Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.
Institute for Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.
Gut. 2022 Aug;71(8):1551-1566. doi: 10.1136/gutjnl-2021-324868. Epub 2021 Aug 30.
The anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab.
We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies.
Regulatory T (T) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (T) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on T cells in vivo was higher than that of/on T cells. We identified a vedolizumab-'resistant' α4β7-expressing β1PI16 T cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials.
Completely blocking T cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful T cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
抗 α4β7 整合素抗体 vedolizumab 以固定剂量用于治疗 IBD。这导致患者的血清浓度范围很广，先前的研究表明，最高暴露水平与临床反应不理想有关。我们旨在确定 vedolizumab 这种非线性暴露-疗效特征的潜在机制。
我们对 300 多名受试者的 500 多个样本进行了特征分析。我们研究了 vedolizumab 与 T 细胞的结合，并研究了动态粘附、迁移、肠道归巢和体内游离结合位点的功能后果。我们采用单细胞 RNA 测序，对表达 α4β7 整合素的 T 细胞群体进行了“耐药性”分析，并在体外和 vedolizumab 治疗的 IBD 患者样本中验证了我们的发现。我们还将我们的发现与 Gemini II 和 III 研究的事后分析进行了相关性分析。
调节性 T (T) 细胞与效应性 T (T) 细胞相比，vedolizumab 结合曲线右移。一致地，在一定浓度范围内，T 细胞体内残留的粘附、迁移、归巢和功能性 α4β7 的可用性高于 T 细胞。我们发现了一个 vedolizumab-“耐药性”表达 α4β7 的β1PI16 T 细胞亚群，具有明显的调节特性，是这种效应的基础。我们的观察结果与 Gemini II 和 III 试验的暴露-疗效数据相关。
使用 vedolizumab 完全阻断 T 细胞迁移，同时基于目标暴露水平允许具有最佳“治疗窗”的强大 T 细胞残留归巢，可能是优化 IBD 患者治疗效果的一种策略。
