Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease.

ABSTRACT: Background: Anti-integrin therapy is a new frontline strategy in the treatment of inflammatory bowel diseases (IBD). The anti-?7 integrin antibody etrolizumab is currently being investigated for safety and efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in several phase III trials. Mechanistically, etrolizumab is known to block ?7 integrin ligand binding and reduces intestinal trafficking of ?7-expressing cells. Etrolizumab blocks ?7 integrin ligand binding and reduces ?7-positive lymphocyte migration and retention in the inflamed gut mucosa, but the exact mechanisms by which this inhibition occurs are not fully understood. Methods: Cellular effects of etrolizumab or etrolizumab surrogate antibody (etrolizumab-s) were investigated in cell culture models and analyzed by flow cytometry, fluorescence microscopy, ImageStream^®, stimulated emission depletion (STED) microscopy and functional dynamic in vitro adhesion assays. Moreover, effects on ?4?7 integrin were compared with the pharmacodynamically similar antibody vedolizumab. Results: As demonstrated by several different approaches, etrolizumab and etrolizumab-s treatment led to internalization of ?7 integrin. This resulted in impaired dynamic adhesion to MAdCAM-1. Internalized ?7 integrin localized in endosomes and re-expression of ?7 was dependent on de novo protein synthesis. In vitro etrolizumab treatment did not lead to cellular activation or cytokine secretion and did not induce cytotoxicity. Internalization of ?4?7 integrin was increased with etrolizumab compared with vedolizumab. Discussion: Our data suggest that etrolizumab does not elicit secondary effector functions on the single cell level. Integrin internalization may be an important mechanism of action of etrolizumab, which might explain some but not all immunological effects observed with etrolizumab.

SUBMITTER: Lichnog C 

PROVIDER: S-EPMC6367223 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature