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

Mol Cancer. 2013 Jun 12;12:60. doi: 10.1186/1476-4598-12-60.

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.

MeSH terms

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

Substances

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