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Original research
Residual homing of α4β7-expressing β1+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab
  1. Emily Becker1,
  2. Mark Dedden1,
  3. Christine Gall2,
  4. Maximilian Wiendl1,
  5. Arif Bülent Ekici3,
  6. Anja Schulz-Kuhnt1,
  7. Anna Schweda1,
  8. Caroline Voskens4,5,
  9. Ahmed Hegazy6,7,8,
  10. Francesco Vitali1,
  11. Raja Atreya1,5,
  12. Tanja Martina Müller1,5,
  13. Imke Atreya1,5,
  14. Markus F Neurath1,5,
  15. Sebastian Zundler1,5
  1. 1Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
  2. 2Institute for Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
  3. 3Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
  4. 4Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
  5. 5Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
  6. 6Department of Gastroenterology, Infectiology and Rheumatology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Berlin, Germany
  7. 7Berlin Institute of Health (BIH), Berlin, Germany
  8. 8Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
  1. Correspondence to Dr Sebastian Zundler, Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Bayern, 91054 Erlangen, Germany; sebastian.zundler{at}uk-erlangen.de

Abstract

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.

  • IBD
  • adhesion molecules
  • T lymphocytes

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Footnotes

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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