Residual homing of alpha 4 beta 7-expressing beta 1(+)PI16(+) regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab

Becker E, Dedden M, Gall C, Wiendl M, Ekici AB, Schulz-Kuhnt A, Schweda A, Bosch-Voskens C, Hegazy A, Vitali F, Atreya R, Müller T, Atreya I, Neurath M, Zundler S (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Gut BMJ Publishing Group

DOI: 10.1136/gutjnl-2021-324868

Abstract

Objective The anti-alpha 4 beta 7 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. Design 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 alpha 4 beta 7 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. Results Regulatory T (T-Reg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (T-Eff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional alpha 4 beta 7 on T-Reg cells in vivo was higher than that of/on T-Eff cells. We identified a vedolizumab-'resistant' alpha 4 beta 7-expressing beta 1(+)PI16(+) T-Reg 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. Conclusion Completely blocking T-Eff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful T-Reg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.

Authors with CRIS profile

Emily Becker Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Mark Dedden Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Christine Gall Lehrstuhl für Biometrie und Epidemiologie Maximilian Wiendl Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Arif Bülent Ekici Institute of Human Genetics Anja Schulz-Kuhnt Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Caroline Bosch-Voskens Professur für Translationale Immundermatologie Francesco Vitali Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Tanja Müller Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Imke Atreya Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Becker, E., Dedden, M., Gall, C., Wiendl, M., Ekici, A.B., Schulz-Kuhnt, A.,... Zundler, S. (2021). Residual homing of alpha 4 beta 7-expressing beta 1(+)PI16(+) regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab. Gut. https://doi.org/10.1136/gutjnl-2021-324868

MLA:

Becker, Emily, et al. "Residual homing of alpha 4 beta 7-expressing beta 1(+)PI16(+) regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab." Gut (2021).

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