开发新型人源化抗TSLP单克隆抗体QX008N，探索抗TSLP抗体和抗IL-4R抗体的联合疗法
2024/10/29
摘要
背景：重症哮喘是一种复杂的慢性呼吸道疾病，目前的常规治疗方法无法有效控制患者的病情。胸腺基质淋巴细胞生成素（TSLP）是诱发和维持哮喘的关键调节因子。因此，在过敏性炎症期间阻断 TSLP 是一种很有前景的治疗方法；然而，新型抗 TSLP 疗法仍有待开发。此外，还应考虑其他信号分子（如 IL-4 和 IL-13）的重要性。此外，据我们所知，尚未评估结合上游和下游信号分子的抑制作用。
目的：本研究旨在开发一种新型人源化抗TSLP抗体，并探索其与抗IL-4R抗体联合治疗哮喘时的疗效。
结果：QX008N 源自兔抗体平台，与Tezepelumab相比，QX008N 对 TSLP 具有很高的亲和力，在体外阻断 TSLP 诱导的信号通路和炎症方面具有更好的疗效。在野猴哮喘模型中，QX008N能改善肺功能，降低嗜酸性粒细胞和IgE水平。此外，QX008N与抗IL-4R抗体合用可增强对体外成本刺激引发的炎症介质产生的抑制作用。在小鼠哮喘模型中，使用抗TTL4R和抗TSLP代用品同时阻断TSLP和IL-4R的疗效超过了单一疗法。据我们所知，在哮喘模型中联合使用抗 TSLP 和 IL-4R 抗体的治疗效果尚未见报道。
结论：这些结果为 QX008N 作为一种创新的抗 TSLP 治疗药物提供了全面的临床前证据，并为开发同时针对 TSLP 和 IL-4R 信号通路的联合疗法提供了初步依据。
Development of a novel humanized anti-TSLP monoclonal antibody, QX008N, and exploration of combination therapy of anti-TSLP antibody and anti-IL-4R antibody
Wang X, Kong Y, Qiu T, Chen T, Liu Y, Shi G, Sun Q, Chen W, Zhang J, Qiu J.
Abstract
Background:Severe asthma is a complex and chronic respiratory disease, and current conventional treatments are not effective in controlling the patients' condition. Thymic stromal lymphopoietin (TSLP) is a key regulatory factor in the initiation and maintenance of asthma. Thus, blocking TSLP during allergic inflammation emerges as a promising therapeutic approach; however, novel anti-TSLP therapies remain to be developed. Furthermore, the importance of other signaling molecules, such as IL-4 and IL-13, should be considered. Moreover, to the best of our knowledge, the inhibitory effect of binding upstream and downstream signaling molecules has not been assessed.
PURPOSE:This study aimed to develop a novel, humanized anti-TSLP antibody and explore the enhancement in its efficacy when combined with anti-IL-4R antibodies to treat asthma.
Results:QX008N, derived from a rabbit antibody platform, exhibits a high affinity for TSLP and superior efficacy in blocking TSLP-induced signaling pathways and inflammation in vitro compared with Tezepelumab. In a cynomolgus monkey asthma model, QX008N ameliorated lung function and reduced the levels of eosinophils and IgE. Moreover, the coadministration of QX008N with anti-IL-4R antibodies enhanced the inhibition of inflammatory mediator production triggered via costimulation in vitro. In mouse asthma models, the simultaneous blockade of TSLP and IL-4R using anti-TL4R and anti-TSLP surrogates surpassed the efficacy of monotherapy. To the best of our knowledge, the therapeutic effect of a combination of anti-TSLP and IL-4R antibodies in an asthma model has not yet been reported.
Conclusion:These results furnish comprehensive preclinical evidence for QX008N as an innovative anti-TSLP therapeutic agent and provide a preliminary rationale for the development of combination therapies that simultaneously target the TSLP and IL-4R signaling pathways.
