P209. In vivo molecular imaging using fluorescent anti-TNF antibodies and confocal laser endomicroscopy predicts response to anti-TNF therapy in Crohn's disease patients
R. Atreya1, H. Neumann1, C. Neufert1, M.J. Waldner1, Y. Zopf1, M. Willma1, C. App2, T. Münster3, H. Kessler4, S. Maas5, B. Gebhardt5, R. Heimke-Brinck6, E. Reuter6, F. Dörje6, T.T. Rau7, T.D. Wang8, R. Kiesslich9, M. Vieth10, E. Hannappel2, M.F. Neurath1, 1Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 2Department of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 3Department of Anesthesiology, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 4Department of Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 5Center for Clinical Studies, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 6Pharmacy Department, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 7Department of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Germany, 8Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, United States, 9Medical Clinic, St. Mary's Hospital, Frankfurt, Germany, 10Institute of Pathology, Klinikum Bayreuth, Germany
Only a subgroup of Crohn's disease (CD) patients responds to anti-TNF therapy. A reliable method to predict the therapeutic response is needed. As these antibodies mediate their immunosuppressive effects by binding to membrane-bound TNF (mTNF) expressing mucosal cells, we hypothesized that in vivo detection of such cells might be used to predict therapeutic efficacy.
Aim of our clinical study (ClinicalTrials.gov: NCT01275508) was to visualize mucosal mTNF expression in humans using confocal laser endomicroscopy (CLE) with topical application of a Good Manufacturing Practice-conform fluorescent anti-TNF antibody (FITC-Adalimumab). This novel in vivo diagnostic modality was used to predict clinical response to subsequent therapy with the anti-TNF antibody Adalimumab in CD patients.
Fifteen CD patients with indication for anti-TNF therapy were prospectively included in this study. The newly developed FITC-Adalimumab was topically applied via a spraying catheter onto the inflamed mucosa of CD patients during a colonoscopy prior to anti-TNF therapy. Fluorescein expression on a cellular level, indicating mucosal mTNF+ cells, was identified and quantified via CLE. CD patients were then treated with Adalimumab and changes of the CDAI score were correlated to the amount of mTNF+ cells in the mucosa. Response to treatment was defined as a decrease in the CDAI ≥100 points from baseline after 12 weeks of therapy.
Adalimumab binding to mTNF+ intestinal cells and visualization of the FITC moiety during CLE enabled assessment of mTNF expression in CD patients in vivo during ongoing endoscopy. No serious adverse events were observed. The significant difference in the mean number of mTNF+ cells per image was 39 for Adalimumab responders and 11 for non-responders. Sensitivity, specificity and accuracy for the prediction of therapeutic responses based on a discriminative factor of 20 positive cells, were 90%, 93% and 91%, respectively. Positive and negative predictive values were 96% and 82%.
Our data indicate a significant correlation between the efficacy of Adalimumab therapy and prior in vivo detected expression of mucosal mTNF+ cells in CD patients. Patients with heightened mTNF expression showed a higher response rate than those with diminished mTNF expression. These data indicate for the first time that molecular imaging with fluorescent antibodies in vivo has the potential to predict therapeutic responses to anti-TNF treatment and opens new avenues for personalized medicine.