Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys
| Autor: | Teresa S. Sellers, Timothy K. Hart, Parnian Zia-Amirhosseini, Ping Tsui, Lester W. Schwartz, Beverly E. Maleeff, Edward R. Appelbaum, Danuta J. Herzyk, Scot Eustis, Elisabeth A. Minthorn, Elise C. Martin, Cook Richard M, Peter J. Bugelski |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Allergy Immunology Drug Evaluation Preclinical Cell Count Antibodies Monoclonal Humanized Eosinophil migration Species Specificity medicine Immunology and Allergy Eosinophilia Animals Anti-Asthmatic Agents Cloning Molecular Interleukin 5 medicine.diagnostic_test business.industry Antibodies Monoclonal respiratory system Eosinophil medicine.disease Asthma Eosinophils Macaca fascicularis Bronchoalveolar lavage medicine.anatomical_structure Toxicity Immunotherapy medicine.symptom Interleukin-5 Safety business Mepolizumab medicine.drug |
| Zdroj: | The Journal of allergy and clinical immunology. 108(2) |
| ISSN: | 0091-6749 |
| Popis: | 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). Conclusion: 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. (J Allergy Clin Immunol 2001;108:250-7.) |
| Databáze: | OpenAIRE |
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