Objective The anti-α4β7 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 α4β7 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 (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-‘resistant’ α4β7-expressing β1+PI16+ TReg 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 TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal ‘therapeutic window’ based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
- adhesion molecules
- T lymphocytes
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Contributors EB and AS performed experiments. EB and SZ designed the study. EB, MW, AS-K, RA, IA, TMM, CV, ANH, FV, MFN and SZ provided clinical samples, protocols or reagents; ABE and MD performed and analysed RNA sequencing; CG, EB and SZ performed statistical analysis of the phase III data; EB, MD, MW, MFN and SZ analysed and interpreted the data. EB and SZ drafted the manuscript with the help of MFN; all authors critically revised the manuscript for important intellectual content.
Competing interests MFN has served as an advisor for Pentax, Giuliani, MSD, Abbvie, Janssen, Takeda and Boehringer. SZ received honoraria from Takeda, Roche and Janssen. MFN and SZ received research support from Takeda, Shire (a part of Takeda) and Roche. The other authors declare no conflicts of interest.
Provenance and peer review Not commissioned; externally peer reviewed.
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