Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates

Abstract

These data demonstrate that blocking the α(4) β(7) integrin exclusively yields gut-selective antiinflammatory activity in primates.

Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

“…These data are nonetheless consistent with more thorough investigations of binding affinities (23,27). …”

“…Therefore, we assessed the effects of antagonizing the a 4 integrins in the rhesus monkey EAE model because this is the only established EAE model (28) in which both vedolizumab and natalizumab are pharmacologically active (Table I). This specific rhMOG protocol was chosen because all animals develop EAE (27) and generally do so prior to the development of strong neutralizing anti-drug Ab responses (23,26). It is characterized by an unpredictable time of onset, extremely rapid development, and deterioration of neurological functions (i.e., within a few days).…”

“…It inhibits the functional activity of the a 4 b 7 integrin by selectively antagonizing binding and adhesion to MAdCAM-1 and to the extracellular matrix glycoprotein fibronectin, but does not antagonize binding to VCAM-1 (22). It elicited anti-inflammatory effects selectively in the gastrointestinal tract of cynomolgus monkeys (23) and demonstrated statistically significant efficacy in placebo-controlled phase 2 clinical trials of patients with active UC (24) and CD (25). Therefore, vedolizumab was used in this investigation to specifically examine whether exclusive antagonism of the a 4 b 7 integrin would compromise immune surveillance of the CNS in rhesus monkey EAE.…”

Emerging biologics in inflammatory bowel disease

“…Based on the experience of a group of multiple sclerosis patients, the estimated incidence of PML was nearly one case per 1000 patients receiving natalizumab [52]. Natalizumab and vedolizumab differ, however, in that natalizumab blocks lymphocyte trafficking to multiple organs, including the brain and gut, while vedolizumab is gutspecific [53]. No significant changes were observed in cerebral spinal fluid T-lymphocyte populations in either humans or primates receiving vedolizumab [53,54].…”

“…Natalizumab and vedolizumab differ, however, in that natalizumab blocks lymphocyte trafficking to multiple organs, including the brain and gut, while vedolizumab is gutspecific [53]. No significant changes were observed in cerebral spinal fluid T-lymphocyte populations in either humans or primates receiving vedolizumab [53,54]. In clinical trials involving vedolizumab, patients were screened for neurological symptoms of PML, and shall be referred for further evaluation should they exhibit any symptoms.…”