Leiden, September 6, 2024 – Researchers from MIMETAS, Roche, and Eberhard Karls University Tübingen publish a new review on the potential of microphysiological systems (MPS) in toxicity testing for new drug modalities. The review highlights how MPS can address the safety challenges posed by innovative therapeutics like antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-T cells, multi-specific antibodies, and adeno-associated viral (AAV)-based gene therapies.
Innovative Solutions for Complex Toxicities
New drug modalities have transformed drug development but bring unpredictable side effects that traditional animal models often fail to predict. MPS, which use advanced microengineering to create perfused tissues, offer a promising alternative. The review identifies four key features of MPS: adjustable cellular complexity, modifiable tissue architecture, dynamic mechanism integration, and multi-organ connections. These features enable MPS to integrate multiple cell types, tailor cell organization to mimic in vivo conditions, use continuous perfusion and biophysical cues to enhance physiological relevance and real-time monitoring, and link organ systems to study systemic interactions and off-target effects comprehensively.
Applications in Drug Safety
The review explores MPS applications in modeling adverse events from new drug modalities. For instance, MPS models can replicate cytokine release syndrome (CRS) development, a common adverse event in CAR-T cell therapies. These models assess vascular dysfunction and cytokine kinetics, providing insights into CRS mechanisms.
For immune-mediated hepatotoxicity from AAV-based gene therapies, liver MPS with Kupffer cells and perfused vasculature offer accurate human liver responses, enabling perfusion of circulating immune cells and measurement of relevant biomarkers like liver enzymes and cytokines.
In ADC-induced peripheral neuropathy, advanced MPS platforms using human-derived cells provide reliable methods to assess neurotoxicity, outperforming traditional animal models.
Thrombocytopenia is a severe side effect of multiple new drug modalities. Bone marrow and vascular inflammation-on-a-chip models offer the ability to study different aspects of the toxicity including megakaryocyte-specific toxicity, platelet formation and microvascular thrombosis.
Overcoming Challenges
While MPS technology is promising, the review addresses challenges like cell sourcing, standardization, and scalability. It calls for greater collaboration between academic, commercial developers, and the pharmaceutical industry to ensure MPS models meet industry needs and regulatory standards.
Conclusion
This review underscores the critical role of MPS in improving drug safety assessments. By offering accurate, human-relevant models, MPS technology enhances the predictive power of non-clinical studies, leading to safer and more effective therapies.
