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In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease

Nature Medicine volume 20, pages 313–318 (2014)Cite this article

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Abstract

As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF+ immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF+ cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF+ cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.

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Figure 1: Ex vivo molecular imaging of mTNF in gut samples of patients with Crohn's disease using fluorescent adalimumab.
Figure 2: In vivo molecular imaging of mTNF+ mucosal immune cells in the gut of patients with Crohn's disease.
Figure 3: Clinical findings of the study.

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Acknowledgements

We thank I. Zöller-Utz, P. Drummer and G. Göhring-Waldeck for excellent technical support, A. May for monitoring our study and S. Brand and F. Kolligs (University Hospital Munich-Grosshadern) for their contribution to the follow-up endoscopies. We thank the whole team of the Endoscopy Unit of the Medical Clinic 1 of the University Erlangen-Nuremberg, which greatly supported this work. We thank all patients who participated in this study. This research was supported by the German Research Foundation (clinical research unit KFO257) and the Emerging Fields Initiative and the Interdisciplinary Center for Clinical Research of the University Erlangen-Nuremberg, which helped to establish the infrastructure needed to conduct this study. Funds from the German Ministry for Science and Education (BMBF ZooMAP 01KI1003G) were used for intestinal sample preparation. The infrastructure of the presented project was supported by the Ludwig Demling Research Prize of the Deutsche Morbus Crohn/Colitis Ulcerosa Vereinigung (R.A.) and the United European Gastroenterology Federation Research Prize (M.F.N.).

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Authors and Affiliations

  1. Medical Clinic 1, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Raja Atreya, Helmut Neumann, Clemens Neufert, Maximilian J Waldner, Ulrike Billmeier, Yurdagül Zopf, Marcus Willma & Markus F Neurath

  2. Department of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Christine App & Ewald Hannappel

  3. Department of Anesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Tino Münster

  4. Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Hermann Kessler

  5. Center for Clinical Studies, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Stefanie Maas & Bernd Gebhardt

  6. Department of Pharmacy, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Ralph Heimke-Brinck, Eva Reuter & Frank Dörje

  7. Department of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Tilman T Rau

  8. Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Wolfgang Uter

  9. Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

    Thomas D Wang

  10. Medical Clinic, St. Mary's Hospital, Frankfurt, Germany

    Ralf Kiesslich

  11. Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany

    Michael Vieth

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Contributions

R.A. and M.F.N. designed and conducted the study, processed the data, performed the experiments, supervised the project and wrote the paper. H.N., C.N., M.J.W. and U.B. conducted the study, designed and performed the experiments and processed the data. Y.Z. and M.W. designed the study and processed the data. C.A., T.M. and H.K. performed the experiments and processed the data. S.M., B.G., T.D.W. and R.K. designed the study and processed the data. R.H.-B., E.R., F.D., T.T.R., W.U., M.V. and E.H. designed and performed the experiments and processed the data. All authors contributed to the review and editing of the manuscript.

Corresponding author

Correspondence to Markus F Neurath.

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Competing interests

R. Atreya holds a professorship at the University of Erlangen-Nuremberg that is supported by a grant from Abbott. M.F.N. or R.A. have served as advisors to MSD, Pentax, Giuliani or Abbott.

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Atreya, R., Neumann, H., Neufert, C. et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease. Nat Med 20, 313–318 (2014). https://doi.org/10.1038/nm.3462

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