Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers
Copyright policy )Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers
Abstract Background Nectin-2 is a Ca2+-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. However, little has been reported about the involvement of Nectin-2 in cancer. Methods To determine the expression of Nectin-2 in cancer tissues and cancer cell lines, we performed gene expression profile analysis, immunohistochemistry studies, and flow cytometry analysis. We also investigated the potential of this molecule as a target for antibody therapeutics to treat cancers by generating and characterizing an anti-Nectin-2 rabbit polyclonal antibody (poAb) and 256 fully human anti-Nectin-2 monoclonal antibodies (mAbs). In addition, we tested anti-Nectin-2 mAbs in several in vivo tumor growth inhibition models to investigate the primary mechanisms of action of the mAbs. Results In the present study, we found that Nectin-2 was over-expressed in clinical breast and ovarian cancer tissues by using gene expression profile analysis and immunohistochemistry studies. Nectin-2 was over-expressed in various cancer cell lines as well. Furthermore, the polyclonal antibody specific to Nectin-2 suppressed the in vitro proliferation of OV-90 ovarian cancer cells, which express endogenous Nectin-2 on the cell surface. The anti-Nectin-2 mAbs we generated were classified into 7 epitope bins. The anti-Nectin-2 mAbs demonstrated antibody-dependent cellular cytotoxicity (ADCC) and epitope bin-dependent features such as the inhibition of Nectin-2-Nectin-2 interaction, Nectin-2-Nectin-3 interaction, and in vitro cancer cell proliferation. A representative anti-Nectin-2 mAb in epitope bin VII, Y-443, showed anti-tumor effects against OV-90 cells and MDA-MB-231 breast cancer cells in mouse therapeutic models, and its main mechanism of action appeared to be ADCC. Conclusions We observed the over-expression of Nectin-2 in breast and ovarian cancers and anti-tumor activity of anti-Nectin-2 mAbs via strong ADCC. These findings suggest that Nectin-2 is a potential target for antibody therapy against breast and ovarian cancers.
- Mitsui (Japan) Japan
- Takeda (Japan) Japan
- University of Tsukuba Japan
Cancer Research, Nectins, Gene Expression, Antineoplastic Agents, Breast Neoplasms, Antibodies, Monoclonal, Humanized, Epitopes, Mice, Cell Line, Tumor, Animals, Humans, Cell Proliferation, Ovarian Neoplasms, Research, Antibody-Dependent Cell Cytotoxicity, Xenograft Model Antitumor Assays, Disease Models, Animal, Oncology, Molecular Medicine, Female, Cell Adhesion Molecules, Protein Binding
Cancer Research, Nectins, Gene Expression, Antineoplastic Agents, Breast Neoplasms, Antibodies, Monoclonal, Humanized, Epitopes, Mice, Cell Line, Tumor, Animals, Humans, Cell Proliferation, Ovarian Neoplasms, Research, Antibody-Dependent Cell Cytotoxicity, Xenograft Model Antitumor Assays, Disease Models, Animal, Oncology, Molecular Medicine, Female, Cell Adhesion Molecules, Protein Binding
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