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.