Superiority of InSphero Human Liver Microtissues for Prediction of Drug-Induced Liver Injury Confirmed

In the most comprehensive evaluation of 3D spheroid hepatic cultures conducted to date, a publication co-authored by lead toxicologists and drug safety experts at AstraZeneca and Genentech revealed InSphero 3D InSight™ Human Liver Microtissues to be a more sensitive and highly specific in vitro model for predicting drug-induced liver injury (DILI) compared to 2D models. The study entitled, “Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury,” was published online Tuesday, June 13 in the journal Archives of Toxicology. Dr. William Proctor, Head of Investigative Toxicology at Genentech, and Alison Foster, Senior Scientist in the Drug Safety and Metabolism group at AstraZeneca, were co-first authors on the publication.

2D PHH assays have been the “gold-standard” model used for DILI testing, yet DILI still remains one of the leading sources for drug attrition, black box warnings, and post-market withdrawal of drugs. Thus, there is a growing need for better predictive tools to assess liver injury earlier in the drug development process. The authors note in the paper that, “3D models have shown promise in small sets of DILI compounds, but a more comprehensive retrospective study of DILI positive and negative drugs to test the predictive power of 3D models head to head with 2D PHH assays had not been performed.”

The study determined that regardless of the threshold used, “Human Liver Microtissues demonstrated increased sensitivity in identifying known hepatotoxicants versus PHH, while specificity was consistent across both assays.” Microtissues also, “outperformed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules.” Furthermore, the authors found that 3D microtissues displayed sufficient structural and functional characteristics to warrant exploratory studies to see if novel biomarkers used in the clinic could also be detected in vitro. Findings revealed that despite each microtissue consisting of ~1000 cells, the mechanistic and exploratory hepatotoxicity biomarkers miR-122, HMGB1, and α-GST could be detected in the culture supernatants, demonstrating that, “3D liver microtissues have the potential to recapitulate in vivo findings in vitro.”

“This landmark study provides convincing, independent evidence that InSphero liver microtissues can help identify hepatotoxic drugs with greater sensitivity without sacrificing specificity, says InSphero Chief Executive Officer and Co-founder Dr. Jan Lichtenberg. “Having two of the world’s leading pharmaceutical companies collaborate to produce this thorough validation further confirms that our 3D models not only better reflect in vivo biology, but also deliver the reproducibility and scalability required to meet the early stage screening demands of large pharma. Our assay-ready 3D InSight™ models offer a cost-effective, turnkey solution that gives toxicologists greater confidence when characterizing risk in lead compound sets.”

3D InSight™ Human Liver Microtissues are a standardized primary human liver model developed by InSphero that display enhanced liver phenotype, metabolic activity, and stability over 28 days in culture, enabling long-term drug exposure studies not attainable with 2D hepatic models.