Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers.

Abstract

BACKGROUND:

Nectin-2 is a Ca(2+)-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.

• Authors: Tsutomu Oshima, Shuji Sato, Junichi Kato, Yuki Ito, Takahiro Watanabe, Isamu Tsuji, Akira Hori, Tomofumi Kurokawa, Toshio Kokubo
• Journal: Molecular cancer (Mol Cancer) Vol. 12 Pg. 60 (Jun 12 2013) ISSN: 1476-4598 [Electronic] England
• PMID: 23758976 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Cell Adhesion Molecules
• Epitopes
• NECTIN3 protein, human
• Nectin3 protein, mouse
• Nectins

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, immunology, pharmacology)
• Antibody-Dependent Cell Cytotoxicity (drug effects, immunology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Breast Neoplasms (genetics, immunology, metabolism)
• Cell Adhesion Molecules (genetics, immunology, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Epitopes (immunology)
• Female
• Gene Expression
• Humans
• Mice
• Nectins
• Ovarian Neoplasms (genetics, immunology, metabolism)
• Protein Binding (drug effects)
• Xenograft Model Antitumor Assays