Science Pool

Date: 27th - 31st March 2022

Location: San Diego Convention Center, CA, United States

Attending: Christopher Strock, Claire White, David Cerny, Felix von Haniel, Illaria Masotto, Matteo Sartori, Michael Campognone, Monday Ogese, Paul Walker, Ralf Geiben Lynn, Stephen Madden

Cyprotex and Evotec will be exhibiting and showcasing their research at the 61st Annual Society of Toxicology Meeting (SOT) and ToxExpo on March 27-31 in San Diego, CA.

Join our scientific specialists at booth #1226-1127 and don't forget to include our hosted seminar and poster presentations in your SOT itinerary!

If you wish to meet with us in San Diego, get in touch via the form below, we will be happy to arrange a meeting.

Our scientific program

Cyprotex Hosted Seminar
Multi-Organ and Species-Specific Safety Profiling using Transcriptomics
Presented by Paul Walker, PhD
Date: March 29, 2022
Time: 10:30 AM - 11:30 AM PDT
Room: 23C

Poster Presentations
Identifying Seizures with MEA: Complementary Human and Rat Neuronal Models Enhance Predictivity
Presented by Chris Strock, PhD
Date: March 28, 2022
Time: 2:30 PM- 4:15 PM PDT
Abstract Number/Poster number: 3289/P439

Development of In Vitro Assays to Predict Potential Immunotoxicological Liabilities of Candidate Drugs using Human Peripheral Blood Mononuclear Cells
Presented by Monday Ogese, PhD
Date: March 29, 2022
Time: 9 AM- 10:45 AM PDT
Abstract Number/Poster number: 4121/P825

Evaluating Functional and Structural Cardiotoxicants using Calcium Flux, HCI and High Throughput Transcriptomics
Presented by Stephen Madden, PhD
Date: March 30, 2022
Time: 9 AM - 10:45 AM PDT
Abstract Number/Poster number: 4377/P331

High Throughput RNA-Seq Profiling of 3D Liver Organoids to Predict Drug-Induced Liver Injury (DILI)
Presented by Paul Walker, PhD
Date: March 30, 2022
Time: 10:45 AM- 12:30 PM PDT
Abstract Number/Poster number: 4449/P449

Learn more about the 61st SOT Annual Meeting and ToxExpo

Quantitative Prediction of Drug-Drug Interactions with Common Statin Co-meds: A Framework for Decision-making within Drug Discovery/Development

The first webinar in this series on drug transporters was presented by Hayley Atkinson from Cyprotex.

About the Webinar

Due to polypharmacy, drug-drug interactions (DDIs) continue to account for 5% of UK hospital admissions and as such remain a major regulatory concern. This is particularly true for common co-meds such as statins which due to their prescribing prevalence in patients with co-morbidities have high potential for DDI. Within Drug Discovery and Development we are moving away from relatively simple hazard identification of DDI potential using basic static equations detailed in regulatory guidance to actual risk analysis and mitigation using quantitative prediction of DDI. Using mechanistic static equations we can predict the AUC change of each statin due to inhibition of its critical enzyme/transporter pathway(s) so that the clinical team can make a decision on whether any potential DDI is simply a pharmacokinetic DDI or a clinically significant DDI requiring intervention. The statin mechanistic equation model requires very few in vitro input parameters and can be utilised towards aiding preclinical development candidate selection and towards reducing unexpected clinical findings in patients providing a useful tool in Drug Discovery and Early Development.

About the Speaker

Hayley Atkinson PhD Associate Principal Scientist | Cyprotex Hayley Atkinson is an Associate Principal Scientist in the permeability and drug transporter team at Cyprotex, UK where she acts as deputy scientific lead for drug transporter studies.  Her research interests include prediction of transporter mediated drug-drug interactions with improved in vitro assays.  Prior to joining Cyprotex in 2013, Hayley received her PhD from the University of Liverpool under Prof. Munir Pirmohamed where she conducted research on anti-epileptic drug transporters at the blood-brain barrier in the context of drug resistance.

Watch the webinar to learn more!

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SARM1 is a NADase whose action triggers the destruction of axons and development of novel SARM1 inhibitors which enables the prevention or delay of neurodegenerative disorders. This paper identifies the binding site for the SARM1 agonist NMN and reveals the structure of full-length SARM1 as elucidated by cryo-electron microscopy (cryo-EM). The structure of apo SARM1 was revealed as an octameric ring, held in an autoinhibitory state by the separation of the active TIR domain at the rim of the ring. The elucidation of autoinhibition release and the identification of the NMN binding site within the autoinhibitory ARM domain opens a path to inhibition of SARM1 via stabilisation of its inactive form. These studies were possible through the close co-ordination of the new cryo-EM team at Evotec, Abingdon with Disarm and academic collaborators in Australia and the USA.

Proposed SARM1 activation mechanism:

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Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence.

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Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). In this recent article, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus

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Over recent years, interest in the multi-attribute method (MAM) has grown and the technique has become an important mass spectrometry-based tool for identifying and quantifying the site-specific product attributes and purity information for biotherapeutics such as monoclonal antibodies (mAbs) and fusion molecules. Improving the throughput of sample preparation without introducing chemical modifications and variability will further increase the utility of MAM in drug development.

