Bronchioalveolar organoids: A preclinical tool to screen toxicity associated with antibody-drug conjugates

Area of Science:

• Toxicology
• Oncology
• Regenerative Medicine

Background:

• Preclinical cancer therapeutic testing faces limitations in predicting off-target toxicity due to inadequate biomimicry in 2D cultures and poor interspecies translatability.
• Organoids, 3D structures from primary cells, offer enhanced recapitulation of native tissue morphology and function for improved preclinical modeling.

Purpose of the Study:

• To utilize human bronchioalveolar organoids to model lung epithelium and investigate off-target toxicities of antibody-drug conjugates (ADCs).
• To assess the utility of organoids in predicting in vivo drug sensitivity and identifying potential adverse effects of ADCs.

Main Methods:

• Bronchioalveolar organoids were generated from primary alveolar epithelial cells of human, rat, and nonhuman primate origins.
• ADCs with three distinct linker-payload combinations (mafodotin, vedotin, deruxtecan) were applied to the organoids.
• Antibody uptake, cell viability, and gene expression changes (RNA sequencing) were analyzed post-exposure.

Main Results:

• Organoids exhibited antibody uptake and viability changes in response to ADC exposure, mirroring in vivo drug sensitivity.
• RNA sequencing revealed inflammatory activation in bronchioalveolar cells specifically in response to the deruxtecan ADC.
• The study demonstrated the potential of organoids to detect ADC-induced toxicity across different species.

Conclusions:

• Human bronchioalveolar organoids serve as a valuable preclinical model for assessing off-target lung toxicities of ADCs.
• Organoid models can identify specific toxic liabilities, such as the inflammatory response to deruxtecan, which may be missed in traditional assays.
• Future research will incorporate immune cells and focus on interstitial lung disease mechanisms within the organoid system.