title: 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.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. tomofumi.kurokawa@takeda.com
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Oshima
authors.forename: Shuji
authors.initials: S
authors.lastname: Sato
authors.forename: Junichi
authors.initials: J
authors.lastname: Kato
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Takahiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Isamu
authors.initials: I
authors.lastname: Tsuji
authors.forename: Akira
authors.initials: A
authors.lastname: Hori
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Kurokawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Kokubo
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D000075983:Nectins; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D000939:Epitopes; C000619014:NECTIN3 protein, human; C000619017:Nectin3 protein, mouse; D000075983:Nectins