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.
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: Akihiro Yamada; Yuga Komaki; Nayan Patel; Fukiko Komaki; Arthur S Aelvoet; Anthony L Tran; Joel Pekow; Sushila Dalal; Russell D Cohen; Lisa Cannon; Konstantin Umanskiy; Radhika Smith; Roger Hurst; Neil Hyman; David T Rubin; Atsushi Sakuraba Journal: Am J Gastroenterol Date: 2017-07-18 Impact factor: 10.864
Authors: Wei-Jian Pan; Kathleen Köck; William A Rees; Barbara A Sullivan; Christine M Evangelista; Mark Yen; Jane M Andrews; Graham L Radford-Smith; Peter J Prince; Kaz O Reynhardt; David R Doherty; Sonal K Patel; Christine D Krill; Kefei Zhou; Jing Shen; Lynn E Smith; Jason M Gow; Jonathan Lee; Anthony M Treacy; Zhigang Yu; Virginia M Platt; Dominic C Borie Journal: Br J Clin Pharmacol Date: 2014-12 Impact factor: 4.335
Authors: W J Pan; H Hsu; W A Rees; S P Lear; F Lee; I N Foltz; P Rathanaswami; K Manchulenko; B M Chan; M Zhang; X Z Xia; S K Patel; P J Prince; D R Doherty; C M Sheckler; K O Reynhardt; C D Krill; B J Harder; J A Wisler; J L Brandvig; J L Lynch; A A Anderson; L C Wienkers; D C Borie Journal: Br J Pharmacol Date: 2013-05 Impact factor: 8.739