Figure 3.

Strategies to target adhesion molecules in disease. Several adhesion molecule inhibitors (both small molecules and mAbs) have been developed to treat inflammatory disorders. To date, efalizumab is the only integrin-blocking therapy to have been approved for use in skin diseases, although it was subsequently withdrawn owing to severe complications. Nonetheless, these drugs illustrate potential opportunities and pitfalls in designing adhesion-based therapeutics. Whereas vedolizumab exhibits exquisite specificity by binding to a conformational epitope unique to the heterodimerization of α₄ and β₇ integrins, natalizumab and efalizumab encountered problems owing to the promiscuity of their integrin targets (α₄ and α_L, respectively). Etrolizumab, a β₇ integrin‒blocking monoclonal in phase III clinical trials for the treatment of IBD may have relevance to skin disease given the importance of α_Eβ₇ on skin-resident T cells (Sandborn et al., 2020). One of methotrexate’s proposed mechanisms is the downregulation of selectin and immunoglobulin superfamily molecules expressed on endothelial cells. However, only limited success has been observed with a monoclonal (PF-00547659) targeting MAdCAM-1 on mucosal endothelium (Sandborn et al., 2018). IBD, inflammatory bowel disease.