Supported exclusively by Millennium Pharmaceuticals Inc., a Takeda Company.
Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates†
Article first published online: 14 MAR 2012
Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 11, pages 2107–2119, November 2012
How to Cite
Fedyk, E. R., Wyant, T., Yang, L.-L., Csizmadia, V., Burke, K., Yang, H. and Kadambi, V. J. (2012), Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates. Inflamm Bowel Dis, 18: 2107–2119. doi: 10.1002/ibd.22940
- Issue published online: 15 OCT 2012
- Article first published online: 14 MAR 2012
- Manuscript Accepted: 14 FEB 2012
- Manuscript Received: 31 JAN 2012
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 α4β7 integrin would exclusively yield gut-selective antiinflammatory activity in primates.
A series of experiments were conducted to investigate potential intra- and extraintestinal effects in healthy nonhuman primates dosed repeatedly with the α4β7-exclusive antagonist vedolizumab (former versions: MLN0002, MLN02, LDP-02) for 4, 13, and 26 weeks.
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 lymphocytes in gastrointestinal tissues corresponded to a significant (P < 0.05) increase in α4β memory helper T lymphocytes in peripheral blood. This elevation was specific to α4β 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.
These data demonstrate that blocking the α4β7 integrin exclusively yields gut-selective antiinflammatory activity in primates. (Inflamm Bowel Dis 2012;)