The Binding Specificity and Selective Antagonism of Vedolizumab, an Anti-α₄β₇Integrin Therapeutic Antibody in Development for Inflammatory Bowel Diseases

Abstract

Vedolizumab is a humanized monoclonal antibody that targets the ␣ 4 ␤ 7 integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-␣ 4 chain monoclonal antibodies, such as natalizumab. This unique pharmacologic profile is largely attributable to four determinants. The first determinant is the restriction of the expression of the ␣ 4 ␤ 7 integrin to subsets of leukocytes. Vedolizumab does not bind to the majority of memory CD4 ϩ T lymphocytes (60%), neutrophils, and most monocytes. The highest level of vedolizumab binding is to a subset (ϳ25%) of human peripheral blood memory CD4 ϩ T lymphocytes that include gut-homing interleukin 17 T-helper lymphocytes. Vedolizumab also binds to eosinophils at high levels, and to naive T-helper lymphocytes, naive and memory cytotoxic T lymphocytes, B lymphocytes, natural killer cells, and basophils at lower levels; vedolizumab binds to memory CD4 ϩ T and B lymphocytes with subnanomolar potency (EC 50 ϭ 0.3-0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the ␣ 4 ␤ 7 integrin, and not to the ␣ 4 ␤ 1 and ␣ E ␤ 7 integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of ␣ 4 ␤ 7 -expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC 50 ] ϭ 0.02-0.06 g/ml) and fibronectin (IC 50 ϭ 0.02 g/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the ␣ 4 ␤ 7 integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of ␣ 4 ␤ 7 integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.

Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

“…Blockade of the a 4 b 7 integrin exclusively with the Act-1 mAb induced antiinflammatory effects and remission of disease in spontaneously colitic cotton-top tamarins (21). Vedolizumab (former versions: MLN0002, MLN02, LDP-02) is also a highly selective mAb that binds exclusively to the gut-tropic a 4 b 7 integrin; it does not bind to other a 4 or b 7 integrins, such as the a 4 b 1 integrin or the a E b 7 integrin (22). It inhibits the functional activity of the a 4 b 7 integrin by selectively antagonizing binding and adhesion to MAdCAM-1 and to the extracellular matrix glycoprotein fibronectin, but does not antagonize binding to VCAM-1 (22).…”

A review of liver disorders in inflammatory bowel disease (IBD)

“…Evidence collected from pre-licensure controlled trials reveal <2% of patients with Vedolizumab demonstrating > 5 times the upper limit of normal ALT elevation; which was similar to the placebo group [132]. No cases of significant liver toxicity has been reported till date.…”

Rôle et ciblage de l’intégrine α4β7 dans la physiopathologie des MICI et de l’infection par le VIH

“…Il joue un rôle central dans l'émergence et la progression de la maladie. Afin d'interférer avec ce processus et de séques-trer les lymphocytes dans les organes lymphoïdes secondaires pour éviter leur migration vers les sites d'inflammation, des anticorps monoclonaux (Acm) ciblant les interactions entre 47 et MAdCAM-1 ont été développés pour le traitement des MICI [8,9].…”