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INFLAMMATION AND IMMUNOPHARMACOLOGY

An Assessment of the Mechanistic Differences Between Two Integrin ₄₁ Inhibitors, the Monoclonal Antibody TA-2 and the Small Molecule BIO5192, in Rat Experimental Autoimmune Encephalomyelitis

Biogen, Inc., Cambridge, Massachusetts

Integrin ₄₁ 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 ₄₁ inhibitors, the anti-rat ₄ 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 (K_D of <10 pM) inhibitor of ₄₁. 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 ₄ integrin expression on the cell surface, which resulted from internalization of ₄ integrin/TA-2 complexes. In contrast, BIO5192 did not modulate cell surface ₄₁. Our results with BIO5192 indicate that ₄₇ does not play a role in this model and that blockade of ₄₁/ligand interactions without down-modulation is sufficient for efficacy in rat EAE. BIO5192 is highly selective and binds with high affinity to ₄₁ from four of four species tested. These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of ₄₁ integrin, will be a valuable reagent for assessing ₄₁ biology and may provide a new therapeutic for treatment of human inflammatory diseases.

Address correspondence to: Diane R. Leone, Biogen, Inc., 12 Cambridge Center, Cambridge, MA 02142. E-mail: diane_leone{at}Biogen.com

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