Suresh Anaganti, Vice President In vivo and Translational Research at NJ Bio, shared about a recent paper he co-authored with colleagues:
“Antibody-drug conjugates (ADCs) have transformed the treatment of several cancers by combining the targeting specificity of an antibody with the potency of a cytotoxic payload. However, interstitial lung disease (ILD) remains a serious and sometimes fatal adverse event associated with certain ADCs. A major challenge in ADC development has been the lack of practical preclinical models that reproduce the delayed onset and cumulative pulmonary injury observed in patients.
In our recently published study, we describe a mouse model designed to evaluate ADC-associated pulmonary toxicity. Unlike conventional acute toxicity studies, the model uses repeated dosing followed by delayed tissue assessment, allowing pulmonary changes to develop over time.
The model reproduced several clinically relevant pathological features, including inflammatory changes, alveolar injury, pneumocyte hyperplasia, fibrin deposition, and fibrosis. Importantly, it distinguished the pulmonary effects of different ADCs and linker-payload designs. Trastuzumab deruxtecan produced delayed and cumulative lung pathology, whereas unconjugated trastuzumab largely preserved normal lung architecture. ADCs incorporating alternative linker–payload designs also produced different degrees of pulmonary injury, demonstrating the model’s potential to compare candidate molecules and support safer ADC optimization.
These findings suggest that ADC-related ILD cannot be evaluated adequately through antibody targeting or payload potency alone. Linker stability, payload release, systemic exposure, tissue distribution, and repeated-dose effects may all contribute to pulmonary risk.
This model is intended to provide an earlier and more accessible way to identify pulmonary safety signals, compare ADC designs, investigate mechanisms of toxicity, and select candidates before resource-intensive nonhuman-primate or regulatory toxicology studies.
As ADC development expands across oncology and into other therapeutic areas, incorporating translational pulmonary safety assessment earlier in development may help improve candidate selection and ultimately reduce the risk of serious ILD in patients.”
Title: Development of a translational murine model for antibody-drug conjugate-induced interstitial lung disease
Authors: Suresh Anaganti, Arti Bhujade, Steven Murkli, Zachary Sparta, Nabin Panth, Alexander Weig, Richa Vartak, Jose Ponte, Julien Dugal-Tessier, Nareshkumar Jain
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