Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys

Background: Allergic respiratory diseases are characterized by large number s of eosinophils and their reactive products in airways and blood; these ar e believed to be involved in progressive airway damage and remodeling. IL-5 is the principal cytokine for eosinophil maturation, differentiation, and survival. Mepolizumab (SB-240563), a humanized monoclonal antibody (mAb) sp ecific for human IL-5, is currently in clinical trials fbr treatment of ast hma. Objective: The purpose of this study was to characterize the pharmacologic activity and long-term. safety profile of an anti-human IL-5 mAb to support clinical trials in asthmatic patients. Methods. Naive and Ascaris suum-sensitive cynomolgus monkeys received vario us dose levels of mepolizumab and were monitored for acute and chronic phar macologic and toxic responses. Results. To support preclinical safety assessment, cynomolgus monkey IL-5 w as cloned, expressed, and characterized. Although monkey IL-5 differs from human IL-5 by 2 amino acids (Ala27Gly and Asn40His), mepolizumab has compar able inhibitory activity against both monkey IL-5 and human IL-5. In A suum -sensitive monkeys, single doses of mepolizumab significantly reduced blood eosinophilia, eosinophil migration into lung airways, and levels of RANTES and IL-6 in lungs for 6 weeks. However, mepolizumab did not affect acute b ronchoconstrictive responses to inhaled A suum. In an IL-2-induced eosinoph ilia model (up to 50% blood eosinophilia), 0.5 mg/kg mepolizumab blocked eo sinophilia by >80%. Single dose and chronic (6 monthly doses) intravenous a nd subcutaneous toxicity studies in naive monkeys found no target organ tox icity or immunotoxicity up to 300 mg/kg. Monkeys did not generate anti-huma n IgG antibodies. Monthly mepolizumab doses greater than 5 mg/kg caused an 80% to 100% decrease in blood and bronchoalveolar lavage eosinophils lastin g 2 months after dosing, and there was no effect on eosinophil precursors i n bone marrow after 6 months of treatment. Eosinophil decreases correlated with mepolizumab plasma concentrations (half-life = 13 days). Conclusion. These studies demonstrate that chronic antagonism of IL-5 by me polizumab in monkeys is safe and has the potential, through long-term reduc tions in circulating and tissue-resident eosinophils, to be beneficial ther apy for chronic inflammatory respiratory diseases.