从靶向单药到多警报素协同，人源化小鼠模型应用于哮喘精准治疗新浪潮

2026-09-09 来源:南模生物点击次数:20

近年来，哮喘的精准治疗已不再局限于2型炎症通路。随着对疾病异质性认识的深入，如何突破传统T2/非T2二元框架，覆盖更广泛的患者群体，已成为新药研发的核心命题。2026年，靶向胸腺基质淋巴细胞生成素（TSLP）的生物制剂特泽利尤单抗在中国正式上市，靶向TSLP及另一未公开靶点的长效双特异性抗体HBM7575/SKB575也同期获批IND。

精准治疗时代的到来，对临床前评价体系提出了更高要求——TSLP、IL-4及其受体在人与小鼠间不存在交叉反应，传统小鼠模型难以准确评估靶向这些人类靶点的药物。因此，构建更贴近人体生理与病理特征的人源化小鼠模型，已成为连接基础研究与临床转化的关键桥梁。南模生物借助丰富的靶点人源化模型，结合原有成熟疾病模型体系，构建了更加契合目前药物研发的哮喘模型，助力前沿研究。

南模生物哮喘相关动物模型

案例一：由OVA+hTSLP诱导的人源化小鼠hIL4/hIL4R/hTSLP/hCRLF2哮喘模型

该模型以人源化hIL4/hIL4R/hTSLP/hCRLF2小鼠为背景，经OVA致敏+人TSLP蛋白增强表型，可在保留经典过敏性炎症框架的同时，特异性激活人TSLP信号通路。这一设计使其能够准确评价抗人TSLP抗体（如Tezepelumab）的体内药效，解决了种属交叉反应带来的评价盲区。

常用诱导方法：

模型数据：

Fig 1. Analysis of inflammatory cell populations in BALF. Flow cytometric quantification of inflammatory cells in BALF. (A) Percentage of macrophages. (B) Percentage of eosinophils. (C) Percentage of lymphocytes.

Fig 2. The efficacy Dupilumab and Tezepelumab on OVA+hTSLP-induced asthma model in hIL4/hIL4R/hTSLP/hCRLF2 mice. (A) Concentration of total serum IgE. (B) Concentration of OVA-specific serum IgE. (C) Relative mRNA expression of mCCL17 in lung tissue. (D) Relative mRNA expression of hIL-4 in lung tissue.

Fig 3. Comprehensive histopathological assessment of lung injury.

Fig 4. Comprehensive histopathological assessment of lung injury. (A) Inflammatory cell infiltration Score. (B) Eosinophil cell infiltration Score. (C) Bronchial Goblet Cell Hyperplasia Score. (D) Airway Basement Membrane Thickening Score. (E) Total Lung Injury Score. (F) PAS Staining Score.

案例二：由OVA+hTSLP诱导的人源化小鼠hIL4/hIL4R/hTSLP/hCRLF2哮喘模型

该模型以hIL4/hIL4R/hTSLP/hCRLF2人源化小鼠为背景，可模拟哮喘中多重上皮警报素（alarmin）协同作用的复杂病理场景，构建了OVA联合hTSLP与hIL33的哮喘模型，可用于模拟哮喘中多重上皮警报素协同作用的复杂病理场景。该模型不仅支持抗人TSLP与抗人IL-33单药的独立评价，更为探索两者联合阻断的叠加或协同疗效提供了可靠的体内平台。

常用诱导方法：

模型数据：

Fig 1. The efficacy of Itepekimab and Tezepelumab on OVA+hTSLP+hIL33-induced asthma model in hIL33/hTSLP/hCRLF2 mice. Mice were challenged with OVA and hTSLP+hIL33 and treated with Itepekimab, Tezepelumab, or a combination. (A) Body weight over time. (B) Percentage change in body weight relative to baseline.

Fig 2. Analysis of inflammatory cell populations in BALF. Flow cytometric quantification of inflammatory cells in BALF. (A) Total inflammatory cell count in BALF. (B) Percentage of lymphocytes among total inflammatory cells. (C) Absolute lymphocytes count in BALF.

Fig 3. Analysis of inflammatory cell populations in BALF. Flow cytometric quantification of inflammatory cells in BALF. (A) Percentage of eosinophils among total inflammatory cells. (B) Absolute eosinophils count in BALF. (C) Percentage of neutrophils among total inflammatory cells. (D) Absolute neutrophils count in BALF.

Fig 4. Analysis of inflammatory cell populations in BALF. Flow cytometric quantification of inflammatory cells in BALF. (A) Percentage of macrophage among total inflammatory cells. (B) Absolute macrophage count in BALF. (C) Percentage of DC cell among total inflammatory cells. (D) Absolute DC cell count in BALF.

Fig 5. The efficacy of Itepekimab and Tezepelumab on OVA+hTSLP+hIL33-induced asthma model in hIL33/hTSLP/hCRLF2 mice. (A) Concentration of total serum IgE.

Fig 6. The efficacy of Itepekimab and Tezepelumab on OVA+hTSLP+hIL33-induced asthma model in hIL33/hTSLP/hCRLF2 mice. (A) Relative mRNA expression of mIL-13 in lung tissue. (B) Relative mRNA expression of mIL-4 in lung tissue. (C) Relative mRNA expression of mIL-5 in lung tissue.

Fig 7. Comprehensive histopathological assessment of lung injury. (A) Representative photographs of H&E-stained lung sections and PAS-stained lung sections.

Fig 8. Comprehensive histopathological assessment of lung injury. (A) Inflammatory cell infiltration Score. (B) Eosinophil cell infiltration Score. (C) Bronchial Goblet Cell Hyperplasia Score. (D) Airway Basement Membrane Thickening Score. (E) Total Lung Injury Score. (F) PAS Staining Score.

除上述品系外，南模生物炎症/自身免疫疾病评价平台自主研发了多种哮喘小鼠模型，采用屋尘螨提取物（house dust mite，HDM）、卵清蛋白（ovalbumin，OVA）等方式，在不同品系（C57BL/6，hIL4/hIL4R mice，BALB/c等）中构建小鼠哮喘模型，并进行了相关验证，可用于哮喘治疗药物的药效评价。

想了解更多详情，可跳转往期推文或点击阅读原文查看详情：世界哮喘日 | 南模生物哮喘模型，助力探究哮喘新疗法。

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