Fluorescent labelled vedolizumab for real-time visualization and quantification of local drug distribution and pharmacodynamics in inflammatory bowel diseases during endoscopy (VISION)

Crohn’s disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract, collectively referred to as inflammatory bowel diseases (IBD). Symptoms mainly include abdominal pain, diarrhoea, bloody stool and cramps, but some patients also experience inflammatory responses in joints, eyes, skin or the liver. Extensive morbidity has been associated with societal burden due to pain, anxiety, and depression. Medical treatment consists of aminosalicylates, corticosteroids, immune modulators and biological agents to induce and maintain clinical remission and ultimately mucosal healing. Vedolizumab is a monoclonal antibody which blocks integrin α4β7 inhibiting trafficking of T-lymphocytes into the gut. Unfortunately, up to 60% of vedolizumab patients experience non-response. The mechanism of action of vedolizumab is not elucidated, predictors of response are unknown and data for local drug distribution in the gut are lacking. In this clinical trial, we investigate the feasibility of assessing local distribution of fluorescently labelled vedolizumab in the gut mucosa of IBD patients to finally enable prediction of therapy response in individual patients.

Study design

Vedolizumab (Entyvio, Takeda Pharma) was labelled to IRDye 800CW under cGMP conditions to yield clinical grade vedolizumab-800CW. Vedolizumab naïve IBD patients were included in this dose-escalation trial. Patients received an intravenous dose of fluorescently labelled vedolizumab of either 0 mg, 4.5 mg, 15 mg or 15 mg + 75 mg unlabelled vedolizumab 3 days prior colonoscopy. In vivo fluorescence imaging was assessed by fibre-based wide-field fluorescence molecular endoscopy (FME) and quantified by spectroscopy in healthy, mildly inflamed and severely inflamed tissue. All assessed tissue was biopsied for histopathological confirmation of the inflammation status, ex vivo examination of the fluorescent signal and fluorescence microscopy.

Thirty-eight patients were included and an interim analysis was performed after 20 patients (5 in each dose group), which showed an 8 fold higher fluorescent signal in severely inflamed tissue in the 15 mg dose group (0.049 Q*μfa,x [mm-1]) compared to the control group (0.006 Q*μfa,x [mm-1]) (p<0.05). Furthermore, in severely inflamed tissue the fluorescent signal within the 15 mg dose group was 2.5 times higher compared to healthy tissue (0.019 Q*μfa,x [mm-1]) (p<0.05). The addition of unlabelled vedolizumab gave similar results to the 15 mg group (p>0.99), suggesting that the drug target was still not saturated. The optimal dosage group of 15 mg was expanded up to 15 IBD patients. Fluorescence microscopy showed clustering of fluorescent signals especially in inflamed mucosa. Additional experiments to assess microscopic distribution of vedolizumab-800CW and detect vedolizumab target cells are ongoing.

VISION | OMIG
Overview figure of VISION study. A: Study design; B: In vivo fluorescence in non-inflamed and inflamed colonic tissue of one patient that received 15 mg vedolizumab-800CW; C: Quantified in vivo fluorescent signal showing a clear dose-dependent correlation to the inflammation severity; D: Ex vivo results showing fluorescence in inflamed tissue and a corresponding fluorescence microscope image.

Results

In vivo quantification of fluorescent vedolizumab revealed a clear dose-dependent correlation between mucosal drug concentrations and the severity of mucosal inflammation. Fluorescence molecular endoscopy is a promising novel tool to get insight in drug distribution in IBD, detect target cells, assess target engagement and possibly predict therapy response in individual patients.