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

• Published in: Inflammatory bowel diseases 2022-11, Vol.28 (11), p.1746-1755
• Main Authors: Schweda, Anna, Becker, Emily, Wiendl, Maximilian, Atreya, Raja, Atreya, Imke, Müller, Tanja M, Neurath, Markus F, Zundler, Sebastian
• Format: Article
• Language: English
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1093/ibd/izac137

Abstract Background Blocking immune cell gut homing via α4β7 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-β7 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 β1+ 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. Lay Summary 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.