A Transgenic Rat Model of DXd ADC ‐Related Interstitial Pneumonitis for Mechanistic and Translational Research

Deruxtecan-based antibody-drug conjugates (DXd ADCs) provide substantial clinical benefit across multiple malignancies but are associated with clinically significant interstitial lung disease (ILD), for which the underlying mechanisms remain incompletely understood. To enable mechanistic and translational studies, we established a transgenic rat model expressing human trophoblast cell-surface antigen 2 (hTROP2) under the control of the surfactant protein C promoter, driving selective expression in alveolar type II (AT2) cells. Repeated administration of a TROP2-directed DXd ADC with an average drug-to-antibody ratio of 7.9 (TROP2-DXd) reproducibly induced lung injury characterized by alveolar epithelial damage, inflammatory cell infiltration, and fibroblast/myofibroblast proliferation. These pathological changes were accompanied by inflammatory and tissue-remodeling transcriptomic responses, including increased expression of fibrosis-associated genes and decreased expression of AT2-associated genes. These molecular alterations showed partial concordance with molecular programs observed in a cynomolgus monkey ILD model. In hTROP2 transgenic rats, prednisolone markedly attenuated TROP2-DXd-related lung injury and inflammatory and tissue-remodeling transcriptomic responses without altering systemic exposure. Although hTROP2 expression is transgene-driven and does not fully recapitulate physiological expression patterns and distribution in normal human lungs, this model provides a controlled experimental system for evaluating epithelial injury-associated mechanisms. Notably, parallel studies in BALB/c and C57BL/6 mice showed no pulmonary findings despite prolonged high-exposure dosing, suggesting species-dependent susceptibility. Collectively, this transgenic rat model represents a unique rodent ILD model that recapitulates key pathological and molecular features and provides a scalable, experimentally tractable platform for mechanistic and translational evaluation across DXd ADCs.