Potential Role of Exosomes in Countering Vedolizumab-Based Therapy in IBD Patients

Introduction Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic and debilitating inflammatory disorders of the gastrointestinal tract. In the development of new treatment options, it was realized that the attenuation of lymphocyte translocation into the inflamed gut tissue results in a reduction in local inflammation and thus decrease IBD severity. Vedolizumab (VDZ) is a monoclonal antibody targeting α 4 β 7 integrin, which is expressed specifically by a subset of gastrointestinal‐homing T‐lymphocytes. Although VDZ showed promising results in various clinical studies, in common with all existing IBD therapies, a significant number of patients do not respond and validated markers and mechanistic insights to predict the populations that will derive sustained benefit are currently lacking. We hypothesized that circulating exosomes express on their surface high levels of α 4 β 7 integrin, which could bind VDZ and interfere with its activity and therapeutic efficacy. Methods Exosomes were isolated from serum of blood donors and VDZ‐treated patients by polymer‐based precipitation (Exoquick), analysed for concentration (Exocet) and validated for exosomal markers expression. The surface expression of α 4 β 7 integrin was evaluated by flow cytometry on exosomes‐bound beads. The levels of exosome‐bound VDZ were investigated by Promonitor‐VDZ ELISA kit and western blot analysis. Finally, exosomes isolated from blood donor's serum were incubated with increasing concentration of VDZ and then exosomal‐bound VDZ levels were analysed. Results Flow cytometry analysis revealed that serum exosomes, either from the patients and from the donors, express high levels of the VDZ target, α 4 β 7 integrin. A significant VDZ levels were measured in exosomes purified from VDZ‐treated patient's serum exosomes. Of note, we found that exosomes purified from blood donor's serum were able to bind VDZ in dose‐dependent manner. Conclusions Our data suggest that circulating serum exosomes bind VDZ, as they express on the surface the target integrin. Accordingly, exosomes might contribute to drug sequestration, possibly affecting the therapeutic efficacy of VDZ in IBD patients. Further studies are needed to define the possible correlation between VDZ exosomal sequestration and patient's response. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .