Abstract
BackgroundNectin-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.MethodsTo 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.ResultsIn 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.ConclusionsWe 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.
Highlights
Nectin-2 is a Ca2+-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions
We show that Nectin-2 is over-expressed in various cancers and that anti-Nectin-2 Monoclonal antibody (mAb) can exert an in vivo anti-tumor effect on breast and ovarian cancer cells, which suggests the potential of Nectin-2 as a target for antibody therapy for cancer treatment
Over-expression of Nectin-2 in breast and ovarian cancers With the aim of identifying target proteins for antibody therapeutics, we searched for membrane-bound proteins that were over-expressed in cancer tissues compared to normal tissues using Affymetrix GeneChip Technology and found that Nectin-2 mRNA was over-expressed in various cancer tissues
Summary
Nectin-2 is a Ca2+-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. The cis-dimers further form homo- and hetero-trans-dimers with other cis-dimers of Nectins on adjacent cells via the Ig1-domain [2,3,4,5,6,7,8]. Nectin-2 has been reported to regulate cell adhesion between epithelial cells through the formation of transdimers between adjacent cells [1]. In addition to its function as a cell adhesion molecule, previous studies have suggested that Nectin-2 acts as an organizer of Sertoli cell-spermatid junctions in the testis [13] and of synapse formation by neurons [14,15] and as an entry receptor for viruses [16]
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