Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Clin Transl Gastroenterol. 2022 Jun 1;13(6):e00494. doi: 10.14309/ctg.0000000000000494.
The anti-α4β7 integrin antibody vedolizumab (VDZ) is successfully used for the treatment of inflammatory bowel diseases. However, only a subgroup of patients respond to therapy. VDZ is administered at a fixed dose, leading to a wide range of serum concentrations in patients. Previous work from our group showed a dose-dependent preferential binding of VDZ to effector compared with regulatory CD4 + T cells. Therefore, we aimed to determine the dose-dependent binding profile of VDZ to other leukocyte subsets.
We characterized α4β7 integrin expression on CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils from patients with inflammatory bowel disease and healthy controls. We studied the binding of VDZ to these cells at different concentrations and investigated the functional consequences for dynamic adhesion and transmigration in vitro .
The expression of α4β7 differed between the analyzed leukocyte subsets and was significantly higher on eosinophils from inflammatory bowel disease patients compared with controls. Almost all α4β7-expressing cells from these subsets were bound by VDZ at a concentration of 10 μg/mL. Dynamic cell adhesion was significantly impaired in all subsets, but there were no dose-dependent differences in the inhibition of adhesion.
Our data suggest that α4β7-expressing CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils are a target of VDZ. However, there do not seem to be concentration-dependent differences, regarding the effects on these cells in the clinically relevant range. Thus, the reported exposure-efficacy characteristic of VDZ can probably mainly be attributed to CD4 + T-cell subsets.
抗 α4β7 整合素抗体维多珠单抗（VDZ）成功用于治疗炎症性肠病。然而，只有一部分患者对治疗有反应。VDZ 以固定剂量给药，导致患者的血清浓度范围很广。我们小组的先前工作表明，VDZ 对效应 CD4+T 细胞的亲和力与调节性 CD4+T 细胞相比具有剂量依赖性。因此，我们旨在确定 VDZ 对其他白细胞亚群的剂量依赖性结合特征。
我们从炎症性肠病患者和健康对照者中鉴定了 CD8+T 细胞、CD19+B 细胞、CD14+单核细胞、自然杀伤细胞和嗜酸性粒细胞上的 α4β7 整合素表达。我们研究了 VDZ 在不同浓度下与这些细胞的结合，并研究了体外动态粘附和迁移的功能后果。
分析的白细胞亚群之间的 α4β7 表达不同，炎症性肠病患者的嗜酸性粒细胞上的表达明显高于对照组。来自这些亚群的几乎所有 α4β7 表达细胞都在 10μg/mL 的浓度下被 VDZ 结合。所有亚群的动态细胞粘附均显著受损，但在粘附抑制方面没有剂量依赖性差异。
我们的数据表明，α4β7 表达的 CD8+T 细胞、CD19+B 细胞、CD14+单核细胞、自然杀伤细胞和嗜酸性粒细胞是 VDZ 的靶标。然而，在临床相关范围内，针对这些细胞的作用似乎没有浓度依赖性差异。因此，VDZ 报道的暴露-疗效特征可能主要归因于 CD4+T 细胞亚群。
