ECCO Grant Study Synopsis: Sebastian Zundler
Sebastian Zundler, ECCO Grant Awardee
Dose-related differential effects of vedolizumab on leukocyte subsets
© Sebastian Zundler
Aim of research
The anti-α4β7 integrin antibody vedolizumab is successfully used for the clinical treatment of IBD. However, some details of its mechanisms are still not clear. Moreover, whether dose intensification of vedolizumab therapy may also increase response rates is the subject of ongoing debate, as some previous studies have suggested a non-linear exposure–efficacy correlation. Since only a portion of patients benefit from vedolizumab therapy, further translational insights into these aspects are an important unmet need for therapy optimisation and the development of personalised treatment approaches.
Based on preliminary data we hypothesise that vedolizumab has a differential preference of binding to distinct leukocyte subsets (e.g. effector and regulatory T cells), resulting in specific profiles of targeted immune cells at a certain level of vedolizumab exposure. This may explain the suggested non-linear exposure–efficacy correlation. Therefore, we aim to elucidate dose-dependent binding characteristics to leukocyte subsets and related functional aspects in vitro and in vivo.
Methodology/experiments that will be used
To achieve these aims, we intend to determine dose-dependent binding of vedolizumab to and saturation of α4β7 integrin on peripheral blood mononuclear cells from IBD patients. Moreover, we aim to confirm our findings on a functional level with assays investigating adhesion, transmigration and in vivo gut homing. These data will be corroborated in an observational study assessing vedolizumab exposure and efficacy of α4β7 integrin blockade on various immune cell subsets in patients clinically treated with vedolizumab. Finally, we aim to make use of next generation sequencing and proteomics to explore the mechanisms underlying the differential preference of vedolizumab for different leukocyte subsets.
Anticipated main impact
These investigations could be key to the determination of optimised (individual) vedolizumab doses by therapeutic drug monitoring.
We anticipate that the intended experiments will be performed by mid-2021.