Etrolizumab

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is characterized by chronic inflammation of the gastrointestinal tract. This inflammation is driven, at least in part, by excessive infiltration and retention of intestinal-homing lymphocytes. An adhesion cascade drives the infiltration of immune cells. The binding of immune cell glycoproteins to their corresponding epithelial cell selectins results in partial retention and the "rolling" of immune cells along the endothelium. A stable arrest is mediated by stronger interactions between immune cell integrins and cell adhesion molecules (CAMs) on the endothelial cell; once arrested, immune cells will extravasate and enter the target tissue. Tissue retention is mediated by similar interactions between cell-surface molecules within the target tissue, which impedes immune cells' re-entry into the systemic circulation.

Integrins are heterodimeric cell-surface receptors comprising transmembrane α and β subunits, of which multiple forms exist. Integrins primarily interact with CAMs, which are cell-surface members of the immunoglobulin superfamily expressed on vascular endothelial cells. Of primary importance to intestinal homing is the mucosal addressin cellular adhesion molecule (MAdCAM-1), which interacts strongly with α4β7 integrins, and vascular cell adhesion molecule (VCAM-1), which binds with lower affinity. MAdCAM-1 also binds to the CS-1 fragment of the extracellular matrix molecule fibronectin. α4β7 integrin is expressed at high levels on intestinal-homing lymphocytes but can also be found on natural killer cells, basophils, eosinophils, macrophages, activated monocytes, and mast cells. Another β7-containing integrin, αEβ7, is primarily expressed by lymphocytes, dendritic cells, mast cells, and innate lymphoid cells within the mucosal immune system, including the respiratory, gastrointestinal, and urogenital tracts, where it interacts with E-cadherin on mucosal tissue cells.

The infiltration and retention of immune cells as a mechanism of IBD is suggested by observations across multiple studies of an increase in the number of, and alteration in the secreted cytokine profile of, α4β7+ and αEβ7+ immune cells in the gastrointestinal tract of IBD patients. These observations mirror an increase in the expression of the relevant CAMs, MAdCAM-1 and E-cadherin, in these patients. Although the mechanism has not been completely elucidated, it is clear that an increase in the number and retention of gut-homing immune cells capable of sustaining an inflammatory microenvironment is a crucial element of IBD pathophysiology.

Etrolizumab is a humanized monoclonal antibody specific for the β7 integrin subunit; it has a Kd of 116 ± 11 pmol/L against human α4β7 and 1800 ± 170 pmol/L against human αEβ7, as assessed by transfection in HEK293 cells. This strong binding provides efficient inhibition of integrin/CAM interactions. Etrolizumab has an IC50 for the α4β7 interactions with MAdCAM-1, VCAM-1, and fibronectin of 0.075 ± 0.034, 0.089 ± 0.009, and 0.119 ± 0.056 nmol/L, respectively. Etrolizumab also inhibits the interaction of αEβ7 with E-cadherin, albeit less effectively (IC50 of 3.96 ± 1.78 nmol/L). While etrolizumab does not exhibit antibody-dependent cytotoxicity, it disrupts the integrin-CAM interactions involved in gut immune cell residence, in part by inducing the endocytic uptake of bound integrin receptors, and therefore reduces the inflammatory burden in IBD.