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

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.