SOT 63rd Annual Meeting and ToxExpo

_{Presenting Author: David Cerny
Session Title: Genotoxicity/DNA Repair
Session Date and Time: 11 March at 11:45 am to1:45 pm MST
Session Location: Salt Palace Convention Center, ToxExpo Hall}

Increased food demand due to a growing global population incentivizes the need to identify and develop safer and more effective food additives as required by regulators such as the FDA and EFSA. In vitro genotoxicity studies are required by these organizations of which assays such as the Comet assay, present lack of consistency in the literature regarding incubation time and analysis. The possible identification of DNA-damage-inducing food additives using automated high content screening with robust data analysis would support de-risking food additives.

_{Presenting Author: You Feng
Session Title: Endocrine Toxicology
Session Date and Time: 12 March at 2:15 pm to  4:15 pm MST
Session Location: Salt Palace Convention Center, ToxExpo Hall}

The endocrine system is comprised of hormones released by internal glands and their target receptors on distant organs. Hormone receptors, including Androgen Receptor (AR), Estrogen Receptor (ER) and Thyroid Hormone Receptor (TR), are a wide family of proteins that bind to specific hormones and activate a broad range of signaling pathways, such as growth, metabolism, development, reproduction, and response to stress. Since these hormone receptors interact with their ligands with high specificity and high affinity, very low concentrations of hormone can induce significant cellular responses. Endocrine disruptors, either natural or man-made, can interfere with the normal actions of hormones and affect the endocrine system, causing serious health problems such as cancer, birth defects, and developmental disorders.

Traditional Endocrine Disruptor Screening Assays use radioactively labeled materials or animal models with high cost and low efficiency. Here we utilized commercially available assays to establish a panel of 384-well high throughput cell-based hormone activation assays and in vitro hormone receptor binding assays with luminescence or fluorescence polarization end points with rapid turnaround time.

_{Presenting Author: Paul Walker
Session Title: Liver: In Vitro
Session Date and Time: 13 March at 11:45 am to 13 March 1:45 om MST
Session Location: Salt Palace Convention Center, ToxExpo Hall}

Drug-induced liver injury (DILI) is a major cause of attrition during the later drug development stages. Often, this leads to the termination of the program after significant investments have been made. Hence, there is a strong need for methods which a) rank drug candidates by their DILI risk as early as possible in the development program and b) estimate a safe dose for subsequent clinical trials.

_{Presenting Author: Ralf Geiben Lynn
Session Title: Liver: In Vitro
Session Date and Time: 13 March at 11:45: am to 1:45 pm MST
Session Location: Salt Palace Convention Center, ToxExpo Hall}

Drug-induced liver injury (DILI) remains a leading cause of drug attrition within the drug discovery and development process alongside clinical observations and potential market withdrawal. The cause of DILI is often multifaceted and complex and often includes a multitude of often interconnected cellular events, such as transporter inhibition, mitochondrial dysfunction, and chemically reactive metabolite (CRM) formation, that ultimately culminate in hepatotoxicity. The cytochrome P450 (CYP450) superfamily of metabolic enzymes are crucial for the excretion of xenobiotics from the body. In many cases, those xenobiotics that harbour potent biological activity are metabolised into daughter chemicals with lower potency than their parent. However, in certain instances the addition of chemical groups can induce the formation of a CRM capable of interacting with cellular macromolecules, ultimately inducing adverse cellular events and consequently liver damage. This process of compound bioactivation can in part be mitigated by the Glutathione (GSH)-conjugation system that is capable of binding with CRM and forming GSH-adducts, preventing adverse effects induced by CRM formation. The resultant depletion of cellular GSH can itself, however, result in downstream adverse events, such as the increase in reactive oxygen species (ROS) and oxidative damage of DNA, proteins, and lipids.

_{Presenting Author: Giulia Iannoto}

The immune system is a complex and dynamic network of cells and molecules responsible for defending the body against pathogens and foreign substances. Immunotoxicology evaluation play an important role to evaluate the impact of biological, or pharmaceutical agents on the immune system and for ensuring the safety of drugs. To establish a baseline for comparison, historical reference ranges of several parameters have been extensively studied and compiled over the years and represent an important tool for identifying deviations from normal levels and understanding the potential effects of test substances. Therefore, the aim of this work was to create an Historical Reference Ranges database for immunotoxicology parameters collected from naïve animals of toxicology studies performed in Evotec GLP Test Facility on Cynomolgus monkey (Macaca fascicularis) and Sprague-Dawley rats as animal models commonly used for non-clinical research.

The preclinical toxicology studies enabling the clinical phase are performed in compliance with the Principles of Good Laboratory Practice (GLP), and for the development of small molecules, these requirements are extensively described in several international guidelines (FDA, OECD, EMA, ICH). However, the transfer of these rules from the Development of a chemical entity to engineered viral vectors or to live cells (named Advanced Therapy Medicinal Products, ATMPs), is sometimes not straightforward, and in some cases poses for some potentially different interpretations and deviations from the guidelines. This is further enhanced by the huge variability of mechanism of action that ATMPs can offer, often combining different synergic mechanisms in a single therapy, and leading to an increased complexity that can be managed only with specific tailored “ad hoc” quality risk assessments. Indeed, current preclinical development of ATMPs requires a product specific approach based on constantly evolving product attributes (i.e mechanism of delivery, pay load/active ingredient, in situ route of administration). This work will present the quality risk assessments carried out in Evotec GLP Test Facility and the processes refinement required to properly manage potential issues, generally impacting the acceptance of the Test Article characterization, Test Article manipulation and formulation, formulation analysis, stability and related acceptance criteria,

the successful setup of surgically-based in situ administration, study protocol endpoints definition and management.

_{Presenting Author: Stephen Madden
Session Title: Advancements in Cardiotoxicity Assessment
Presentation Date and Time: 12 March 2:00 PM to 2:15 pm MST
Location: Room 250 D‚ Salt Palace Convention Center}

Cardiotoxicity remains one of the most commonly reported adverse drug reactions that leads to drug attrition during pre-clinical and clinical drug development. Drug-induced cardiotoxicity can affect all components of the cardiovascular system and may develop as a functional change in cardiac electrophysiology (acute alteration of the mechanical function of the myocardium) and/or as a structural change, resulting in damage to the cardiac tissue¹. Development of non-clinical models with better predictive value and cutting-edge in vitro strategies are required to significantly improve cardiac safety in drug discovery and development. A previous pilot study using 42 reference compounds provided proof of concept of the synergism of our multiparametric in vitro assay and high-throughput RNA-sequencing. Here, an expansion of the compound set was used to further validate our cardiotoxicity assessment approach.