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How advanced cell models can be used for toxicity investigations during drug development – A case example
Abstracts / Toxicology Letters 280S (2017) S78–S79
proliferation, while in other cases phenotypic species comparisons recapitulating the in vivo effect in rodents and absence thereof in a human system can be used to support projects moving forward in development. These data show that using modern in vitro approaches making use of cellular models from pre-clinical species and human are able to mimic and de-risk effects frequently hampering drug programs entering late development stages. http://dx.doi.org/10.1016/j.toxlet.2017.07.208 ISS 1b-04 Chemoproteomic approaches for off-target hazard identification
S79
their test portfolio. Either as a test model for screening to reduce the early failure risk in preclinical animal studies, or to investigate adverse drug effects that occurred in preclinical species, these advanced models may support the transfer of a safe drug candidate into the clinical testing phase. The willingness to integrate such complex in vitro models into a regular testing scheme in industry is dependent on the level of validation. However, for mechanistic investigations a test model may be used more flexible in a weight of evidence approach. Extracted from our internal in vitro toxicology toolbox an example is described as to how a 3D cell model can be used in a repeated dose approach at two different stages of drug development. http://dx.doi.org/10.1016/j.toxlet.2017.07.210
Marcus Bantscheff Cellzome, GSK, Heidelberg, Germany Target profiling methodologies enable the identification of offtarget activities of candidate drug molecules that represent safety hazards. Assay panels currently used in the industry predominantly cover those few protein families that constitute established target classes in drug discovery, and proteins established as initiating factors for adverse outcome pathways. However, these panels tend not to cover the remaining >90% of the chemically tractable proteins. Proteomics-based technologies enable a more comprehensive and less biased assessment of compounds off-targets across the proteome. This presentation will introduce available chemoproteomics approaches and their application to identify unexpected targets of marketed drugs and early stage compounds that explain their (poly-) pharmacological activities, and adverse effects. http://dx.doi.org/10.1016/j.toxlet.2017.07.209 ISS 1b-05 How advanced cell models can be used for toxicity investigations during drug development – A case example Mario Beilmann Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Cell models comprised of multiple cell types in three-dimensional structures, and able to be maintained for several weeks in culture, have been advanced to a degree to which toxicologists in the pharmaceutical industry start to begin adding individual models to
ISS 1b-06 Integrating transcriptomic profiling in early safety screening – A case study Freddy Van Goethem Mechanistic & Investigative Toxicology, Janssen R&D, Beerse, Belgium Within predictive toxicology and early safety screening, there is a current need to better understand the underlying mechanisms of in vitro positive toxicity screening results. This paradigm-shift to a more mechanistically-based hazard identification/classification relies heavily on the development and use of innovative technologies, hereby employing human in vitro cell cultures and translational biomarkers. To allow the identification of early hazard, prioritize chemical series and steering chemical design, safety assessment should ideally be integrated into the early phases of the discovery process. To exemplify this strategic objective, we previously demonstrated the integration of high-dimensional transcriptomics and high content image analysis in a proof-ofconcept approach for early safety (genotoxicity) screening. This data integration approach showed the potential to flag toxicity issues by utilizing data from exploratory experiments that are typically generated for target evaluation purposes during early drug discovery. Besides the use of gene expression-based signatures, next-generation screening test platforms can be applied to translate and classify in vitro micronucleus results (Tier-1 hazard flags) into a more mode of action-based analysis. It is known that indirect DNA damaging compounds (e.g. aneugens, kinase inhibitors) typically induce non-linear dose-responses, which allow the use of a threshold concept and thus a better risk assessment. http://dx.doi.org/10.1016/j.toxlet.2017.07.211
proliferation, while in other cases phenotypic species comparisons recapitulating the in vivo effect in rodents and absence thereof in a human system can be used to support projects moving forward in development. These data show that using modern in vitro approaches making use of cellular models from pre-clinical species and human are able to mimic and de-risk effects frequently hampering drug programs entering late development stages. http://dx.doi.org/10.1016/j.toxlet.2017.07.208 ISS 1b-04 Chemoproteomic approaches for off-target hazard identification
S79
their test portfolio. Either as a test model for screening to reduce the early failure risk in preclinical animal studies, or to investigate adverse drug effects that occurred in preclinical species, these advanced models may support the transfer of a safe drug candidate into the clinical testing phase. The willingness to integrate such complex in vitro models into a regular testing scheme in industry is dependent on the level of validation. However, for mechanistic investigations a test model may be used more flexible in a weight of evidence approach. Extracted from our internal in vitro toxicology toolbox an example is described as to how a 3D cell model can be used in a repeated dose approach at two different stages of drug development. http://dx.doi.org/10.1016/j.toxlet.2017.07.210
Marcus Bantscheff Cellzome, GSK, Heidelberg, Germany Target profiling methodologies enable the identification of offtarget activities of candidate drug molecules that represent safety hazards. Assay panels currently used in the industry predominantly cover those few protein families that constitute established target classes in drug discovery, and proteins established as initiating factors for adverse outcome pathways. However, these panels tend not to cover the remaining >90% of the chemically tractable proteins. Proteomics-based technologies enable a more comprehensive and less biased assessment of compounds off-targets across the proteome. This presentation will introduce available chemoproteomics approaches and their application to identify unexpected targets of marketed drugs and early stage compounds that explain their (poly-) pharmacological activities, and adverse effects. http://dx.doi.org/10.1016/j.toxlet.2017.07.209 ISS 1b-05 How advanced cell models can be used for toxicity investigations during drug development – A case example Mario Beilmann Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Cell models comprised of multiple cell types in three-dimensional structures, and able to be maintained for several weeks in culture, have been advanced to a degree to which toxicologists in the pharmaceutical industry start to begin adding individual models to
ISS 1b-06 Integrating transcriptomic profiling in early safety screening – A case study Freddy Van Goethem Mechanistic & Investigative Toxicology, Janssen R&D, Beerse, Belgium Within predictive toxicology and early safety screening, there is a current need to better understand the underlying mechanisms of in vitro positive toxicity screening results. This paradigm-shift to a more mechanistically-based hazard identification/classification relies heavily on the development and use of innovative technologies, hereby employing human in vitro cell cultures and translational biomarkers. To allow the identification of early hazard, prioritize chemical series and steering chemical design, safety assessment should ideally be integrated into the early phases of the discovery process. To exemplify this strategic objective, we previously demonstrated the integration of high-dimensional transcriptomics and high content image analysis in a proof-ofconcept approach for early safety (genotoxicity) screening. This data integration approach showed the potential to flag toxicity issues by utilizing data from exploratory experiments that are typically generated for target evaluation purposes during early drug discovery. Besides the use of gene expression-based signatures, next-generation screening test platforms can be applied to translate and classify in vitro micronucleus results (Tier-1 hazard flags) into a more mode of action-based analysis. It is known that indirect DNA damaging compounds (e.g. aneugens, kinase inhibitors) typically induce non-linear dose-responses, which allow the use of a threshold concept and thus a better risk assessment. http://dx.doi.org/10.1016/j.toxlet.2017.07.211