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.

Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer

“…The mechanism by which T-DXd is involved in the development of ILD is currently unknown. Preclinical studies in monkeys found that high level of T-DXd exposure resulted in the development of a similar pathology to what was observed in the treatment-associated ILD/ pneumonitis in humans [43]. In this model, T-DXd was detected in HER2-negative lung alveolar macrophages, but not in the airway epithelium including HER2-positive bronchial and bronchiolar epithelial cells.…”

Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions

“…An in vivo study conducted in cynomolgus monkeys injected with T-DXd at different doses revealed histopathological lung features of diffuse lymphocytic infiltrates and slight fibrosis with an incidence that was dose-dependent and dose-frequency-dependent. Immunohistochemical analysis further confirmed that T-DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells suggesting a possible mechanism of lung injury related to target-independent uptake of T-DXd into alveolar macrophages [47]. Additional work will be necessary to clarify these findings and their clinical implications.…”

The first reported case of trastuzumab induced interstitial lung disease associated with anti-neutrophil cytoplasmic antibody vasculitis – A case report and a prospective cohort study on the usefulness of neutrophil derived biomarkers in monitoring vasculitis disease activity during follow-up

“…Receiving T-Dxd in a monkey model developed interstitial lung disease, whereas receiving Dxd does not. Although most ILD lesions were found within the alveoli, the HER2 expression in lungs was limited to the bronchial level [ 22 ]. Vasculitis due to a pathway via ANCA autoantibodies, an indirect mechanism by the immune system, could explain why the injury was not at the location where T-Dxd was uptaken.…”