Residual homing of α4β7-expressing β1⁺PI16⁺ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab.

Abstract

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. 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. 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 α4β7 on T_Reg cells in vivo was higher than that of/on T_Eff cells. We identified a vedolizumab-'resistant' α4β7-expressing β1⁺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. 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.