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Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2‐targeting Ab–drug conjugate, in monkeys
Cancer Science ( IF 4.5 ) Pub Date : 2020-10-14 , DOI: 10.1111/cas.14686 Kazuyoshi Kumagai 1 , Tetsuo Aida 2 , Yoshimi Tsuchiya 1 , Yuki Kishino 3 , Kiyonori Kai 1 , Kazuhiko Mori 1
Cancer Science ( IF 4.5 ) Pub Date : 2020-10-14 , DOI: 10.1111/cas.14686 Kazuyoshi Kumagai 1 , Tetsuo Aida 2 , Yoshimi Tsuchiya 1 , Yuki Kishino 3 , Kiyonori Kai 1 , Kazuhiko Mori 1
Affiliation
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Trastuzumab deruxtecan (T‐DXd: DS‐8201a) is an anti‐human epidermal growth factor receptor 2 (HER2) Ab–drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T‐DXd‐induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T‐DXd‐induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T‐DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose‐dependent and dose‐frequency‐dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T‐DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T‐DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T‐DXd‐related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T‐DXd‐induced ILD/pneumonitis in which target‐independent uptake of T‐DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T‐DXd therapy.
中文翻译：
猴中与曲妥珠单抗deruxtecan（一种人类表皮生长因子受体2靶向Ab-药物结合物）有关的间质性肺炎
曲妥珠单抗deruxtecan（T‐DXd：DS‐8201a）是一种抗人表皮生长因子受体2（HER2）Ab-药物，与exatecan的衍生物deruxtecan（DXd）共轭。这项研究的目的是表征食蟹猴中T‐DXd诱导的肺毒性。每3周一次将曲妥珠单抗deruxtecan静脉注射到猴子中，持续6周（10、30和78.8 mg / kg）或3个月（3、10和30 mg / kg）。为了评估DXd在T‐DXd诱导的毒性中的作用，将DXd一水合物每周一次静脉注射给猴子，持续4周（1、3和12 mg / kg）。在以30 mg / kg或更高剂量给予T‐DXd的猴子中观察到间质性肺炎。弥漫性淋巴细胞浸润和轻度纤维化的组织病理学特征与患者抗癌药物相关的间质性肺疾病（ILD）/肺炎相似，发生率与剂量和频率有关。接受DXd一水合物的猴子没有肺毒性，尽管在接受T‐DXd的猴子中DXd暴露水平高于DXd。尽管在肺泡水平发现了病变，但猴肺中的HER2表达仅限于支气管水平。免疫组织化学分析证实，T‐DXd定位主要在肺泡巨噬细胞中，而不在肺上皮细胞中。这些发现表明，猴子是研究T-DXd相关性ILD /肺炎的合适模型。该结果对于有关T-DXd诱导的ILD /肺炎可能机制的假设的产生也很有价值，在这种机制中，可能涉及靶标独立吸收T-DXd进入肺泡巨噬细胞。
更新日期：2020-12-14
中文翻译：
猴中与曲妥珠单抗deruxtecan（一种人类表皮生长因子受体2靶向Ab-药物结合物）有关的间质性肺炎
曲妥珠单抗deruxtecan（T‐DXd：DS‐8201a）是一种抗人表皮生长因子受体2（HER2）Ab-药物，与exatecan的衍生物deruxtecan（DXd）共轭。这项研究的目的是表征食蟹猴中T‐DXd诱导的肺毒性。每3周一次将曲妥珠单抗deruxtecan静脉注射到猴子中，持续6周（10、30和78.8 mg / kg）或3个月（3、10和30 mg / kg）。为了评估DXd在T‐DXd诱导的毒性中的作用，将DXd一水合物每周一次静脉注射给猴子，持续4周（1、3和12 mg / kg）。在以30 mg / kg或更高剂量给予T‐DXd的猴子中观察到间质性肺炎。弥漫性淋巴细胞浸润和轻度纤维化的组织病理学特征与患者抗癌药物相关的间质性肺疾病（ILD）/肺炎相似，发生率与剂量和频率有关。接受DXd一水合物的猴子没有肺毒性，尽管在接受T‐DXd的猴子中DXd暴露水平高于DXd。尽管在肺泡水平发现了病变，但猴肺中的HER2表达仅限于支气管水平。免疫组织化学分析证实，T‐DXd定位主要在肺泡巨噬细胞中，而不在肺上皮细胞中。这些发现表明，猴子是研究T-DXd相关性ILD /肺炎的合适模型。该结果对于有关T-DXd诱导的ILD /肺炎可能机制的假设的产生也很有价值，在这种机制中，可能涉及靶标独立吸收T-DXd进入肺泡巨噬细胞。
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