背景：重症哮喘是一种复杂的慢性呼吸道疾病，目前的常规治疗方法无法有效控制患者的病情。胸腺基质淋巴细胞生成素（TSLP）是诱发和维持哮喘的关键调节因子。因此，在过敏性炎症期间阻断 TSLP 是一种很有前景的治疗方法；然而，新型抗 TSLP 疗法仍有待开发。此外，还应考虑其他信号分子（如 IL-4 和 IL-13）的重要性。此外，据我们所知，尚未评估结合上游和下游信号分子的抑制作用。
目的：本研究旨在开发一种新型人源化抗TSLP抗体，并探索其与抗IL-4R抗体联合治疗哮喘时的疗效。
结果：QX008N 源自兔抗体平台，与Tezepelumab相比，QX008N 对 TSLP 具有很高的亲和力，在体外阻断 TSLP 诱导的信号通路和炎症方面具有更好的疗效。在野猴哮喘模型中，QX008N能改善肺功能，降低嗜酸性粒细胞和IgE水平。此外，QX008N与抗IL-4R抗体合用可增强对体外成本刺激引发的炎症介质产生的抑制作用。在小鼠哮喘模型中，使用抗TTL4R和抗TSLP代用品同时阻断TSLP和IL-4R的疗效超过了单一疗法。据我们所知，在哮喘模型中联合使用抗 TSLP 和 IL-4R 抗体的治疗效果尚未见报道。
结论：这些结果为 QX008N 作为一种创新的抗 TSLP 治疗药物提供了全面的临床前证据，并为开发同时针对 TSLP 和 IL-4R 信号通路的联合疗法提供了初步依据。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Int Immunopharmacol. 2024 Dec 5; DOI: 10.1016/j.intimp.2024.113102)
(Int Immunopharmacol. 2024 Dec 5; DOI: 10.1016/j.intimp.2024.113102)
Development of a novel humanized anti-TSLP monoclonal antibody, QX008N, and exploration of combination therapy of anti-TSLP antibody and anti-IL-4R antibody
Wang X, Kong Y, Qiu T, Chen T, Liu Y, Shi G, Sun Q, Chen W, Zhang J, Qiu J.
Abstract
Background:Severe asthma is a complex and chronic respiratory disease, and current conventional treatments are not effective in controlling the patients' condition. Thymic stromal lymphopoietin (TSLP) is a key regulatory factor in the initiation and maintenance of asthma. Thus, blocking TSLP during allergic inflammation emerges as a promising therapeutic approach; however, novel anti-TSLP therapies remain to be developed. Furthermore, the importance of other signaling molecules, such as IL-4 and IL-13, should be considered. Moreover, to the best of our knowledge, the inhibitory effect of binding upstream and downstream signaling molecules has not been assessed.
PURPOSE:This study aimed to develop a novel, humanized anti-TSLP antibody and explore the enhancement in its efficacy when combined with anti-IL-4R antibodies to treat asthma.
Results:QX008N, derived from a rabbit antibody platform, exhibits a high affinity for TSLP and superior efficacy in blocking TSLP-induced signaling pathways and inflammation in vitro compared with Tezepelumab. In a cynomolgus monkey asthma model, QX008N ameliorated lung function and reduced the levels of eosinophils and IgE. Moreover, the coadministration of QX008N with anti-IL-4R antibodies enhanced the inhibition of inflammatory mediator production triggered via costimulation in vitro. In mouse asthma models, the simultaneous blockade of TSLP and IL-4R using anti-TL4R and anti-TSLP surrogates surpassed the efficacy of monotherapy. To the best of our knowledge, the therapeutic effect of a combination of anti-TSLP and IL-4R antibodies in an asthma model has not yet been reported.
Conclusion:These results furnish comprehensive preclinical evidence for QX008N as an innovative anti-TSLP therapeutic agent and provide a preliminary rationale for the development of combination therapies that simultaneously target the TSLP and IL-4R signaling pathways.
上一篇：
用洋葱球茎提取物治疗小鼠哮喘模型可预防和逆转过敏性炎症
下一篇：
Benralizumab治疗过敏性哮喘：随机、双盲、安慰剂对照试验
