Etrolizumab-s Does Not Induce Residual Trafficking of Regulatory T Cells.

ABSTRACT

BACKGROUND: Blocking immune cell gut homing via α4ß7 integrin with the monoclonal antibody vedolizumab is an established therapeutic strategy in inflammatory bowel disease. However, despite promising preclinical and phase 2 clinical data, the anti-ß7 antibody etrolizumab yielded disappointing results in a large phase 3 trial program in UC. Mechanistic explanations are still lacking. We have recently shown that vedolizumab is associated with residual homing of regulatory T (Treg) cells in a certain exposure range and aimed to investigate whether a similar mechanism applies for etrolizumab. METHODS: We used flow cytometry, competitive dynamic adhesion, and transmigration assays to assess binding of the etrolizumab surrogate (etrolizumab-s) antibody FIB504 to Treg and effector T cells (Teff) and to explore the impact on cell trafficking. RESULTS: We observed only minimal differences in the binding of etrolizumab-s to Treg and Teff cells. Dynamic adhesion and transmigration of Treg and Teff cells was not substantially differentially affected at relevant concentrations. The ß1+ and PI16+ Treg cells were only resistant to etrolizumab-s at low concentrations. CONCLUSIONS: Etrolizumab does not seem to induce notable residual trafficking of Treg cells. Thus, the Teff overweight in the inflamed gut might persist despite reduced overall T cell recruitment. This might be one piece of the puzzle to explain recent clinical results in phase 3.

The efficacy of etrolizumab in phase 3 was disappointing. Our data suggest that, unlike vedolizumab, etrolizumab does not induce relevant residual trafficking of regulatory T cells. This might be one part of the explanation for recent observations in clinical trials.