A humanized monoclonal antibody targeting the beta7 integrin selectively blocks intestinal homing of T lymphocytes.

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Stefanich EG, Danilenko DM, Wang H, O'Byrne S, Erickson R, Gelzleichter T, Hiraragi H, Chiu H, Ivelja S, Jeet S, Gadkari S, Hwang O, Fuh F, Looney C, Howell K, Albert V, Balazs M, Refino C, Fong S, Iyer S, Williams M

A humanized monoclonal antibody targeting the beta7 integrin selectively blocks intestinal homing of T lymphocytes.

Br J Pharmacol. 2011 Apr;162(8):1855-70. doi: 10.1111/j.1476-5381.2011.01205.x.

PubMed ID

21232034 [ View in PubMed

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Abstract

BACKGROUND AND PURPOSE: rhuMAb Beta7 is a humanized anti-human beta7 monoclonal antibody currently in phase I in inflammatory bowel disease. rhuMAb Beta7 binds the beta7 subunit of the integrins alpha4beta7 and alphaEbeta7, blocking interaction with their ligands. These integrins play key roles in immune cell homing to and retention in mucosal sites, and are associated with chronic inflammatory diseases of the gastrointestinal tract. The goal of this study was to evaluate the mucosal specificity of rhuMAb Beta7. EXPERIMENTAL APPROACH: We assessed the effect of murine anti-Beta7 on lymphocyte homing in mouse models of autoimmune disease. We also compared the effect of rhuMAb Beta7 on circulating mucosal-homing versus peripheral-homing T cells in naive non-human primates. KEY RESULTS: In cynomolgus monkeys, occupancy of beta7 integrin receptors by rhuMAb Beta7 correlated with an increase in circulating beta7(+) mucosal-homing lymphocytes, with no apparent effect on levels of circulating beta7(-) peripheral-homing lymphocytes. rhuMAb Beta7 also inhibited lymphocyte homing to the inflamed colons of severe combined immunodeficient mice in CD45RB(high) CD4(+) T-cell transfer models. Consistent with a lack of effect on peripheral homing, in a mouse model of experimental autoimmune encephalomyelitis, anti-beta7 treatment resulted in no amelioration of CNS inflammation. CONCLUSIONS AND IMPLICATIONS: The results presented here suggest that rhuMAb Beta7 selectively blocks lymphocyte homing to the gastrointestinal tract without affecting lymphocyte trafficking to non-mucosal tissues. rhuMAb Beta7 provides a targeted therapeutic approach with the potential for a more attractive benefit:risk ratio than currently available inflammatory bowel disease therapies.

DrugBank Data that Cites this Article

Drugs

Etrolizumab

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Etrolizumab	Integrin beta-7	Protein	Humans	Yes	Binder Antibody	Details