Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys

Abstract

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.

Keywords: DS-8201a; HER2; cynomolgus monkey; interstitial lung disease; trastuzumab deruxtecan.

Figure 1

Lung interstitial inflammation associated with trastuzumab deruxtecan (T‐DXd) treatment in cynomolgus monkeys. A, B, Inflammatory cell infiltrates such as neutrophils and lymphocytes in the alveolar wall, intraalveolar fibrosis, alveolar edema, and aggregates of foamy alveolar macrophages were observed at 78.8 mg/kg T‐DXd in the 6‐week toxicity study (A, H&E; B, Masson‐trichrome). C, D, Thickening of the alveolar wall with lymphocytic inflammation and fibrosis was observed at 30 mg/kg T‐DXd in the 3‐month toxicity study (C, H&E; D, Masson trichrome). Bar, 100 μm

Figure 2

Representative photomicrographs of immunohistochemistry for human epidermal growth factor receptor 2 (HER2) in monkey lungs. A‐C, Bronchial and bronchial gland epithelium showed positive for HER2 in an animal of the vehicle control group (6‐week toxicity study). D, Regenerative alveolar epithelium in the affected areas showed positive for HER2 in an animal given 30 mg/kg trastuzumab deruxtecan (3‐month toxicity study). Bar, 50 μm

Figure 3

Representative photomicrographs of immunohistochemistry for deruxtecan (DXd) in monkey lungs. A, B, Vehicle control, 6‐week toxicity study. No positive staining of DXd was observed. C, 78.8 mg/kg trastuzumab deruxtecan (T‐DXd), 6‐week toxicity study. No obvious DXd positive signal in the bronchiolar epithelium was detected. D, E, 30 mg/kg T‐DXd, 3‐month toxicity study. Alveolar macrophages in the alveolus as well as blood components were positive for DXd (arrows). F, 30 mg/kg T‐DXd, 3‐month toxicity study. No positive staining of DXd was detected after the 3‐month recovery period. Bar, 20 μm

Figure 4

Representative photomicrographs of double immunohistochemistry (IHC) in monkey lungs. Double IHC for deruxtecan (DXd) and cytokeratin (A‐D) and for DXd and Iba‐1 (E, F) was undertaken in monkey lungs from the 6‐week toxicity study of trastuzumab deruxtecan (T‐DXd). Blue, DAPI; green, deruxtecan (DXd); red, cytokeratin or Iba‐1. A, B, E, No DXd staining was observed in a vehicle control animal. C, D, No clear colocalization of DXd and cytokeratin was found in the bronchial epithelium or alveolar epithelium of the animal given 78.8 mg/kg T‐DXd, although edematous fluid in the alveolus and a few regenerative alveolar epithelial cells showed positive for DXd. F, Iba‐1‐positive macrophages were also positive for DXd