title: A humanized monoclonal antibody targeting the β7 integrin selectively blocks intestinal homing of T lymphocytes.
abstract: OBJECTIVE
  rhuMAb Beta7 is a humanized anti-human β7 monoclonal antibody currently in phase I in inflammatory bowel disease. rhuMAb Beta7 binds the β7 subunit of the integrins α4β7 and αEβ7, 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.
  
  
  METHODS
  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 naïve non-human primates.
  
  
  RESULTS
  In cynomolgus monkeys, occupancy of β7 integrin receptors by rhuMAb Beta7 correlated with an increase in circulating β7(+) mucosal-homing lymphocytes, with no apparent effect on levels of circulating β7(-) 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-β7 treatment resulted in no amelioration of CNS inflammation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: Stefanich
authors.forename: D M
authors.initials: DM
authors.lastname: Danilenko
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: O'Byrne
authors.forename: R
authors.initials: R
authors.lastname: Erickson
authors.forename: T
authors.initials: T
authors.lastname: Gelzleichter
authors.forename: H
authors.initials: H
authors.lastname: Hiraragi
authors.forename: H
authors.initials: H
authors.lastname: Chiu
authors.forename: S
authors.initials: S
authors.lastname: Ivelja
authors.forename: S
authors.initials: S
authors.lastname: Jeet
authors.forename: S
authors.initials: S
authors.lastname: Gadkari
authors.forename: O
authors.initials: O
authors.lastname: Hwang
authors.forename: F
authors.initials: F
authors.lastname: Fuh
authors.forename: C
authors.initials: C
authors.lastname: Looney
authors.forename: K
authors.initials: K
authors.lastname: Howell
authors.forename: V
authors.initials: V
authors.lastname: Albert
authors.forename: M
authors.initials: M
authors.lastname: Balazs
authors.forename: C
authors.initials: C
authors.lastname: Refino
authors.forename: S
authors.initials: S
authors.lastname: Fong
authors.forename: S
authors.initials: S
authors.lastname: Iyer
authors.forename: M
authors.initials: M
authors.lastname: Williams
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000276:immunology; D003092:Colitis / Q000188:drug therapy / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D039641:Integrin beta Chains / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039641:Integrin beta Chains; D016201:Receptors, Lymphocyte Homing; C091368:integrin beta7; C559198:etrolizumab