title: Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys.
abstract: BACKGROUND
  Allergic respiratory diseases are characterized by large numbers of eosinophils and their reactive products in airways and blood; these are 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) specific for human IL-5, is currently in clinical trials for treatment of asthma.
  
  
  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 various dose levels of mepolizumab and were monitored for acute and chronic pharmacologic and toxic responses.
  
  
  RESULTS
  To support preclinical safety assessment, cynomolgus monkey IL-5 was cloned, expressed, and characterized. Although monkey IL-5 differs from human IL-5 by 2 amino acids (Ala27Gly and Asn40His), mepolizumab has comparable 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 bronchoconstrictive responses to inhaled A suum. In an IL-2--induced eosinophilia model (up to 50% blood eosinophilia), 0.5 mg/kg mepolizumab blocked eosinophilia by >80%. Single-dose and chronic (6 monthly doses) intravenous and subcutaneous toxicity studies in naive monkeys found no target organ toxicity or immunotoxicity up to 300 mg/kg. Monkeys did not generate anti-human IgG antibodies. Monthly mepolizumab doses greater than 5 mg/kg caused an 80% to 100% decrease in blood and bronchoalveolar lavage eosinophils lasting 2 months after dosing, and there was no effect on eosinophil precursors in bone marrow after 6 months of treatment. Eosinophil decreases correlated with mepolizumab plasma concentrations (half-life = 13 days).
  
  
  CONCLUSIONS
  These studies demonstrate that chronic antagonism of IL-5 by mepolizumab in monkeys is safe and has the potential, through long-term reductions in circulating and tissue-resident eosinophils, to be beneficial therapy for chronic inflammatory respiratory diseases.
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Hart
authors.forename: R M
authors.initials: RM
authors.lastname: Cook
authors.forename: P
authors.initials: P
authors.lastname: Zia-Amirhosseini
authors.forename: E
authors.initials: E
authors.lastname: Minthorn
authors.forename: T S
authors.initials: TS
authors.lastname: Sellers
authors.forename: B E
authors.initials: BE
authors.lastname: Maleeff
authors.forename: S
authors.initials: S
authors.lastname: Eustis
authors.forename: L W
authors.initials: LW
authors.lastname: Schwartz
authors.forename: P
authors.initials: P
authors.lastname: Tsui
authors.forename: E R
authors.initials: ER
authors.lastname: Appelbaum
authors.forename: E C
authors.initials: EC
authors.lastname: Martin
authors.forename: P J
authors.initials: PJ
authors.lastname: Bugelski
authors.forename: D J
authors.initials: DJ
authors.lastname: Herzyk
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma / Q000628:therapy*; D002452:Cell Count; D003001:Cloning, Molecular; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects*; D007167:Immunotherapy; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D012449:Safety; D013045:Species Specificity
chemical_list: D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015848:Interleukin-5; C434107:mepolizumab