Japan Agency for Medical Research and Development (AMED)
JP22ak0101099
日本
Japan Agency for Medical Research and Development (AMED)
JP21am0101117
日本
Japan Agency for Medical Research and Development (AMED)
JP22ama121003
日本
Japan Agency for Medical Research and Development (AMED)
JP17pc0101020
日本
Japan Science and Technology
JPMJOP1861
日本
Japan Society for the Promotion of Science (JSPS)
JP21K06453
日本
Japan Society for the Promotion of Science (JSPS)
JP20K22630
Kyoto University Foundation
日本
Takeda Science Foundation
日本
JEOL YOKOGUSHI Research Alliance Laboratories of Osaka University
日本
引用
ジャーナル: Commun Biol / 年: 2023 タイトル: Development of a 1:1-binding biparatopic anti-TNFR2 antagonist by reducing signaling activity through epitope selection. 著者: Hiroki Akiba / Junso Fujita / Tomoko Ise / Kentaro Nishiyama / Tomoko Miyata / Takayuki Kato / Keiichi Namba / Hiroaki Ohno / Haruhiko Kamada / Satoshi Nagata / Kouhei Tsumoto / 要旨: Conventional bivalent antibodies against cell surface receptors often initiate unwanted signal transduction by crosslinking two antigen molecules. Biparatopic antibodies (BpAbs) bind to two different ...Conventional bivalent antibodies against cell surface receptors often initiate unwanted signal transduction by crosslinking two antigen molecules. Biparatopic antibodies (BpAbs) bind to two different epitopes on the same antigen, thus altering crosslinking ability. In this study, we develop BpAbs against tumor necrosis factor receptor 2 (TNFR2), which is an attractive immune checkpoint target. Using different pairs of antibody variable regions specific to topographically distinct TNFR2 epitopes, we successfully regulate the size of BpAb-TNFR2 immunocomplexes to result in controlled agonistic activities. Our series of results indicate that the relative positions of the two epitopes recognized by the BpAb are critical for controlling its signaling activity. One particular antagonist, Bp109-92, binds TNFR2 in a 1:1 manner without unwanted signal transduction, and its structural basis is determined using cryo-electron microscopy. This antagonist suppresses the proliferation of regulatory T cells expressing TNFR2. Therefore, the BpAb format would be useful in designing specific and distinct antibody functions.
全体 : Cryo-EM structure of biparatopic antibody Bp109-92 in complex wit...
全体
名称: Cryo-EM structure of biparatopic antibody Bp109-92 in complex with TNFR2
要素
複合体: Cryo-EM structure of biparatopic antibody Bp109-92 in complex with TNFR2
タンパク質・ペプチド: Tumor necrosis factor receptor superfamily member 1B,Maltose/maltodextrin-binding periplasmic protein
タンパク質・ペプチド: TR109 heavy chain
タンパク質・ペプチド: TR109 light chain
タンパク質・ペプチド: TR92 heavy chain
タンパク質・ペプチド: TR92 light chain
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超分子 #1: Cryo-EM structure of biparatopic antibody Bp109-92 in complex wit...
超分子
名称: Cryo-EM structure of biparatopic antibody Bp109-92 in complex with TNFR2 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all
由来(天然)
生物種: Homo sapiens (ヒト)
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分子 #1: Tumor necrosis factor receptor superfamily member 1B,Maltose/malt...
分子
名称: Tumor necrosis factor receptor superfamily member 1B,Maltose/maltodextrin-binding periplasmic protein タイプ: protein_or_peptide / ID: 1 詳細: fusion protein of TNFR2 from human fused with MalE from E.Coli K-12 コピー数: 1 / 光学異性体: LEVO