Functional human 3D in vitro models as a preclinical screening platform for understanding the hepatotoxicity and liver biodistribution of biologics

Primary human hepatocytes rapidly lose their functionality in conventional 2D cultures, which significantly limits their usefulness as an in vitro model to study hepatotoxicity, particularly of biological and nanoparticle therapeutics, which commonly accumulate and exert their effects over prolonged periods of time.

Thus, in the absence of relevant in vitro systems, animal models constitute a cornerstone to predict the toxicity of newly developed biologics.

The liver is however an organ with pronounced species differences with regards to expression and catalytic activities of factors involved in drug absorption, distribution, metabolism and excretion.

This is further amplified for nucleotide- and antibody-based therapeutics where sequence and epitope differences between species are common problems during preclinical development.We have previously developed a 3D human liver model that accurately predicts the hepatotoxicity of small molecules, which is by now widely used in industry.

Here, we aim to extend this work and develop and benchmark a platform that can predict hepatotoxicity and liver biodistribution of biologics (antisense oligonucleotides, siRNAs, therapeutic antibodies) and different nanoparticles (lipid-based, polymeric and inorganic).

This system aspires to improve the predictability and translatability of findings as well as to mitigate the need for animal models, thus reducing the number of animals needed in pre-clinical discovery and development.