Potential Mechanisms of Interstitial Lung Disease Induced by Antibody–Drug Conjugates Based on Quantitative Analysis of Drug Distribution

Abstract Antibody–drug conjugates (ADC) are a rapidly advancing category of therapeutic agents with notable anticancer efficacy. However, the emergence of interstitial lung disease as a severe ADC-associated adverse event highlights the need to better understand the underlying mechanisms. In this study, xenograft model mice with tumors expressing different levels of the trophoblast antigen 2 (TROP2) were generated by subcutaneously transplanting the various TROP2-expressing cancer lines. The mice received different doses of TROP2–eribulin, a novel TROP2-targeting ADC, composed of an anti-TROP2 antibody and the eribulin payload, joined by a cleavable linker. The concentration and distribution of TROP2–eribulin, as well as the pharmacokinetics of eribulin release, were assessed in tumor and lung tissues. Analysis of tumor tissue showed that the concentration of released eribulin was approximately 10-fold higher in NCI-H2110 (high TROP2 expression) than in A549 (low TROP2 expression), whereas analysis of lung tissue showed that TROP2–eribulin was distributed in lung tissue in a dose-dependent manner, regardless of TROP2 expression, with significantly more eribulin released in the high-dose group than in the other dose groups (P < 0.05). Immunofluorescence assay analysis showed that TROP2–eribulin localized to alveolar macrophages. In the analysis using human leukemia monocytic cell, the concentration of eribulin released from TROP2–eribulin was significantly reduced by the use of an Fc receptor inhibitor (P < 0.05). These results revealed that Fcγ receptor–mediated uptake by alveolar macrophages releases the cytotoxic payload into lung tissue, helping to clarify the pathogenesis of ADC-induced interstitial lung disease.