PDF(Pubmed)
Abstract：
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.
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.
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.
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.
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.
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.
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.
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.
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.
摘要：
背景：炎症性肠病（IBDs）在治疗无反应方面提出了重大挑战，需要开发新的治疗方法。尽管靶向TNF-α（肿瘤坏死因子-α）的生物药物已在一些IBD患者中显示出临床成功，很大一部分仍然没有回应。
方法：我们设计了双特异性纳米抗体（BsNbs），能够同时靶向人巨噬细胞表达的膜TNF-α（hmTNF-α）和IL-23。此外,我们将人IgG1Fc(hIgG1Fc)的恒定区与BsNb融合以产生BsNb-Fc。我们的研究包括BsNb和BsNb-Fc的体外和体内表征。
结果：BsNb-Fc表现出改善的血清半衰期，靶向能力和效应子功能比BsNb。这表明，BsNb-Fc表现出优于抗TNF-αmAb（英夫利昔单抗，IFX）与抗IL-12/IL-23p40mAb（ustekinumab，UST)通过Transwell共培养测定。值得注意的是,在由2,4,6-三硝基苯磺酸（TNBS）和葡聚糖硫酸钠（DSS）引起的小鼠急性结肠炎模型中，BsNb-Fc有效缓解结肠炎严重程度。此外,BsNb-Fc在TNBS诱导的结肠炎中优于IFX和UST组合，显著减少由TNBS和DSS产生的结肠炎小鼠的结肠炎症。
结论：这些发现强调了BsNb-Fc的功效增强和生物稳定性改善，提示其作为IBD患者对TNF-α抑制反应不足的有希望的治疗选择的潜力。
结论：创建了双特异性纳米抗体（BsNb），以靶向TNF-α和IL-23p19，表现出高亲和力和显着的稳定性。在共培养实验期间,BsNb-Fc抑制CD4+T细胞中细胞因子的释放。BsNb-Fc可有效减轻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组合。
方法：我们设计了双特异性纳米抗体（BsNbs），能够同时靶向人巨噬细胞表达的膜TNF-α（hmTNF-α）和IL-23。此外,我们将人IgG1Fc(hIgG1Fc)的恒定区与BsNb融合以产生BsNb-Fc。我们的研究包括BsNb和BsNb-Fc的体外和体内表征。
结果：BsNb-Fc表现出改善的血清半衰期，靶向能力和效应子功能比BsNb。这表明，BsNb-Fc表现出优于抗TNF-αmAb（英夫利昔单抗，IFX）与抗IL-12/IL-23p40mAb（ustekinumab，UST)通过Transwell共培养测定。值得注意的是,在由2,4,6-三硝基苯磺酸（TNBS）和葡聚糖硫酸钠（DSS）引起的小鼠急性结肠炎模型中，BsNb-Fc有效缓解结肠炎严重程度。此外,BsNb-Fc在TNBS诱导的结肠炎中优于IFX和UST组合，显著减少由TNBS和DSS产生的结肠炎小鼠的结肠炎症。
结论：这些发现强调了BsNb-Fc的功效增强和生物稳定性改善，提示其作为IBD患者对TNF-α抑制反应不足的有希望的治疗选择的潜力。
结论：创建了双特异性纳米抗体（BsNb），以靶向TNF-α和IL-23p19，表现出高亲和力和显着的稳定性。在共培养实验期间,BsNb-Fc抑制CD4+T细胞中细胞因子的释放。BsNb-Fc可有效减轻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组合。
