靶向IL-5的长效三价双特异性纳米体治疗嗜酸性哮喘的临床前研究
2022/11/22
摘要
背景：嗜酸性粒细胞性哮喘是一种常见的重症哮喘亚型，发病率和死亡率都很高。细胞因子IL-5已被证明是疾病发展和进展的关键驱动因素。尽管经批准的针对IL-5/IL-5R的单克隆抗体（mAb）显示出良好的安全性和有效性，但一些患者反应不佳，频繁给药导致药物不依从。
结果：我们构建了一个新的三价双特异性纳米体（Nb），由3个VHH组成，它们与来自免疫噬菌体展示库的2个不同的IL-5表位和1个白蛋白表位结合。这种三价IL-5-HSA Nb表现出与美泊利单抗（Nucala）类似的IL-5/IL-5R阻断活性，后者是一种经批准的靶向IL-5单抗。令人惊讶的是，这种三价Nb在抑制TF-1细胞增殖方面的活性是美泊利珠单抗的58倍。在灵长类动物研究中，三价IL-5-HSA Nb表现出优异的药代动力学特性，单次给药后两个月内，外周血嗜酸性粒细胞水平仍受到显著抑制。此外，三价IL-5-HSA Nb可以在具有高纯度和良好热稳定性的P.pastoris X-33酵母系统中大规模生产。
结论：这些发现表明，三价双特异性IL-5-HSA Nb有可能成为靶向IL-5的下一代治疗剂，用于治疗重症嗜酸性粒细胞性哮喘。
Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma
Linlin Ma, Min Zhu, Guanghui Li, Junwei Gai, Yanfei Li, Huaiyu Gu, Peng Qiao, Xiaofei Li, Weiwei Ji, Rui Zhao, Yue Wu, Yakun Wan
Abstract
Background：Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence.
Results：We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability.
Conclusions：These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma.
背景：嗜酸性粒细胞性哮喘是一种常见的重症哮喘亚型，发病率和死亡率都很高。细胞因子IL-5已被证明是疾病发展和进展的关键驱动因素。尽管经批准的针对IL-5/IL-5R的单克隆抗体（mAb）显示出良好的安全性和有效性，但一些患者反应不佳，频繁给药导致药物不依从。
结果：我们构建了一个新的三价双特异性纳米体（Nb），由3个VHH组成，它们与来自免疫噬菌体展示库的2个不同的IL-5表位和1个白蛋白表位结合。这种三价IL-5-HSA Nb表现出与美泊利单抗（Nucala）类似的IL-5/IL-5R阻断活性，后者是一种经批准的靶向IL-5单抗。令人惊讶的是，这种三价Nb在抑制TF-1细胞增殖方面的活性是美泊利珠单抗的58倍。在灵长类动物研究中，三价IL-5-HSA Nb表现出优异的药代动力学特性，单次给药后两个月内，外周血嗜酸性粒细胞水平仍受到显著抑制。此外，三价IL-5-HSA Nb可以在具有高纯度和良好热稳定性的P.pastoris X-33酵母系统中大规模生产。
结论：这些发现表明，三价双特异性IL-5-HSA Nb有可能成为靶向IL-5的下一代治疗剂，用于治疗重症嗜酸性粒细胞性哮喘。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Respir Res. 2022 Nov 19;23(1):316. doi: 10.1186/s12931-022-02240-1.)
(Respir Res. 2022 Nov 19;23(1):316. doi: 10.1186/s12931-022-02240-1.)
Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma
Linlin Ma, Min Zhu, Guanghui Li, Junwei Gai, Yanfei Li, Huaiyu Gu, Peng Qiao, Xiaofei Li, Weiwei Ji, Rui Zhao, Yue Wu, Yakun Wan
Abstract
Background：Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence.
Results：We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability.
Conclusions：These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma.
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哮喘患者增加大剂量吸入皮质类固醇的效果：英国数据库研究
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