The main objective of this research is to generate specific human monoclonal antibodies (HuMAbs) that can be applied in the treatment of pancreatic cancer. This will be achieved by (1) systematically examining the critical factors promoting antibody (Ab) isotype switching from IgM to IgG in the model of in vitro immunization (IVI), (2) carefully selecting the HuMAbs that are specific and cytotoxic to pancreatic cancer cells by in vitro studies, (3) defining the tumor antigens recognized by the selected HuMAbs using immunochemical and biochemical methods and 4) critically evaluating the ability of tumor-targeting and anti-tumor effect of the selected HuMAb in the nude mouse model. The IVI protocol will be studied systematically with the goal to obtain target-specific human monoclonal IgG: (1) to study the supportive effects of various lymphokines on human B cells in the IVI (2) to study the effect of duration of IVI on the IgG production and (3) to select the optimal tumor antigen in the IVI protocol. Screening of HuMAbs will be achieved using xenograft human pancreatic cancer cells and cell lines. The specificity of the HuMAbs will be further determined by immunohistochemical staining a large panel of human tissues including benign and malignant origins. The cytotoxicity of antibodies against fresh and cultured tumor cells will be examined in two assays: complement dependent cytotoxicity (CDC) and Ab dependent, cell-mediated cytotoxicity (ADCC). The tumor antigens preferentially expressed on carcinoma will be characterized immunochemically and biochemically. HuMAb(s) selected from the in vitro studies will be evaluated in vivo for (1) radioimmunoscintigraphy of xenograft human pancreatic cancer and the biodistribution of radiolabeled Ab in tumor and normal tissues and (2) a tumor inhibitory effect. This study is aimed to generate clinically useful HuMAbs in the treatment of pancreatic cancer. The knowledge of promoting antigen-specific monoclonal IgG will significantly advance the field of HuMAbs. The systematically conducted preclinical-studies both in vitro and in vivo will prepare the selected HuMAb(s) for clinical evaluation.
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