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

John Gubatan,1 Kian Keyashian,1 Samuel JS Rubin,2,3 Jenny Wang,2 Cyrus A Buckman,2 Sidhartha Sinha1 1Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA; 2Stanford University School of Medicine, Stanford, CA, USA; 3Immunology Program, Stanford University School of Medicine, Stanford, CA, USACorrespondence: John Gubatan Email jgubatan@stanford.eduAbstract: 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 α 4β 7 and its subunits has been exploited as a therapeutic target in IBD. Natalizumab (anti-α 4) is approved for moderate to severe Crohn’s disease (CD), but its use is limited due to potential risk of progressive multifocal leukoencephalopathy. Vedolizumab (anti-α 4β 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-β 7) blocks leukocyte trafficking via α 4β 7 and cell adhesion via αEβ 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-α 4β 7 IgG2), PN-943 (orally administered and gut-restricted α 4β 7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α 4), and ontamalimab (anti-MAdCAM-1 IgG).Keywords: anti-integrin, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, vedolizumab, natalizumab, etrolizuma