Science Pool

Peripheral neuropathy can be induced by many chemotherapeutics. Symptoms include numbness, tingling or abnormal sensations which can impact on the long-term quality of a patient’s life. Animal models used to evaluate these side effects may be difficult to interpret and are labor-intensive. In this study, we further optimized a previously developed DRG assay by comparing the neurite outgrowth responses of a group of chemotherapeutics from different classes at 24 h and 72 as an in vitro cell-based model for peripheral neuropathy. Cytotoxicity was assessed alongside neurite outgrowth. Taxanes (paclitaxel, docetaxel), microtubule interfering agents (vincristine, vinblastine, colchicine, nocodazole) and epothilones (ixabepilone) were assessed.

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The generation of anti-drug antibodies (ADA) towards a therapeutic agent can have severe implications with respect to drug safety and efficacy. Therefore, identification of this risk during the initial phase of development is imperative to improve both patient outcomes and downstream attrition rates. As preclinical species often fail to mimic the complexity of the human immune system, the immunogenic potency of therapeutic agents and their potential to elicit a human-specific proinflammatory response can be grossly underestimated during in vivo safety assessment. In our research, a high-throughput in vitro approach to immunogenicity screening was developed using two distinct models: i) peripheral blood mononuclear cells (PBMC) and ii) monocyte-derived dendritic cells (MoDC) isolated from the blood of healthy human donors. The effect of serum-free culture conditions was also evaluated. The immunogenicity of monoclonal antibodies, small molecules associated with delayed-onset hypersensitivity reactions and oligonucleotides were assessed in each model through lymphocyte proliferation and cytokine release.

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The periodic activation and inactivation of various cardiac ion channels enables the regular and synchronous contraction of the heart. Therefore, any disruption of the cardiac ion channel signaling network can result in a change in membrane potential and in the shape of cardiac action potential (AP). As a result, the cardiac excitation-contraction coupling can be modified which may lead to arrhythmias and potential patient death. Local Extracellular Action Potential (LEAP) is a technique which enables non-invasive, label-free monitoring of cardiac action potential in a high-throughput real-time format. In our research, we used the Axion LEAP MEA assay to analyse the effect of various selective and non-selective ion channel inhibitors on cardiac AP by quantification of action potential morphology, repolarization irregularities, and arrhythmic risk factors such as triangulation.

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Drug-induced cardiotoxicity may result from a functional change in cardiac electrophysiology (acute alteration of the mechanical function of the myocardium) and/or from a structural change, resulting in damage to the cardiac tissue. In our research, the effects of 42 reference compounds in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were investigated in a combined risk assessment strategy. Functional cardiotoxicity was evaluated through kinetic monitoring of calcium transients (CaT), while structural morphology changes and gross cytotoxicity were assessed using high-content imaging (HCI) and cellular ATP measurements. In addition, whole genome high-throughput RNA-sequencing (ScreenSeq) was performed in matched-sister plates. Data were analysed to determine differentially expressed genes (DEGs) and any associated perturbed pathways.

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Mitochondrial dysfunction has been implicated in numerous drug induced adverse events, such as liver failure and cardiac toxicity. Read about how Cyprotex uses a combination of in vitro approaches to detect mitochondrial toxicity and analyse the potential mechanism of action in our poster.

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Take a look at our scientific poster, ‘VEGFR-3 signature expression by histology to classify patient population for the selective VEGFR-3 inhibitor EVT801’, recently presented by our experts at AACR 2023. 

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Drug-drug interaction (DDI) studies are an important part of the regulatory drug development process. The US FDA, EMA and Japanese PMDA have issued guidance on the conduct of these DDI studies, however, a harmonised guidance is currently under review (ICH M12) and is expected to be adopted in April 2024. The risk of DDI can be assessed in vitro and data analysed using models of varying complexity.  As identifying potential safety issues is the main purpose of these studies, many of the models have been developed to over-estimate the risk of DDI .This, however, needs to be balanced with the risk of false positives and the potential of unnecessary clinical DDI studies which are expensive and time consuming to perform. It is essential, therefore, to choose the most accurate model when analysing data from in vitro DDI studies.   

In this poster, we focus on:

• an evaluation of the various models for predicting clinical CYP3A4 induction risk from in vitro data
• a comparison of basic R₃ values (with and without a scaling factor) with correlation methods (relative induction score (RIS) and I_max/EC₅₀ values)

Read our poster to learn more about our research!

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LC-MS/MS produces highly sensitive, specific and reproducible data, however, throughput can be a limitation and this can lead to a bottleneck in sample analysis from pharmacokinetic (PK) studies.

In this poster, we focus on:

• the development of ultra-fast separation chromatography to improve efficiency of sample analysis in small molecule PK studies
• a comparison of the rapid separation method with conventional column technology for the analysis of plasma and blood samples from a PK study

Read our poster to learn more about our research!

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The Echo^® MS system, developed by Sciex, uses Acoustic Ejection Mass Spectrometry (AEMS). This chromatography-free technology generates sample droplets and introduces small reproducible volumes of 2.5nL (scalable to 25nL with multiple injections) to the mass spectrometer via an Open Port Interface with minimal carryover. It not only reduces sample requirements, it also facilitates dramatic increases in throughput with the potential to run 1 second cycle times. Despite these advantages, current potential limitations include reduced sensitivity compared to conventional LC-MS/MS and interference due to lack of separation.

In this poster, we focus on:

• the evaluation of the Echo^® MS technology for its application in routine ADME screening
• a comparison of the Echo^® MS with established, routine LC-MS/MS methods for the analysis of samples generated from microsomal stability and cytochrome P450 (CYP) inhibition assays

Read our poster to learn more about our research!

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Chinook Therapeutics and Evotec joined forces for a patient-centric target identification supported by strong translational evidence to initiate drug discovery programs with a focus on tubular failed repair and cross-talk in the tubulointerstitial niche.

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