Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease.

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Lichnog C, Klabunde S, Becker E, Fuh F, Tripal P, Atreya R, Klenske E, Erickson R, Chiu H, Reed C, Chung S, Neufert C, Atreya I, McBride J, Neurath MF, Zundler S

Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease.

Front Pharmacol. 2019 Feb 1;10:39. doi: 10.3389/fphar.2019.00039. eCollection 2019.

PubMed ID

30774593 [ View in PubMed

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Abstract

Background: Anti-integrin therapy is a new frontline strategy in the treatment of inflammatory bowel diseases (IBD). The anti-beta7 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 beta7 integrin ligand binding and reduces intestinal trafficking of beta7-expressing cells. Etrolizumab blocks beta7 integrin ligand binding and reduces beta7-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((R)), stimulated emission depletion (STED) microscopy and functional dynamic in vitro adhesion assays. Moreover, effects on alpha4beta7 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 beta7 integrin. This resulted in impaired dynamic adhesion to MAdCAM-1. Internalized beta7 integrin localized in endosomes and re-expression of beta7 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 alpha4beta7 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.

DrugBank Data that Cites this Article

Drugs

Etrolizumab

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Etrolizumab	Integrin beta-7	Protein	Humans	Yes	Binder Antibody	Details