Anti-claudin-4 extracellular domain antibody enhances the antitumoral effects of chemotherapeutic and antibody drugs in colorectal cancer
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Rina Fujiwara-Tani1, Takamitsu Sasaki1, Yi Luo1,2, Kei Goto1, Isao Kawahara1, Yukiko Nishiguchi1, Shingo Kishi1, Shiori Mori1, Hitoshi Ohmori1, Masuo Kondoh3 and Hiroki Kuniyasu1
1Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
2Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
3Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Hiroki Kuniyasu, email: [email protected]
Keywords: claudin; tight junction
Received: August 20, 2018 Accepted: November 26, 2018 Published: December 21, 2018
Claudin-4 (CLDN4) is a major epithelial tight junction protein overexpressed in many cancers to maintain the tumor environment. In this report, we aimed to determine the efficacy of targeting CLDN4 in colorectal cancer (CRC) using an anti-CLDN4 extracellular domain antibody, 4D3. CLDN4 was upregulated in CRC metastatic foci. CLDN4 expression in CRC cells was reduced by upregulation of TNFα, which was induced by Clostridium perfringens enterotoxin produced by gut flora. In a nude mouse liver metastasis model, inhibition of metastasis was increased by combination treatment with 5-fluorouracil (FU) and 4D3 compared to that with 5-FU alone. Moreover, combination treatment with 4D3 and anti-epithelial growth factor receptor (EGFR) antibody C225 resulted in more pronounced inhibition of in vitro sphere formation and tumor growth in nude mice compared to that observed with C225 alone. Moreover, the time interval between the administration of 4D3 and that of C225 was important for maximizing the C225-induced inhibition of EGFR phosphorylation. In a nude mouse model, sequential treatment with 4D3 and C225 with a 6-h time interval resulted in more pronounced inhibition of tumor growth than concurrent treatment. These findings suggest that the targeting of CLDN4 enhances the antitumoral effects of chemotherapeutic agents and molecular targeting antibodies when used in combination.
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