Abstract
Vedolizumab is a humanized monoclonal antibody that targets the α4β7 integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-α4 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 α4β7 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 (∼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 (EC50 = 0.3–0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the α4β7 integrin, and not to the α4β1 and αEβ7 integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of α4β7-expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC50] = 0.02–0.06 μg/ml) and fibronectin (IC50 = 0.02 μg/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the α4β7 integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of α4β7 integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.
Footnotes
-
This work was supported by Millennium Pharmaceuticals Inc.
-
Some of these data were presented at the 2008 Advances in Inflammatory Bowel Diseases Crohn's and Colitis Foundation's Clinical and Research Conference; 2008 Dec 4–7; Hollywood, FL; and at the 4th Congress of the European Crohn's and Colitis Organisation; 2009 Feb 5–7; Hamburg, Germany.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.109.153973.
-
ABBREVIATIONS: IBD, inflammatory bowel disease; BSA, bovine serum albumin; CD, Crohn's disease; Fc, fragment crystallizable; GI, gastrointestinal; GMFI, geometric mean fluorescence intensity; mAb, monoclonal antibody; IL, interleukin; MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1; PBMC, peripheral blood mononuclear cell; PBS, phosphate-buffered saline; PML, progressive multifocal leukoencephalopathy; Th17, T-helper 17; UC, ulcerative colitis; VCAM-1, vascular cell adhesion molecule 1.
- Received March 26, 2009.
- Accepted June 8, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|