Nectin-2 is a potential target for antibody therapy of breast and ovarian cancersReport as inadecuate




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Molecular Cancer

, 12:60

First Online: 12 June 2013Received: 21 December 2012Accepted: 31 May 2013DOI: 10.1186-1476-4598-12-60

Cite this article as: Oshima, T., Sato, S., Kato, J. et al. Mol Cancer 2013 12: 60. doi:10.1186-1476-4598-12-60

Abstract

BackgroundNectin-2 is a Ca-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.

KeywordsNectin-2 Antibody Cancer Antibody-dependent cellular cytotoxicity AbbreviationsADCCAntibody-dependent cellular cytotoxicity

CDCComplement-dependent cytotoxicity

D-PBSDulbecco’s phosphate- buffered saline

ELISAEnzyme-linked immunosorbent assay

FBSFetal bovine serum

FCMFlow cytometry

IgImmunoglobulin

IHCImmunohistochemistry

mAbMonoclonal antibody

MFIMedian fluorescent intensity

PBMCPeripheral blood mononuclear cells

poAbPolyclonal antibody

SDStandard deviation

TGITumor growth inhibition.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-12-60 contains supplementary material, which is available to authorized users.

Tsutomu Oshima, Shuji Sato contributed equally to this work.

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Author: Tsutomu Oshima - Shuji Sato - Junichi Kato - Yuki Ito - Takahiro Watanabe - Isamu Tsuji - Akira Hori - Tomofumi Kurokawa -

Source: https://link.springer.com/







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