Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys
Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys
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DOI：
10.1067/mai.2001.116576
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发表时间：
2001-08-01
影响因子：
14.2
通讯作者：
Herzyk, DJ
中科院分区：
文献类型：
--
作者：
Hart, TK;Cook, RM;Herzyk, DJ
背景：过敏性呼吸道疾病的特点是气道和血液中存在大量嗜酸性粒细胞及其反应产物；这些被认为与进行性气道损伤和重塑有关。 IL-5 是嗜酸性粒细胞成熟、分化和存活的主要细胞因子。美泊利单抗 (SB-240563) 是一种针对人 IL-5 的人源化单克隆抗体 (mAb)，目前正处于治疗哮喘的临床试验中。 目的：本研究的目的是表征其药理活性和长期活性。抗人 IL-5 mAb 的安全性，支持哮喘患者的临床试验。方法。幼稚和蛔虫敏感食蟹猴接受不同剂量水平的美泊利单抗，并监测急性和慢性药理学和毒性反应。结果。为了支持临床前安全性评估，对食蟹猴 IL-5 进行了克隆、表达和表征。尽管猴 IL-5 与人 IL-5 有 2 个氨基酸（Ala27Gly 和 Asn40His）不同，但美泊利单抗对猴 IL-5 和人 IL-5 具有相当的抑制活性。在 A suum 敏感猴中，单剂量美泊利单抗可显着降低血液嗜酸性粒细胞增多、嗜酸性粒细胞迁移至肺气道，以及肺部 RANTES 和 IL-6 水平，持续 6 周。然而，美泊利单抗并不影响吸入 A suum 的急性支气管收缩反应。在 IL-2 诱导的嗜酸性粒细胞增多模型（血液嗜酸性粒细胞增多高达 50%）中，0.5 mg/kg 美泊利单抗可阻断嗜酸性粒细胞增多>80%。对幼猴进行的单剂量和慢性（6 个月剂量）静脉内和皮下毒性研究发现，剂量高达 300 mg/kg 时，没有出现靶器官毒性或免疫毒性。猴子不会产生抗人 IgG 抗体。每月美泊利单抗剂量大于 5 mg/kg 导致给药后 2 个月内血液和支气管肺泡灌洗液嗜酸性粒细胞减少 80% 至 100%，治疗 6 个月后对骨髓中的嗜酸性粒细胞前体没有影响。嗜酸性粒细胞减少与美泊利单抗血浆浓度相关（半衰期 = 13 天）。结论。这些研究表明，美泊利单抗在猴子体内对 IL-5 的长期拮抗作用是安全的，并且通过长期减少循环和组织驻留的嗜酸性粒细胞，有可能成为慢性炎症性呼吸道疾病的有益疗法。
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 fbr 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.