A bispecific antibody strategy to target multiple type 2 cytokines in asthma.
A bispecific antibody strategy to target multiple type 2 cytokines in asthma.
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DOI：
10.1016/j.jaci.2018.06.002
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Lambrecht BN
中科院分区：
文献类型：
--
作者：
Godar M;Deswarte K;Vergote K;Saunders M;de Haard H;Hammad H;Blanchetot C;Lambrecht BN
哮喘是一种慢性炎症性气道疾病，其中先天性和适应性免疫细胞共同作用，导致嗜酸性粒细胞炎症、杯状细胞化生（GCM）和支气管高反应性（BHR）。在使用针对白细胞介素（IL）-4Rα或IL - 5的生物制剂的临床试验中，只有一部分中重度哮喘患者反应良好，这表明在患者亚组（称为内型）中存在不同的病理生理机制在起作用。然而，使用双特异性抗体（Ab）阻断多种细胞因子的效果尚未得到测试。
在一种小鼠屋尘螨（HDM）哮喘模型中，用一种新型的IL - 4Rα/IL - 5双特异性抗体同时靶向IL - 4、IL - 13和IL - 5信号通路。
使用基于美洲驼的抗体平台产生了两种中和IL - 4Rα和IL - 5的单克隆抗体。然后将它们的重链（HC）和轻链（LC）在哺乳动物细胞中共转染，产生一种异质性抗体混合物，使用双抗独特型纯化工艺从其中分离出双特异性抗体。最后，使C57BL/6J小鼠对HDM提取物致敏和激发，并在激发过程中用这些抗体进行治疗。
我们成功地产生并鉴定了针对IL - 4Rα和IL - 5的单特异性和双特异性抗体。单特异性抗体能够抑制嗜酸性粒细胞增多和/或IgE合成，而只有IL - 4Rα/IL - 5双特异性抗体以及单特异性抗体的组合还能额外抑制GCM和BHR。
2型细胞因子协同作用，导致暴露于HDM的小鼠出现GCM和BHR。
这些临床前结果表明，产生针对多种细胞因子信号通路的双特异性抗体作为哮喘特征（包括难以治疗的GCM）的更优抑制剂是可行的。
Asthma is a chronic inflammatory airway disease in which innate and adaptive immune cells act together to cause eosinophilic inflammation, goblet cell metaplasia (GCM) and bronchial hyperreactivity (BHR). In clinical trials employing biologicals against interleukin (IL)-4Rα or IL-5, only a subset of moderate-to-severe asthmatics responded favorably, suggesting that distinct pathophysiological mechanisms are at play in subgroups of patients, called endotypes. However, the effect of multiple cytokine blockade using bispecific antibodies (Ab) has not been tested. To target simultaneously IL-4, IL-13 and IL-5 signaling pathways with a novel IL-4Rα/IL-5 bispecific Ab in a murine house dust mite (HDM) model of asthma. Two monoclonal Abs neutralizing IL-4Rα and IL-5 were generated using a llama-based Ab platform. Their heavy (HC) and light chains (LC) where then co-transfected in mammalian cells, resulting in a heterogeneous Ab mixture from which the bispecific Ab was isolated using a dual anti-idiotypic purification process. C57BL/6J mice were finally sensitized and challenged to HDM extracts and treated during challenge with the Abs. We successfully generated and characterized the monospecific and bispecific Abs targeting IL-4Rα and IL-5. The monospecific Abs could suppress eosinophilia and/or IgE synthesis whereas only the IL-4Rα/IL-5 bispecific Ab and the combination of monospecific Abs additionally inhibited GCM and BHR. Type 2 cytokines act synergistically to cause GCM and BHR in HDM-exposed mice. These preclinical results show the feasibility of generating bispecific Abs that target multiple cytokine signaling pathways as superior inhibitors of asthma features, including the difficult-to-treat GCM.
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DOI：
10.1056/nejmra0910061
发表时间：
2010-12-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Fahy JV;Dickey BF
通讯作者：
Dickey BF
影响因子：
5.3
作者：
Godar M;Blanchetot C;de Haard H;Lambrecht BN;Brusselle G
通讯作者：
Brusselle G
影响因子：
4.8
作者：
de Haard, HJ;van Neer, N;Hoogenboom, HR
通讯作者：
Hoogenboom, HR
影响因子：
15.9
作者：
Basilico, Cristina;Hultberg, Anna;Michieli, Paolo
通讯作者：
Michieli, Paolo
影响因子：
12.4
作者：
Jacobsen EA;Doyle AD;Colbert DC;Zellner KR;Protheroe CA;LeSuer WE;Lee NA;Lee JJ
通讯作者：
Lee JJ