In this publication, we focus on:

• the development of a fully automated MAM sample preparation protocol incorporating rapid desalting (< 15 min) using miniaturized size-exclusion chromatography columns in pipette tips on an automated liquid handling system which leads to complete rapid digestion of mAbs in approximately 3 hours with excellent reproducibility
• analysis of samples using electrospray ionization mass spectrometry coupled to a U-HPLC system with dual column switching 
• comparison of the new sample preparation method versus manual low artefact sample preparation including analysis of reproducibility, recovery, efficiency and flexibility

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Evotec strives to provide partners and customers with less expensive, faster, and more flexible approaches for discovering, developing and manufacturing biotherapeutics.

With the acquisition of Just Biotherapeutics in 2019, Evotec made a major push into biologics, and has successfully built a fully-integrated platform to drive monoclonal antibody (“mAb”) programmes from concept through to commercialisation. The company generates antibody lead candidates by providing access to in vivo and in vitro sources of antibodies, combined with state-of-the-art technologies to ensure success for a broad range of targets and disease states. In addition, if needed, selected lead candidates can be further optimised using powerful computational platforms such as Evotec’s proprietary Abacus™ in silico tool suite to enhance the productivity, but also ease of manufacturing and formulation stability.

For in vivo immunisation, Evotec is offering the ATX-Gx^TM mouse platform developed by its collaboration partner Alloy Therapeutics. This platform is a suite of immunocompetent transgenic mice for best-in-class in vivo discovery of fully human monoclonal antibodies. These mice are engineered to drive the greatest potential diversity and broadest epitopic coverage of unique human antibodies binding to a specific target of interest.

ATX-Gx^TM mice provide:

• a fully human heavy chain repertoire,
• human kappa and human lambda chain repertoire,
• haplotype diversity, and
• limited immunodominance.

Taken together, these immunocompetent transgenic mice represent the complete functional human antibody repertoire, and their fully functional, robust immune response is equivalent to the response of wild type mice. They are also available on multiple genetic backgrounds such as BALB/c or BL/6.

ATX-Gx^TM has been extensively validated and continuously expanded for more than 12 years and is currently used by over 75 antibody discovery groups in large biopharma and small-to-midsize biotech companies as well as academic research labs.

Following immunisation, Evotec is combining traditional hybridoma technology with automated devices for high throughput clone selection, screening, recombinant expression and purification to shorten and simplify the process of hybridoma establishment. Screening is performed with high-throughput technologies, such as the iQue® Advanced Flow Cytometry Platform. Next-generation sequencing is used to obtain VH/VL information, followed by an in silico analysis using Just – Evotec Biologics Abacus® software tool. Once VH/VL information is available, several hundred mAbs can be produced in parallel in small scale. This high quality material can then be used for further downstream characterisation, such as functional activities that allow the selection of potential lead candidates.

This streamlined workflow to generate high-quality antibody panels for functional assessment adds to Evotec’s comprehensive suite of large molecule discovery tools, disease biology, state-of-the-art cell line development, machine learning design tools, manufacturing, preclinical IND-enabling studies, as well as FIH clinical support, and commercialisation.

Evotec’s AI-driven antibody discovery can be accessed as stand-alone services or through Evotec’s seamlessly integrated antibody drug discovery platform

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The 11^th edition of our Drug Discovery Update (DDup) is dedicated to biotherapeutics discovery and development with a focus on artificial intelligence and machine learning and its opportunity in transforming antibody discovery.

In this edition, it covers:

• an introduction to antibodies including:
  • an overview of monoclonal antibodies as therapeutic agents
  • a history of antibody drug discovery platforms
• how Just - Evotec Biologics are exploiting artificial intelligence and machine learning to generate a novel humanoid antibody library biased towards highly desirable features
• a description of the process from idea to IND and beyond for antibody discovery and development
• facts and figures on the market for therapeutic antibodies
• an overview of function-focused antibody (FFmab) screening
• an interviews with the experts

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Date: 4-6 April 2022

Location: Hilton Gateshead, Newcastle UK

Attendee: Oksana Nikolayenko & Tim Potter

Learn more about BTS Annual Congress 2022

N-Methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has been recently identified as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy.

Identification of a new hit for GluN2A PAMs is however difficult due to the similarity of PAM binding sites between GluN2A and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs), another member of the ionotropic glutamate receptor family.

In this collaborative publication with Takeda, we focus on:

• Identification of an hit compound with moderate AMPAR-binding activity, though a Ca²⁺ influx-based high throughput screening campaign with a compound set including an internal AMPAR-focused compound library
• The strategy using a structure-based drug design (SBDD) approach to minimize the AMPAR-binding activity while improving GluN2A activity
• The use of the potent and brain-penetrable GluN2A-selective positive allosteric modulators GluN2A PAM discovered as in vivo tool exhibiting significant neuroplastic enhancement in the rat hippocampus 24h after oral administration, having potential application for cognitive enhancement in neuropsychiatric diseases

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