新型双特异性纳米抗体通过靶向 TNF-α 和 IL-23p19 生物活性减轻实验性肠炎小鼠的炎症反应。
Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF-α and IL-23p19 bioactivities.
机构信息
Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
出版信息
Clin Transl Med. 2024 Mar;14(3):e1636. doi: 10.1002/ctm2.1636.
BACKGROUND
Inflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non-response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF-α (tumour necrosis factor-α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond.
METHODS
We designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage-expressed membrane TNF-α (hmTNF-α) and IL-23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb-Fc. Our study encompassed in vitro and in vivo characterization of BsNb and BsNb-Fc.
RESULTS
BsNb-Fc exhibited an improved serum half-life, targeting capability and effector function than BsNb. It's demonstrated that BsNb-Fc exhibited superior anti-inflammatory effects compared to the anti-TNF-α mAb (infliximab, IFX) combined with anti-IL-12/IL-23p40 mAb (ustekinumab, UST) by Transwell co-culture assays. Notably, in murine models of acute colitis brought on by 2,4,6-trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb-Fc effectively alleviated colitis severity. Additionally, BsNb-Fc outperformed the IFX&UST combination in TNBS-induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS.
CONCLUSION
These findings highlight an enhanced efficacy and improved biostability of BsNb-Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF-α inhibition.
KEY POINTS
A bispecific nanobody (BsNb) was created to target TNF-α and IL-23p19, exhibiting high affinity and remarkable stability. BsNb-Fc inhibited the release of cytokines in CD4+T cells during co-culture experiments. BsNb-Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.
背景
炎症性肠病（IBD）在治疗反应方面存在重大挑战，需要开发新的治疗方法。虽然针对 TNF-α（肿瘤坏死因子-α）的生物药物在一些 IBD 患者中显示出临床疗效，但仍有相当一部分患者没有反应。
方法
我们设计了能够同时靶向人巨噬细胞表达的膜 TNF-α（hmTNF-α）和 IL-23 的双特异性纳米抗体（BsNbs）。此外，我们将人 IgG1 Fc（hIgG1 Fc）的恒定区融合到 BsNb 上，构建了 BsNb-Fc。我们对 BsNb 和 BsNb-Fc 进行了体外和体内表征。
结果
BsNb-Fc 具有比 BsNb 更长的血清半衰期、更好的靶向能力和效应功能。Transwell 共培养实验表明，BsNb-Fc 比抗 TNF-α mAb（英夫利昔单抗，IFX）联合抗 IL-12/IL-23p40 mAb（乌司奴单抗，UST）具有更好的抗炎作用。值得注意的是，在 2,4,6-三硝基苯磺酸（TNBS）和葡聚糖硫酸钠（DSS）诱导的急性结肠炎小鼠模型中，BsNb-Fc 有效缓解了结肠炎的严重程度。此外，在 TNBS 诱导的结肠炎中，BsNb-Fc 优于 IFX&UST 联合治疗，显著降低了 TNBS 和 DSS 诱导的结肠炎小鼠的结肠炎症。
结论
这些发现突出了 BsNb-Fc 的增强疗效和改善的生物稳定性，表明其作为 TNF-α 抑制治疗反应不足的 IBD 患者的潜在治疗选择。
关键点
创建了一种双特异性纳米抗体（BsNb），可同时靶向 TNF-α 和 IL-23p19，具有高亲和力和显著的稳定性。BsNb-Fc 在共培养实验中抑制了 CD4+T 细胞中细胞因子的释放。BsNb-Fc 有效缓解了 DSS 或 TNBS 诱导的急性结肠炎小鼠模型的结肠炎严重程度，优于 IFX&UST 联合治疗。
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