In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes.
Vedolizumab (VDZ) is a humanized monoclonal antibody in development for the treatment of inflammatory bowel disease. VDZ binds to the α4β7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues. To understand whether VDZ has additional effects that may affect its overall safety as a therapeutic molecule, we examined other potential actions of VDZ. In vitro assays with human peripheral blood lymphocytes demonstrated that VDZ fails to elicit cytotoxicity, lymphocyte activation, and cytokine production from memory T lymphocytes and does not interfere with the suppressive ability of regulatory T cells. Furthermore, we demonstrated that VDZ induces internalization of α4β7 and that the integrin is rapidly re-expressed and fully functional after VDZ withdrawal. These studies provide insight into the mechanisms underlying the observed safety profile of VDZ in clinical trials.
Takeda Cambridge US; Cambridge, MA USA.
Timothy
T
Wyant
Takeda Cambridge US; Cambridge, MA USA.
Lili
L
Yang
Takeda Pharmaceuticals Inc., International; Deerfield, IL USA.
Eric
E
Fedyk
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding
D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D016023:Integrins; C071777:integrin alpha4beta7; C543529:vedolizumab
in vitro; inflammatory bowel disease; integrin; lymphocyte binding; receptor internalization; safety profile; vedolizumab