Open AccessTherapeutic antitumor efficacy of monoclonal antibody against Claudin‐4 for pancreatic and ovarian cancers
Author(s) -
Suzuki Masayo,
KatoNakano Mariko,
Kawamoto Shinobu,
Furuya Akiko,
Abe Yuzuru,
Misaka Hirofumi,
Kimoto Naoya,
Nakamura Kazuyasu,
Ohta So,
Ando Hiroshi
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01239.x
Subject(s) - monoclonal antibody , cancer research , biology , pancreatic cancer , ovarian cancer , flow cytometry , antibody , in vivo , chinese hamster ovary cell , cytotoxicity , microbiology and biotechnology , in vitro , cell culture , cancer , immunology , biochemistry , genetics
Claudin‐4 (CLDN4) is a tetraspanin transmembrane protein of tight junction structure and is highly expressed in pancreatic and ovarian cancers. In this study, we aimed to generate an anti‐Claudin‐4 monoclonal antibody (mAb) and evaluate its antitumor efficacy in vitro and in vivo . To isolate specific mAb, we generated CLDN3, 4, 5, 6, and 9, expressing Chinese hamster ovary (CHO) cells, and then used them as positive and negative targets through cell‐based screening. As a result, we succeeded in isolating KM3900 (IgG2a), which specifically bound to CLDN4, from BXSB mice immunized with pancreatic cancer cells. Immunoprecipitation and flow cytometry analysis revealed that KM3900 recognized the conformational structure and bound to extracellular loop 2 of CLDN4. Furthermore, binding of KM3900 was detected on CLDN4‐expressing pancreatic and ovarian cancer cells, but not on negative cells. Next, we made the mouse–human chimeric IgG1 (KM3934) and evaluated its antitumor efficacy. KM3934 induced dose‐dependent antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity in vitro , and significantly inhibited tumor growth in MCAS or CFPAC‐1 xenograft SCID mice in vivo ( P < 0.05). These results suggest that mAb therapy against CLDN4 is promising for pancreatic and ovarian cancers. ( Cancer Sci 2009; 100: 1623–1630)