Novel regulatory mechanism of human Toll-like receptor 4 function by the inhibitory monoclonal antibody

抑制性单克隆抗体调控人Toll样受体4功能的新机制

• 批准号: 24790112
• 负责人: TSUKAMOTO HIROKI
• 金额: $ 2.91万
• 依托单位: Tohoku University (2013)Saga University (2012)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24790112/
• 关键词: TLR4; MD-2; リポ多糖; モノクローナル抗体; 敗血症; 抗体医薬; 免疫学

In this study, novel inhibitory monoclonal antibodies against human Toll-like receptor 4 (TLR4), which are potential leading antibodies for anti-sepsis antibody drugs, were developed. These antibodies inhibited the production of proinflammatory cytokines, the upregulation of costimulatory molecules and the activation of NF-kappaB in lipopolysaccharide (LPS)-stimulated cells such as human peripheral blood mononuclear cells. The inhibitory activities were mediated by novel mechanism that is the induction of inactive TLR4 oligomerization, the inhibition of LPS-induced TLR4 internalization, but not the inhibition of TLR4-LPS binding. In addition, the epitope to which the binding of antibody inhibits the TLR4 function was found on extracellular domain of TLR4 independently of MD-2. Identification and chracterization of this epitope may provide a promising drug discovery target sturucture for the development of anti-septic antibody drugs.

本研究开发了针对人Toll样受体4（TLR4）的新型抑制性单克隆抗体，该抗体是抗脓毒症抗体药物的潜在先导抗体。这些抗体抑制促炎细胞因子的产生、共刺激分子的上调以及脂多糖 (LPS) 刺激的细胞（例如人外周血单核细胞）中 NF-κB 的激活。抑制活性是由新机制介导的，即诱导无活性的 TLR4 寡聚化、抑制 LPS 诱导的 TLR4 内化，但不抑制 TLR4-LPS 结合。此外，在TLR4的胞外结构域上发现了与抗体结合抑制TLR4功能的表位，与MD-2无关。该表位的鉴定和表征可能为抗感染抗体药物的开发提供有前景的药物发现靶标结构。

项目成果

Enzymatic synthesis of di-fucosylated chitooligosaccharide by human and rhizobiaα1,6-fucosyltransferases

人和根瘤菌α1,6-岩藻糖基转移酶酶促合成二岩藻糖基化壳寡糖

• 发表时间: 2012
• 作者: Ihara H;Hanashima S;Tsukamoto H;Yamaguchi Y;Taniguchi N;Ikeda Y
• 通讯作者: Ikeda Y

Reduced surface expression of TLR4 by a V254I point mutation may account for the low LPS responder phenotype of BALB/c B cells

V254I 点突变导致 TLR4 表面表达减少可能是 BALB/c B 细胞低 LPS 反应表型的原因

• 发表时间: 2012
• 作者: Tsukamoto H;Fukudome K;Takao S;Tsuneyoshi N;Ohta S;Nagai Y;Ihara H;Miyake K;Ikeda Y;Kimoto M
• 通讯作者: Kimoto M

移植片対宿主病と移植片対腫瘍効果における細胞外アデノシン産生系の機能解析とその薬学的制御に関する研究

细胞外腺苷产生系统的功能分析及其在移植物抗宿主病和移植物抗肿瘤作用中的药物调控研究

• 作者: 中曽根正皓;鈴木直人;金光祥臣;塚本宏樹;富岡佳久;塚本宏樹;塚本宏樹
• 通讯作者: 塚本宏樹

Handbook of Glycosyltransferases and Related Genes, Mannosyl (β-1,4-)-glycoproteinβ-1,4-N-acetylglucosaminyltransferase (MGAT3);β1,4-N-Acetylglucosaminyltransferase III (GnT-III, GlcNAc-T III)(Taniguchi N, Honke K, Fukuda M, Narimatsu H, Yamaguchi Y, Anga

糖基转移酶和相关基因手册，甘露糖基（β-1,4-）-糖蛋白β-1,4-N-乙酰氨基葡萄糖转移酶（MGAT3）；β1,4-N-乙酰氨基葡萄糖转移酶III（GnT-III，GlcNAc-T III）（谷口） N、本家 K、福田 M、成松 H、山口 Y、Anga

• 发表时间: 2014
• 作者: Ikeda Y;Ihara H;Tsukamoto H;Gu J;Taniguchi N
• 通讯作者: Taniguchi N

A validated quantitative liquid chromatography-tandem quadrupole mass spectrometry method for monitoring isotopologues to evaluate global modified cytosine ratios in genomic DNA

• DOI: 10.1016/j.jchromb.2014.01.050
• 发表时间: 2014-03-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Tsuji, Makoto;Matsunaga, Hironori;Tomioka, Yoshihisa
• 通讯作者: Tomioka, Yoshihisa