Development of Drugs to Target Interactions Between Leukocytes and Endothelial Cells and Treatment Algorithms for Inflammatory Bowel Diseases

Increased understanding of the pathogenesis of inflammatory bowel diseases (IBDs) has led to new therapeutic strategies. One of these is to target the molecules that regulate interactions between leukocytes and endothelial cells at sites of inflammation (mainly leukocyte integrins and endothelial cell adhesion molecules of the immunoglobulin superfamily). These molecules have been validated as therapeutic targets for IBD; several have shown efficacy, and 2 have been approved by the Food and Drug Administration for treatment of IBD. Natalizumab, the first anti-integrin antibody tested for treatment of IBD, blocks the alpha 4 subunit. Although it is effective, its clinical use has been limited by its association with risk of progressive multifocal leukoencephalopathy. Other, allegedly more selective drugs that affect leukocyte recruitment in the gastrointestinal tract have been developed or are under investigation and could increase safety. These include vedolizumab and AMG 181 (antibodies against alpha(4)beta(7)), etrolizumab (anti-beta(7)), and PF-00547659 (anti-mucosal vascular addressin cell adhesion molecule 1). Other agents have been developed to block alpha(4) (the small molecule AJM300), CCR9 (the small molecule CCX282-B), and CXCL10 (the antibody eldelumab). We review the scientific rationale for inhibiting interactions between leukocytes and endothelial cells to reduce intestinal inflammation and analyze the clinical studies that have been performed to test these new molecules, with particular attention to safety. We propose an evidence-based clinical positioning of this class of drugs.