Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease

Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between alpha 4 beta 7 and its ligand, mucosal addressin cellular adhesion molecule-1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by alpha E beta 7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease pathobiology. This review will provide an overview of integrin structure, function and signalling, and highlight the role that these molecules play in leukocyte homing and retention. Anti-integrin therapeutics, including gut-selective antibodies against the beta 7 integrin subunit [etrolizumab] and the alpha 4 beta 7 integrin heterodimer [vedolizumab and abrilumab], and the non-gut selective anti-alpha 4 integrin [natalizumab], will be discussed, as well as novel targeting approaches using small molecules.