Novel Treg expansion method based on TNFR2-selective receptor clustering.

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14877
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kobe Gakuin University
• Principal Investigator: Inoue Masaki 神戸学院大学, 薬学部, 助手 (80757097)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 腫瘍壊死因子 / TNF / 制御性T細胞 / TNFR2 / イムノサイトカイン

Outline of Final Research Achievements

We established a regulatory T cells (Tregs) expansion method based on TNFR2-selective receptor clustering effect for the treatment of immune diseases, rejection after organ transplantation, and graft-versus-host disease after hematopoietic stem cell transplantation. We identified a TNFR2-selective agonistic TNF mutant in a previous study. In this study, we created a novel immunocytokine which was fused TNFR2 agonist and TNFR2 scFv. The immunocytokine enhanced a signal transduction activity via TNFR2 with sustaining the TNFR2 selective binding activity. Furthermore, this molecule significantly expanded human effector Tregs ex vivo. Therefore, we considered that the immunocytokine would be beneficial as a novel Treg expander.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

本イムノサイトカインは、TNFR2アゴニストが刺激を与えつつ、抗体が受容体同士を相互に架橋するという二重特異性をもつ、新しい作用機序のTreg増幅分子である。膜結合型TNF特有のTNFR2シグナル伝達様式である受容体クラスタリング作用を誘導できるため、強力なTNFR2シグナルを介した、効果的かつ選択的なTreg増幅が可能となった。末梢性免疫寛容の誘導に重要となる、最も免疫抑制活性の高いエフェクターTregを増幅できた。新規モダリティの治療薬候補として期待でき、学術的・社会的に意義があると考える。