Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives

Leukocyte trafficking to the gastrointestinal tract is recognized to play a role in the pathogenesis of inflammatory bowel disease (IBD). Integrins are expressed on immune cells and interact with cell adhesion molecules (CAM) to mediate leukocyte trafficking. Blockade of the gut-tropic integrin alpha 4 beta 7 and its subunits has been exploited as a therapeutic target in IBD. Natalizumab (anti-alpha 4) is approved for moderate to severe Crohn's disease (CD), but its use is limited due to potential risk of progressive multifocal leukoencephalo-pathy. Vedolizumab (anti-alpha 4 beta 7) is approved for the treatment of ulcerative colitis (UC) and CD. It is the most widely used anti-integrin therapy in IBD and has been shown to be effective in both induction and maintenance therapy, with a favorable safety profile. Several models incorporating clinical, genetic, immune, gut microbial, and vitamin D markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-beta 7) blocks leukocyte trafficking via alpha 4 beta 7 and cell adhesion via alpha E beta 7 integrins. Large phase 3 clinical trials evaluating efficacy of etrolizumab in the induction and maintenance of patients with IBD are underway. Other investigational anti-integrin therapies include abrilumab (anti-alpha 4 beta 7 IgG2), PN-943 (orally administered and gut-restricted alpha 4 beta 7 antagonist peptide), AJM300 (orally active small molecule inhibitor of alpha 4), and ontamalimab (anti-MAdCAM-1 IgG).

Automated summary

Leukocyte trafficking to the gastrointestinal tract plays a role in the pathogenesis of IBD. Blockade of gut-tropic integrin alpha 4 beta 7 has been explored as a therapeutic target, with Natalizumab and Vedolizumab approved for use in CD and UC. Vedolizumab is the most widely used anti-integrin therapy in IBD, showing effectiveness in both induction and maintenance therapy with a favorable safety profile.