© 2005 The Japanese Biochemical Society
Regular Paper |
Human Anti–Human IL-18 Antibody Recognizing the IL-18–Binding Site 3 with IL-18 Signaling Blocking Activity
1 Department of Bioengineering, Faculty of Engineering, Kagoshima University, Korimoto 1-21-40, Kagoshima, Kagoshima 890-0065; 2 Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu, Gifu 501-1194; 3 Department of Immunology and Medical Zoology, Hyogo College of Medicine, Mukogawacho 1-1, Nishinomiya, Hyogo 663-8501; 4 The Chemo-Sero-Therapeutic Research Institute, Kyokushi Kikuchi, Kumamoto 869-1298; and 5 Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Tokyo
* To whom correspondence should be addressed at: Department of Bioengineering, Faculty of Engineering, Kagoshima University, Korimoto 1-21-40 Korimoto, Kagoshima 890-0065. Tel: +81-99-285-8345, Fax: +81-99-258-4706, E-mail: kazu{at}be.kagoshima-u.ac.jp
IL-18 is an important regulator in both innate and acquired immune responses. The aberrant expression of IL-18 is associated with severe inflammatory conditions, such as autoimmune diseases and allergies. Thus, human antibodies with inhibitory activity on IL-18 signaling may be useful for therapeutic applications. We report here the first establishment of an antagonistic anti–IL-18 complete human antibody, h18-108, employing a human single chain antibody (scFv)–displaying phage library. The h18-108 scFv inhibited the IFN-
production of a human myelomonocytic cell line, KG-1. Flow cytometry analysis showed that h18-108 blocked the binding of IL-18 to KG-1 cells. Epitope mapping analysis using two kinds of random peptide–displaying phage libraries and an IL-18 alanine mutant (D98A) demonstrated that the h18-108 scFv binds to the site 3 of IL-18, which is suggested to be an association site with the IL-18 receptor ß. The complete human Fab and IgG forms of h18-108 have been successfully constructed to attain increases in both binding affinity and inhibitory activity.
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