Development of complete human monoclonal antibodies and immune complexes for use in the treatment of cancers

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Antibody-based therapy has recently gathered attention as a new targeted therapy for cancer and the field of antibody engineering has shown remarkable progress. Human monoclonal antibodies (Mab) developed in our laboratory, using mice that produce complete human antibodies (KM mouse), demonstrate almost no immunogenicity towards humans and do not develop antibodies towards foreign proteins even with repeated administration. The following antibodies were developed during this study period and investigations into their possible clinical applications were performed.1. The HMMC-1 (human monoclonal antibody against mullerian cancer) was established using an endometrial cancer cell line as immunogen. The antibody demonstrates high specificity towards endometrial and ovarian cancer, while it shows complement-dependent cytotoxicity in vitro. The HMMC-1 epitope was shown to be a novel carbohydrate structure unique to gynecologic cancers. Using surgical specimens from endometrial cancer, the ant … More ibody demonstrated stronger immunohistochemical staining in metastatic tumors compared to primary tumors in the same patient. In addition, using an in vivo lymph node metastasis mouse model developed in our laboratory, the antibody showed an anti-tumor effect towards retroperitoneal lymph node metastasis formed from orthotopically-implanted primary uterine tumors in nude mice. Thus, this antibody demonstrates anti-tumor effects towards lymph node metastasis.2. The HMOCC-1 (human monoclonal antibody against ovarian clear cell adenocarcinoma) and HMOCC-2 Mabs were developed using the ovarian clear cell adenocarcinoma cell line RMG-1 as immunogen. Both Mabs demonstrate high positive rates towards gynecologic cancers, especially ovarian cancer. The HMOCC-1 Mab demonstrates an inhibitory effect towards cell adhesion, more specifically between tumor cells and peritoneal mesothelial cells, as shown by in vitro assays. Furthermore, the HMOCC-2 Mab was shown to possess an epitope on the CAl25 molecule, often used as a marker for ovarian cancer and also demonstrates anti-tumor effects towards subcutaneous tumors implanted in nude mice.3. A Mab was developed using human hCG (human chorionic gonadotropin) as immunogen and was named 8-1A. The Mab recognizes intact hCG and did not cross-react with LH. Future studies are planned to address the possible inhibitory effects of this Mab towards the biological function of hCG. In the future, we plan to investigate the characteristics and anti-tumor effects of these antibodies and possibly test the anti-tumor effects of the various Mabs towards gynecologic cancers in the perspective of future clinical applications. Less