Early detection of safety liabilities of new therapies is a critical biopharmaceutical challenge. Addressing this challenge could significantly advance drug discovery. Advanced human cell models, including microphysiological systems (MPS), aim to recapitulate the architecture, cell-to-cell interactions, and microenvironment of a given tissue, making them more representative of complex in vivo biology than standard two-dimensional culture. Hence, human MPS are particularly well-suited suited to enhancing translation of pre-clinical model outcomes to clinical settings.

In Clinical Pharmacology and Safety Sciences at AstraZeneca, we are developing advanced human cell models tailored to various organs and safety applications, depending on the context of use. This presentation will showcase one example of successful adoption of MPS for pre-clinical safety assessment: our human 3D static and fluidic (MPS) bone marrow (BM) models. Our models recapitulate key aspects of living BM, maintaining stem/progenitor cells and supporting differentiation into erythroid, myeloid and megakaryocyte lineages. This allows capture of lineage-specific haematotoxicity associated with monotherapy and combination therapies, informing candidate drug selection, and guiding oncology drug combination dosing and scheduling. Integrating data from these models with Quantitative Systems Toxicology modeling approaches is crucial for accurate safety assessments and clinical translation. 

Despite the potential of advanced cell models to enhance the human relevance of pre-clinical safety assessments, challenges to their widespread adoption and development in the pharmaceutical industry remain. These challenges include a lack of standardization, high costs and time requirements, and low sample quantities for downstream analyses. This presentation will also address these challenges and present opportunities to further improve advanced cell models and thereby drive their adoption in the industry.

Learning Objectives:

1. Describe how advanced human cell models, including MPS, enhance the translation of pre-clinical outcomes to clinical settings.

2. Illustrate how human bone marrow MPS capture lineage-specific hematotoxicity to inform drug selection and dosing strategies.

3. Discuss current challenges to adopting advanced cell models in the pharmaceutical industry and propose opportunities for improvement.