Limited dose-dependent effects of vedolizumab on various leukocyte subsets

Abstract

OBJECTIVES: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.METHODS: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.RESULTS: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.DISCUSSION: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.

Using fluorescently labeled vedolizumab to visualize local drug distribution during colonoscopy and identify mucosal target cells in patients with inflammatory bowel disease

“…Specifically, our fluorescence microscopic analysis revealed both surface and intracellular vedo-800CW binding. In addition, consistent with recent findings 14,17,19 we found that vedolizumab binds to a variety of immune cell types, including plasma cells, macrophages, and eosinophils whereas an actual correlation between T cells and vedo-800CW was not observed. These findings support the hypothesis that T cell migration to the mucosa is prevented and that T cells are likely not the sole therapeutic target of vedolizumab.…”

“…10,19 Here, we found intracellular localization of vedolizumab in both macrophages and eosinophils, consistent with previous studies showing an interaction between vedolizumab and α4β7expressing macrophages and eosinophils. 12,17,29 Although this interaction between vedolizumab and various immune cell types is well established, the consequences of this drug binding to different immune cell types remain poorly understood and require further study.…”

“…[8][9][10] In contrast, recent studies suggest that a wide range of α4β7-expressing immune cells may be involved in mediating vedolizumab's anti-inflammatory effects. [11][12][13][14][15][16][17][18][19] However, none of these experimental studies directly visualized the tissue distribution of vedolizumab or its interaction with target cells in the inflamed gut mucosa.…”

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis

“…There are conflicting data regarding the primary mechanism of action of VDZ. VDZ has been reported to bind to CD4 T, CD8 T, B, NK, and granulocytes in the peripheral blood 51,52 . Here we confirm that VDZ shifts α 4 β 7 + cells from the colon to the circulation for most cell types, but this results in a small net change in tissue cell frequency for most cell subsets, apart from MNPs.…”

Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing

“…In this context, the data that we present in this manuscript shed a new light on etrolizumab, since we show that non‐classical monocytes are a target of the antibody. Although an impact of etrolizumab on innate immune cell subsets in general and non‐classical monocytes in special had to be concluded in analogy to what is known for vedolizumab, 27 , 39 , 40 , 41 these data are the first to show that this effect may go beyond vedolizumab due to the expression of αEβ7 by a fraction of these cells. Indeed, our functional analyses demonstrate that etrolizumab specifically impedes the adhesion of non‐classical monocytes not only to MAdCAM‐1, but also to E‐Cadherin.…”