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FLUORESCENTLY LABELLED VEDOLIZUMAB VISUALIZES LOCAL DRUG DISTRIBUTION DURING COLONOSCOPY AND IDENTIFIES MUCOSAL TARGET CELLS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

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Introduction

Biological treatment in inflammatory bowel disease (IBD) patients is currently hampered by high non-response rates. To enhance personalized medicine and predict response to biological therapeutics such as vedolizumab, the working mechanism should be elucidated. We aimed to visualize macroscopic and microscopic vedolizumab distribution, assess target saturation and detect drug target cells during quantitative fluorescence molecular endoscopy (qFME) to improve understanding of the mechanism of action.

Aims & Methods

Vedolizumab-800CW was developed in-house and GMP produced. Forty-three qFME procedures were performed in thirty-seven IBD patients. Dose escalation was performed using 0.0mg, 4.5mg and 15mg. Subsequently, two patient cohorts were added that received 75mg or 300mg unlabelled vedolizumab prior to vedolizumab-800CW to assess target saturation. Extensive ex vivo analyses were performed to correlate in vivo findings to immune status, fluorescence, microscopic distribution and potential target cells.

Results

Macroscopically and microscopically a significant difference between inflamed and non-inflamed tissue was visualized and quantified (0.0227 and 0.0470 mm^-1, p<0.0001) for the 15 mg cohort. In addition, ex vivo analyses showed a clear dose-dependent increase (p<0.0001) of the fluorescent drug signal, whereas a decrease could be established after adding an unlabelled dose (p<0.0001). Fluorescence microscopy revealed clear membrane binding of vedolizumab-800CW to inflammatory cells and migration into the inflamed mucosa. Various immune cell types were abundantly present in areas with high vedolizumab signal compared to areas with low signal, whereas this was most prominent for plasma cells.

Conclusion

QFME using vedolizumab-800CW enabled visualization and quantification of macroscopic and microscopic vedolizumab distribution in the inflamed target organ. In addition, it showed the potential of qFME to improve understanding in of local drug distribution, target cell identification and target engagement, which could improve understanding of targeted drugs.