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More MS news articles for March 2003

An Assessment of the Mechanistic Differences Between Two Integrin {alpha}4{beta}1 Inhibitors, the mAb TA-2 and the Small Molecule BIO5192, in rat EAE

J Pharmacol Exp Ther 2003 Mar 6
Leone DR, Giza K, Gill A, Dolinski BM, Yang W, Perper S, Scott D, Lee WC, Cornabise M, Wortham K, Nickerson-Nutter C, Chen L, LePage D, Spell C, Whalley ET, Petter R, Adams SP, Lobb RR, Pepinsky RB.

Integrin alpha4beta1 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 alpha4beta1 inhibitors, the anti-rat alpha4 mAb 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 <3 pM) inhibitor of alpha4beta1.

Dosing regimens were identified for both inhibitors that 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 alpha4 integrin expression on the cell surface, which resulted from internalization of alpha4beta1 integrin / TA-2 complexes.

In contrast, BIO5192 did not modulate cell surface alpha4beta1.

Our results with BIO5192 indicate that alpha4beta7 does not play a role in this model, and that blockade of alpha4beta1 / ligand interactions without downmodulation is sufficient for efficacy in rat EAE.

BIO5192 is highly selective and binds with high affinity to alpha4beta1 from 4 out of 4 species tested.

These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of alpha4beta1 integrin, will be a valuable reagent for assessing alpha4beta1 biology and may provide a new therapeutic for treatment of human inflammatory diseases.