title: Exclusive antagonism of the α4 β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates.
abstract: BACKGROUND
  Biological therapies that antagonize specific molecules have demonstrated efficacy in inflammatory bowel diseases, but infections resulting from systemic immunosuppression underscore the need for safer therapies. The objective of this investigation was to determine if antagonism of the α(4) β(7) integrin would exclusively yield gut-selective antiinflammatory activity in primates.
  
  
  METHODS
  A series of experiments were conducted to investigate potential intra- and extraintestinal effects in healthy nonhuman primates dosed repeatedly with the α(4) β(7) -exclusive antagonist vedolizumab (former versions: MLN0002, MLN02, LDP-02) for 4, 13, and 26 weeks.
  
  
  RESULTS
  No adverse clinical effects of vedolizumab were observed in healthy cynomolgus monkeys up to the highest doses tested (100 mg/kg). Histomorphologic analyses indicated a reduction in the frequency of leukocytes in gastrointestinal tissue, but not other organs. A significant (P < 0.05) decrease in the frequency of β 7+ lymphocytes in gastrointestinal tissues corresponded to a significant (P < 0.05) increase in α(4) β 7+ memory helper T lymphocytes in peripheral blood. This elevation was specific to α(4) β 7+ memory helper T lymphocytes; levels of other leukocyte subsets remained unaffected. Systemic opportunistic infections were not observed, and vedolizumab did not inhibit adaptive or innate immune responses systemically.
  
  
  CONCLUSIONS
  These data demonstrate that blocking the α(4) β(7) integrin exclusively yields gut-selective antiinflammatory activity in primates.
authors.affiliation: Department of Drug Safety Evaluation, A Takeda Company, Cambridge, Massachusetts 02139, USA. Eric.Fedyk@mpi.com
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fedyk
authors.forename: Tim
authors.initials: T
authors.lastname: Wyant
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Yang
authors.forename: Vilmos
authors.initials: V
authors.lastname: Csizmadia
authors.forename: Kristine
authors.initials: K
authors.lastname: Burke
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Vivek J
authors.initials: VJ
authors.lastname: Kadambi
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D000069442:Natalizumab; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016023:Integrins; D000069442:Natalizumab; C071777:integrin alpha4beta7; C543529:vedolizumab