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A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit¹

Patricia L. Podolin^2,*, Brian J. Bolognese^*, James J. Foley^*, Dulcie B. Schmidt^*, Peter T. Buckley^*, Katherine L. Widdowson^*, Qi Jin^*, John R. White, Judithann M. Lee, Richard B. Goodman, Tonja R. Hagen, Osamu Kajikawa, Lisa A. Marshall, Douglas W. P. Hay^* and Henry M. Sarau^*

^* Respiratory and Inflammation Center of Excellence for Drug Discovery, and Department of Protein Agents and Human Gene Therapy and Project and Portfolio Management, GlaxoSmithKline, King of Prussia, PA 19406; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98108

Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits ¹²⁵I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC₅₀ = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC₅₀ = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-, IL-8, PGE₂, leukotriene B₄, and leukotriene C₄ levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF- and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC₅₀ = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.

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