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Humanization and Epitope Mapping of Neutralizing Anti-Human Fas Ligand Monoclonal Antibodies: Structural Insights into Fas/Fas Ligand Interaction¹

Tsukasa Nisihara^*, Yoshitaka Ushio^*, Hirohumi Higuchi^*, Nobuhiko Kayagaki^,, Noriko Yamaguchi^,, Kenji Soejima^*, Seishi Matsuo^*, Hiroaki Maeda^*, Yasuyuki Eda^*, Ko Okumura^, and Hideo Yagita^2,,

^* The Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan; Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan

Fas ligand (L)/CD95L, a proapoptotic member of the TNF family, is a potential target for clinical intervention in various diseases. In the present study, we generated a humanized anti-human FasL mAb and characterized the epitopes of neutralizing mAbs by extensive alanine-scanning mutagenesis of human FasL. The predicted molecular model of FasL trimer revealed that the mAbs recognize largely overlapped conformational epitopes that are composed of two clusters, one around the outer tip-forming D-E loop and another near the top of FasL. Both of these sites on FasL are critically involved in the direct interaction with the corresponding receptor, Fas. These results suggest that the mAbs efficiently neutralize FasL cytotoxicity by masking both of these FasL/Fas contact sites.

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