The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
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Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER
The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
J Pharmacol Exp Ther. 2009 Sep;330(3):864-75. doi: 10.1124/jpet.109.153973. Epub 2009 Jun 9.
- PubMed ID
- 19509315 [ View in PubMed]
- Abstract
Vedolizumab is a humanized monoclonal antibody that targets the alpha(4)beta(7) integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-alpha(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 alpha(4)beta(7) integrin to subsets of leukocytes. Vedolizumab does not bind to the majority of memory CD4(+) T lymphocytes (60%), neutrophils, and most monocytes. The highest level of vedolizumab binding is to a subset (approximately 25%) of human peripheral blood memory CD4(+) 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(+) T and B lymphocytes with subnanomolar potency (EC(50) = 0.3-0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the alpha(4)beta(7) integrin, and not to the alpha(4)beta(1) and alpha(E)beta(7) integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of alpha(4)beta(7)-expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC(50)] = 0.02-0.06 microg/ml) and fibronectin (IC(50) = 0.02 microg/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the alpha(4)beta(7) integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of alpha(4)beta(7) integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Vedolizumab Integrin alpha-4 Protein Humans YesAntibodyDetails Vedolizumab Integrin beta-7 Protein Humans YesAntibodyDetails