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

AI Article Synopsis

  • Cancer treatments often lead to unexpected toxicity in non-cancerous tissues, which standard preclinical tests might miss due to their limitations in simulating real human biology.
  • A new approach uses three-dimensional organoids made from human lung cells to better model the lung epithelium and assess the toxicity of antibody-drug conjugates (ADCs), leading to more relevant results.
  • RNA sequencing revealed that one of the ADCs, deruxtecan, triggered an inflammatory response in bronchioalveolar cells, indicating potential off-target effects that warrant further investigation, including the role of specific cell types and immune responses.

Article Abstract

Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.

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Source
http://dx.doi.org/10.1016/j.taap.2024.116886DOI Listing

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