Shibata Hiroko, Yoshioka Yasuo, Abe Yasuhiro, Ohkawa Akiko, Nomura Tetsuya, Minowa Kyoko, Mukai Yohei, Nakagawa Shinsaku, Taniai Madoka, Ohta Tsunetaka, Kamada Haruhiko, Tsunoda Shin-ichi, Tsutsumi Yasuo
Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation (NIBIO), Ibaraki, Osaka 567-0085, Japan.
Biomaterials. 2009 Dec;30(34):6638-47. doi: 10.1016/j.biomaterials.2009.08.041. Epub 2009 Sep 17.
Blocking the binding of TNF-alpha to TNF receptor subtype-1 (TNFR1) is an important strategy for the treatment of rheumatoid arthritis (RA). We recently succeeded in developing a TNFR1-selective antagonistic TNF mutant, R1antTNF. Here, we report the anti-inflammatory effects of R1antTNF in a murine collagen-induced arthritis model. To improve the in vivo stability of R1antTNF, we first engineered PEG (polyethylene glycol)-modified R1antTNF (PEG-R1antTNF). In prophylactic protocols, PEG-R1antTNF clearly improved the incidence, and the clinical score of arthritis due to its long plasma half-life. Although, the effect of PEG-R1antTNF on the incidence and production of IL1-beta was less than that of the existing TNF-blocking drug Etanercept, its effect on severity was almost as marked as Etanercept. Interestingly, in therapeutic protocols, PEG-R1antTNF showed greater therapeutic effect than Etanercept. These data suggest that the anti-inflammatory effects of PEG-R1antTNF depend on the stage of arthritis. Recently, there has been much concern over the reactivation of viral infection caused by TNF blockade. Unlike Etanercept, PEG-R1antTNF did not reactivate viral infection. Together, these results indicate that selective inhibition of TNF/TNFR1 could be effective in treating RA and that PEG-R1antTNF could serve as a promising anti-inflammatory drug for this purpose.
阻断肿瘤坏死因子-α（TNF-α）与肿瘤坏死因子受体亚型-1（TNFR1）的结合是治疗类风湿性关节炎（RA）的重要策略。我们最近成功开发了一种TNFR1选择性拮抗性TNF突变体，即R1antTNF。在此，我们报告R1antTNF在小鼠胶原诱导性关节炎模型中的抗炎作用。为提高R1antTNF的体内稳定性，我们首先构建了聚乙二醇（PEG）修饰的R1antTNF（PEG-R1antTNF）。在预防性方案中，PEG-R1antTNF因其较长的血浆半衰期，明显改善了关节炎的发病率和临床评分。虽然PEG-R1antTNF对白细胞介素-1β（IL1-β）的发病率和产生的影响小于现有的TNF阻断药物依那西普，但其对严重程度的影响几乎与依那西普一样显著。有趣的是，在治疗性方案中，PEG-R1antTNF显示出比依那西普更大的治疗效果。这些数据表明，PEG-R1antTNF的抗炎作用取决于关节炎的阶段。最近，人们对TNF阻断导致病毒感染重新激活非常关注。与依那西普不同，PEG-R1antTNF不会重新激活病毒感染。综上所述，这些结果表明，选择性抑制TNF/TNFR1可能对治疗RA有效，并且PEG-R1antTNF有望作为一种抗炎药物用于此目的。
