Structural optimization of a TNFR1-selective antagonistic TNF-alpha mutant to create new-modality TNF-regulating biologics

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06540
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kobe Gakuin University
• Principal Investigator: Inoue Masaki 神戸学院大学, 薬学部, 助教 (80757097)
• Co-Investigator(Kenkyū-buntansha): 角田 慎一 神戸学院大学, 薬学部, 教授 (90357533)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 腫瘍壊死因子 / TNF阻害薬 / 1型TNF受容体

Outline of Final Research Achievements

Excessive activation of the proinflammatory cytokine tumor necrosis factor-α (TNFα) is a major cause of autoimmune diseases, including rheumatoid arthritis. TNFα induces immune responses via TNF receptor 1 (TNFR1) and TNFR2. Signaling via TNFR1 induces proinflammatory responses, whereas TNFR2 signaling is suggested to suppress the pathophysiology of inflammatory diseases. Here, we developed a TNFR1-selective, antagonistic TNFα mutant (T2) derivative, scT2-Fc, which represents a single-chain form of trimeric T2 with a human IgG-Fc domain. scT2-Fc had properties similar to those of T2, including TNFR1-selective binding avidity, TNFR1 antagonistic activity, and thermal stability, and had a significantly extended plasma t1/2 in vivo. In a murine rheumatoid arthritis model, scT2-Fc delayed the onset of collagen-induced arthritis, suppressed arthritis progression in mice, and required a reduced frequency of administration.

Free Research Field

蛋白質工学

Academic Significance and Societal Importance of the Research Achievements

scT2-Fcは、(1)2価アンタゴニストによるTNFR1シグナル阻害活性の向上、(2)IgG-Fc融合の分子量増大による血中半減期の延長、(3)TNFR2シグナル温存による制御性T細胞の免疫抑制効果の維持、などの分子特性を有することで、TNF阻害薬よりも高い治療効果を発揮したと示唆された。生体内で長期間、炎症の抑制や免疫抑制活性の維持ができ、抗TNF抗体など他の免疫疾患治療薬に優位性を示すと考えられた。