Dissecting ADC pulmonary toxicity: A murine ADC-associated ILD model to guide and inform ADC discovery

Antibody drug conjugates (ADCs) built upon topoisomerase I inhibitors such as deruxtecan have reshaped the therapeutic landscape of solid tumors, yet their promise continues to be constrained by interstitial lung disease (ILD), a clinically significant toxicity whose mechanistic origin remains incompletely understood. Herein, using a translational murine ILD platform, we dissect the architectural determinants of ADC-induced lung injury and reveal a striking divergence in pulmonary responses driven by drug-linker chemistry. Trastuzumab-GGFG-DXd reproduced the delayed-onset alveolar inflammation, macrophage-rich infiltrates, and fibrotic remodeling characteristic of clinical and non-human primate ILD, whereas structurally distinct comparators including an SN38-based ADC, novel camptothecin ADCs, and ADCs featuring payload-free linkers result in unexpected findings that suggest ILD is much more than a payload-derived toxicity. This data highlights the importance of evaluating ILD-related toxicity in the discovery process whereas previously toxicity screening is reserved for lead optimization stages. Employing our murine ILD platform, we were able to study and evaluate numerous combinations of novel camptothecin payloads and novel linkers arriving at significantly reduced or no ILD without compromising the efficacy in low HER-2 expressing JIMT1 efficacy model. These findings establish a predictive and scalable murine platform for ADC-associated ILD and propose a conceptual reframing of ADC safety engineering, one in which ILD related toxicity evaluation can guide rational ADC design.