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A toxicological evaluation of the C‐terminal fragment of Clostridium perfringens enterotoxin as a claudin‐3/‐4 binder
Author(s) -
Iida Manami,
Suzuki Hidehiko,
Li Xiangru,
Kakutani Hideki,
Nagase Shotaro,
Doyama Ryo,
Watari Akihiro,
Kondoh Masuo,
Yagi Kiyohito
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.895.5
Subject(s) - enterotoxin , claudin , clostridium perfringens , antigenicity , pharmacology , tight junction , chemistry , medicine , absorption (acoustics) , antibody , microbiology and biotechnology , immunology , biology , biochemistry , gene , escherichia coli , genetics , bacteria , physics , acoustics
Claudins (CLs) are tetratransmembrane proteins that function as intercellular sealing components of tight junctions. Recent progress in epithelial pharmaceutical sciences provides us new insight into the use of CLs as potent targets for drug development. The C‐terminal fragment of Clostridium perfringens enterotoxin (C‐CPE) was the first identified CL‐3/‐4 binder. We previously showed that CL‐3/‐4 could play a role in the mucosal absorption of drugs, in cancer therapy, and in mucosal vaccination using C‐CPE as a CL binder. Since CL‐3/‐4, are highly expressed in the liver and kidney, evaluations of the safety and antigenicity of C‐CPE are needed for future clinical applications. Here, we evaluated whether C‐CPE in mice leads to tissue injury or production of antibodies. Intravenous administration of 5 mg/kg C‐CPE, which is a dose over 25‐fold higher than that used in a murine mucosal absorption model, did not increase biochemical markers of liver and kidney injury, even after 11 weekly injections. Similarly, nasal administration of 2 mg/kg C‐CPE weekly for 11 weeks did not increase these biochemical markers, but 6 administrations of C‐CPE resulted in elevation of C‐CPE‐specific serum IgG. These results indicate that development of a CL modulator with lower antigenicity will be essential for future clinical application of a C‐CPE‐based mucosal absorption enhancer.