873847-20-2Relevant articles and documents
An assessment of the mechanistic differences between two integrin α4β1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis
Leone,Giza,Gill,Dolinski,Yang,Perper,Scott,Lee,Cornebise,Wortham,Nickerson-Nutter,Chen,Lepage,Spell,Whalley,Petter,Adams,Lobb,Pepinsky
, p. 1150 - 1162 (2007/10/03)
Integrin α4β1 plays an important role in inflammatory processes by regulating the migration of lymphocytes into inflamed tissues. Here we evaluated the biochemical, pharmacological, and pharmacodynamic properties and efficacy in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, of two types of α4β1 inhibitors, the anti-rat α4 monoclonal antibody TA-2 and the small molecule inhibitor BIO5192 [2(S)-{[1(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino} 4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}amino)- pentanoylamino]-butyric acid]. TA-2 has been extensively studied in rats and provides a benchmark for assessing function. BIO5192 is a highly selective and potent (KD of 4β1. Dosing regimens were identified for both inhibitors, which provided full receptor occupancy during the duration of the study. Both inhibitors induced leukocytosis, an effect that was used as a pharmacodynamic marker of activity, and both were efficacious in the EAE model. Treatment with TA-2 caused a decrease in α4 integrin expression on the cell surface, which resulted from internalization of α4 integrin/TA-2 complexes. In contrast, BIO5192 did not modulate cell surface α4β1. Our results with BIO5192 indicate that α4β7 does not play a role in this model and that blockade of α4β1/ligand interactions without down-modulation is sufficient for efficacy in rat EAE. BIO5192 is highly selective and binds with high affinity to α4β1 from four of four species tested. These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of α4β1 integrin, will be a valuable reagent for assessing α4β1 biology and may provide a new therapeutic for treatment of human inflammatory diseases.
