Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti-β7 integrin therapy for inflammatory bowel disease

Background: Novel treatments with superior benefit-risk profiles are needed to improve the long-term prognosis of patients with inflammatory bowel disease (IBD). Etrolizumab-a monoclonal antibody that specifically targets 7 integrins-is currently under phase III clinical evaluation in IBD. Aim: This review summarises the available pharmacological and pharmacokinetic/pharmacodynamic data for etrolizumab to provide a comprehensive understanding of its mechanism of action (MOA) and pharmacological effects. Methods: Published and internal unpublished data from nonclinical and clinical studies with etrolizumab are reviewed. Results: Etrolizumab exerts its effect via a unique dual MOA that inhibits both leucocyte trafficking to the intestinal mucosa and retention within the intestinal epithelial layer. The gut-selectivity of etrolizumab results from its specific targeting of the beta 7 subunit of alpha 4 beta 7 and alpha E beta 7 integrins. Etrolizumab does not bind to alpha 4 beta 1 integrin, which mediates lymphocyte trafficking to tissues including the central nervous system, a characteristic underlying its favourable safety with regard to progressive multifocal leucoencephalopathy. Phase I/II studies in patients with ulcerative colitis (UC) showed linear pharmacokinetics when etrolizumab was administered subcutaneously at 100 mg or higher once every 4weeks. This dose was sufficient to enable full beta 7 receptor occupancy in both blood and intestinal tissues of patients with moderate to severe UC. The phase II study results also suggested that patients with elevated intestinal expression of alpha E integrin may have an increased likelihood of clinical remission in response to etrolizumab treatment. Conclusion: Etrolizumab is a gut-selective, anti-beta 7 integrin monoclonal antibody that may have therapeutic potential for the treatment of IBD.