Presentation TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2

玉田, 太郎  ,  新見, 大輔(協和発酵キリン株式会社 創薬技術研究所)  ,  池田, 昌弘(協和発酵キリン株式会社 免疫アレルギー研究所)  ,  森, 英治(協和発酵キリン株式会社 研究開発企画部)  ,  元木, 一宏(協和発酵キリン株式会社 がん研究所)

The fully human monoclonal antibody KMTR2 acts as a strong direct agonist for TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). To investigate the mechanism of direct agonistic activity induced by KMTR2, the crystal structure of the extracellular region of TRAIL-R2 and a Fab fragment derived from KMTR2 (KMTR2-Fab) was determined to 2.1 Å resolution. Two KMTR2-Fabs assembled with the CDR2 region of the light chain via two-fold crystallographic symmetry, suggesting that the KMTR2-Fab assembly tended to enhance TRAIL-R2 oligomerization. A single mutation at Asn53 to Arg located at the two-fold interface in the KMTR2 resulted in a loss of its apoptotic activity. These results indicate that the strong agonistic activity, such as apoptotic signaling and tumor regression, induced by KMTR2 is attributed to TRAIL-R2 superoligomerization induced by the interdimerization of KMTR2.

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