Etrolizumab Treatment Does Not Modify Levels of VCAM-1 in Ulcerative Colitis Patients

Abstract

Introduction: Etrolizumab, an anti-β7 mAb, targets the integrins α4β7 and αEβ7 and inhibits the interaction of α4β7 with MAdCAM-1 and VCAM-1, and αEβ7 with E-cadherin. IBD patients have higher expression levels of MAdCAM-1 and ICAM-1 in the gut tissue compared to controls. Expression levels of VCAM-1 (Jones et al., 1995; Panes et al., 2003), an adhesion molecule involved in cell trafficking across the blood-brain barrier, are reported to be similar between IBD patients and controls. We demonstrated that etrolizumab treatment in patients with moderate-to-severe ulcerative colitis (UC) modulates MAd-CAM-1 and E-cadherin in serum and colonic tissue (Vermeire et al., 2012; Fuh et al., 2015; unpublished data) whereas natalizumab has been shown to decrease serum VCAM-1 in multiple sclerosis patients (Millonig et al., 2010). We explored the role of etrolizumab treatment on VCAM-1 and ICAM-1 serum levels and expression in colonic tissue among patients in the Phase 2 EUCALYPTUS study. Methods: Phase 2 UC patients were randomized into 1 of 3 different treatment arms during an induction period of 10 weeks: placebo (n=36), etrolizumab 100mg (n=28), and etrolizumab 300mg (n=34). Soluble VCAM-1 and ICAM-1 were measured at baseline and during the treatment period using commercially available ELISA assays and tissue expression was assessed in biopsy tissue by qPCR. Results: No differences were observed in serum soluble VCAM-1 levels in the etrolizumab- or placebotreated arms, nor was an association found with clinical remission or response. Similar results were observed in VCAM-1 expression in colonic tissue on day 43 and day 71. There was no dose-related decrease of ICAM-1 expression in serum or colonic tissue in the treated arms. However, levels of expression in colonic tissue of clinical responders, in both etrolizumab and placebo treated arms, had a median reduction of ≥50% at day 43 that was maintained through day 71. Conclusion: Lack of changes in VCAM-1 levels in both colonic tissue and in serum is consistent with the mechanism of action of etrolizumab, which does not block interaction of α4β1 with VCAM-1. The observed downmodulation of ICAM-1 expression is likely due to a decrease in tissue inflammation and not direct targeting of the pathway. These and prior data indicate that etrolizumab modulates expression of gut-specific MAdCAM-1 and suggests that it does not affect lymphocyte trafficking to the CNS via VCAM-1 modulation. Funded by Genentech.