Research article summary (published 7 Jun 2009):

The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.

Full 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.

Author information

Author/s: Soler, Dulce (D); Chapman, Tobias (T); Yang, Li-Li (LL); Wyant, Tim (T); Egan, Robert (R); Fedyk, Eric R (ER);

Affiliation: Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther), published in United States. (Language: eng)

Reference: 2009-Sep; vol 330 (issue 3) : pp 864-75

Dates: Created 2009/08/21; Completed 2009/09/21;

PMID: 19509315, status: MEDLINE (last retrieval date: 9/21/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Antibodies, Monoclonal - pharmacology B-Lymphocytes - drug effects; metabolism Basophils - drug effects; metabolism Binding, Competitive - drug effects CD4-Positive T-Lymphocytes - drug effects; metabolism Cell Adhesion - drug effects Cell Line Fibronectins - metabolism Humans Immunohistochemistry

Immunohistochemistry Inflammatory Bowel Diseases - drug therapy Integrin alpha4beta1 - drug effects; metabolism Integrins - antagonists & inhibitors; metabolism Interleukin-17 - metabolism Killer Cells, Natural - drug effects; metabolism Leukocytes - drug effects; metabolism Protein Binding T-Lymphocytes, Helper-Inducer - metabolism Vascular Cell Adhesion Molecule-1 - metabolism

Associated Chemicals: Antibodies, Monoclonal (0) ; Fibronectins (0) ; Integrin alpha4beta1 (0) ; Integrins (0) ; Interleukin-17 (0) ; Vascular Cell Adhesion Molecule-1 (0) ; integrin alpha4beta7 (0) ; vedolizumab (0)

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