to have high clinical possibility as targeting immunotherapy for pancreatic cancer by its high specificity and ADCC or CDC inducing ability. In the current study, we are preparing to produce humanized antibody for the clinical application to more firmly reduce the immunogenicity and side effect in the actual clinical trial. Less