ELRIG-Forum 2020: Abstracts
Nil Ege, The Institute of Cancer Research: Royal Cancer Hospital, UK
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis and resistance to conventional chemotherapy remains the main challenge in PDAC treatment. One explanation for the failure of drug discovery programs on pancreatic cancer is the use of physiologically irrelevant pre-clinical models lacking the complexity of the tumours observed in vivo. PDAC tumours are hetero-cellular system where cancer associated pancreatic stellate cells (PSCs) are highly abundant and contribute to a desmoplastic microenvironment influencing tumour progression and drug resistance.
To answer the need for more complex in vitro models, we have designed a hetero-cellular 3D screening model, co-culturing cancer cells with PSCs, and have managed to mimic the desmoplasia observed in PDAC tumours. Furthermore, we have successfully multiplexed several read-outs allowing us to differentiate mechanisms of action of compounds: cell death, metabolic arrest, spheroid growth and dispersion. By comparing results from monoculture (cancer cells only) and in coculture conditions, we are now able to detect stroma-mediated resistance and identify compounds showing activity even in presence of a desmoplastic stroma. Selected hit compounds are then validated in a panel of PDAC cell lines and PSCs and target deconvolution is performed using proteomic-based approaches.
Nina Grossmann, Discovery Pharmacology, Merck, Darmstadt, Germany
At Merck, a proprietary library of roughly 1 Mio drug like compounds is screened in 10-15 HTS campaigns per year. Respective assays range from simple binding analysis to complex phenotypic assays with multiple read-out parameters. To as early as possible understand the molecular mode of action of active compounds, we also implement mode of action assays, such as competition assays or jump dilution assays into the HTS campaigns. Furthermore, selectivity and interference assays complement each HTS run to sort out false positives and promiscuous compounds on the fly.At Merck, a proprietary library of roughly 1 Mio drug like compounds is screened in 10-15 HTS campaigns per year. Respective assays range from simple binding analysis to complex phenotypic assays with multiple read-out parameters. To as early as possible understand the molecular mode of action of active compounds, we also implement mode of action assays, such as competition assays or jump dilution assays into the HTS campaigns. Furthermore, selectivity and interference assays complement each HTS run to sort out false positives and promiscuous compounds on the fly.Thus, each HTS campaign demands the development of multiple robust and high-quality assays in very short time. New generation liquid handlers allow for a significant automatization of such activities and can both, speed up assay development and allow for the generation of more assays with the same resources. In the last two years, we evaluated several of such devices and finally implemented a range of flexible bench top dispensing robots in our labs. Using these, we were able to speed up assay development, multiplex assays and save reagents. Furthermore, we could reduce miniaturization efforts by directly developing assays on 1536-well plates. This talk will exemplify, how we use these robots to quickly set up robust high throughput assays.
Dr. Ola Engkvist, AstraZeneca, Mölndal, Sweden
Artificial intelligence is underway to transform the society through technologies like self-driving cars. Also, in drug discovery machine learning and artificial intelligence methods has received increased attention. [1] The increased attention is not only due to methodological progress in machine learning and artificial intelligence, but also progress in automation for screening, chemistry, imaging and -omics technologies, which have generated very large datasets suitable for machine learning.
W. Alexander Mengel, AbbVie Deutschland GmbH & Co. KG, Analytical R&D, Germany
Cell based potency assays (bioassays) are a central element of the analytical control strategy of biologics since they are the only method capable of testing a drug´s effect in living cells. The requirements for bioassays in pharmaceutical development are high: On the one hand, the drug´s intended physiological Mode of Action (MoA) must be accurately captured. On the other hand, the assay must show a high degree of precision, accuracy and robustness to ensure reproducibility across laboratories around the world. Moreover, a certain degree of flexibility regarding assay performance must be maintained to facilitate routine sample measurement. Finding the right balance between these key requirements is the challenge for potency assay development.
Georg Fertig, PhD, Head of Dept. Lead Identification, Large Molecule Research
Roche Pharma Research and Early Development (pRED)
Roche Innovation Center Munich, Germany
The generation of bi-functional bispecific antibodies requires the combination of two monospecific binders, which bind to the right epitope of the respective target in the right format. High-throughput generation and screening of such antibodies will be discussed in the context of an effective and robust technology platform an automated production of bsAb binder-format combination matrices the format, which defines the function.
