Science Pool

Evotec possesses a comprehensive drug discovery platform to support oligonucleotide-based drug discovery from in silico design to clinical translation. Oligonucleotides therapeutics have been emerging as novel therapeutic modality for a vast range of diseases constantly growing resulting in 15 drugs currently approved. Here, we show our ongoing effort to further expand this platform by employing the recently developed splintR-qPCR as a novel bio-analytical method for quantification of oligonucleotides in tissues and comparing it to LC/MS and bDNA in use in Evotec. Within an Evotec internal R&D proof of concept study, the splintR-qPCR was proven as valid and comparable method to bDNA and gold-standard LC/MS. The high sensitivity, throughput and low costs compared to LC/MS and bDNA assay place splintR-qPCR as pivotal method that will strengthen Evotec oligonucleotides expertise on PKPD modelling.

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About this Webinar

In this short recording, Dr Pia Thommes, VP Anti-Infectives and Virology Therapeutic Leader discusses:

• Current challenges in Infectious Diseases drug discovery
• Human SARS-CoV-2 and other emerging viruses
• Industry relevant in vivo models
• The wider reaching consequences of the COVID pandemic

More about Dr Pia Thommes.

Pia gained her PhD in Molecular Genetics and followed this with a postdoctoral in biochemistry, focusing on DNA replication and cell cycle. She has 12 years experience in drug discovery of antivirals at GW/GSK, 4 years work in oncology on DNA Damage Response at KuDOS/ AZ. In 2012 Pia took on a role as Scientific Operations Director at Euprotec, a specialist CRO for infectious disease, this was incorporated into the Evotec family in 2014. Currently Pia is working as VP of Anti-infectives in Alderley Park and also Therapeutic Area Lead for Virology.

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While the public has taken note of RNA-based medicine only with the advent of mRNA-based Corona virus vaccines, biopharmaceutical research and development has been working on mRNA-based medicine for almost two decades. Evotec also expanded the druggable target space to RNA and in the last years added considerable know-how in RNA-based medicine.

RNA is used by cells in multiple ways: mRNA is conveying genetic information from DNA to the ribosomes which also are made from RNA (ribosomal RNA), where another RNA species (tRNA) is transporting amino acids to the ribosomal apparatus so that a protein can be synthesized. In addition to mRNA, there are also shorter RNA molecules being used in the cell for the regulation of genes and entire genetic cascades.

This provides for plenty of potential interventions: antisense (ASO) and short interfering RNA (siRNA) can up or down regulate an RNA target, e.g., to block the translation of an unwanted or diseased protein or to suppress or stimulate the expression of genes. RNA can be targeted with (complementary) RNA, but it is also possible to alter or block the translation, re-locate or initiate RNA, degradation, etc. by small molecules interfering with the three-dimensional structure of RNAs or protein-RNA-complexes.

During our recent Innovation Week, Evotec experts Steffen Grimm, Group Leader, Hit ID & Biophysics, and Hilary Brooks, Senior Research Scientist, In Vitro Pharmacology, hosted a session called "The early bird catches the helix: Expanding the druggable target space to RNA".

In the session, they discussed how to:

• Expand the potential for drugs targeting RNA to offer alternative solutions for diseases with otherwise undrugged targets
• Target RNA providing highly specific solutions for protein removal, alternative splicing or pathway regulation via noncoding RNA
• Use the small molecule RNA targeting platform to contribute to new opportunities for target identification and validation

RNA as Therapeutics
Using RNA as therapeutics is not trivial. Nucleic acids introduced from outside may trigger adverse reactions by the innate immune system. A lot of knowledge is necessary to ensure delivery, avoid degradation and inflammation and to fine-tune the stability and function of the molecules. RNA may also have off-target effects. To ensure efficacy and safety, monitoring these early on needs to be incorporated into the developmental workflow. High quality synthetic RNA is costly to make, therefore a scaleable process and the relevant analytics must be established early in the process to accompany both the discovery and development stages of research with quality test material; Eventually producing GMP grade RNA at a commercial scale (several hundred grams) for human administration.

Evotec already has integrated all capabilities under one roof, allowing for the complete preclinical data set, reduced transition times and efficient communication to the regulators. For antisense oligonucleotide therapy, efficient hit sequences that knock down target expression can be selected in a matter of weeks. Toxicity profiling is a priority to establishing final leads and, subsequently, project-specific dose, duration and delivery will be established using optimized backbone chemistry. Using its in-silico capabilities as well as iPSCs, animal models, transcriptomics, etc. Evotec is able to predict toxicity and efficacy, and de-risk unwanted immune stimulation as well as off-target effects. For manufacturing, Evotec is discovery-capable and already building medium-scale capacity (up to 50g) which will be ready by 2023.

For inhibiting the translational machinery, Evotec has established an RNA small molecule targeting platform and established in various case studies, molecules binding to RNA, and demonstrating a significant effect in vitro without affecting cell viability. Evotec’s capabilities also allow the creation of a representation of the 3-dimensional structure of the target complex and its interaction with the compounds.

Evotec’s experienced team of scientists with proven drug discovery and development expertise already have a track record of driving RNA targeting projects forward. Its integrated medicinal and computational chemistry capabilities, combined with bioinformatics, structural biology, pharmacology, and drug safety expertise allows for the identification and characterization of RNA target species and their modulation by different modalities. Partner projects can be driven all the way from target identification to IND and beyond. Evotec therefore is a low-risk outsourcing partner and a company continually investing in its platform to the benefit of the customer.

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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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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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Pneumonia induced by multidrug resistant (MDR) Acinetobacter baumannii strains is among the most common and deadly forms of healthcare acquired infections. Animal models play a critical role during the preclinical assessment of novel therapeutic approaches, however, only a self-limiting pneumonia with no or limited local bacterial replication is frequently obtained when MDR A. baumannii is the pathogen.

To strengthen and characterise a sustained lung infection model, in this publication, we focus on:

• the ability of intranasal inoculation, intratracheal instillation and oropharyngeal aspiration methods of administration of the bacterial challenge to induce a robust pneumonia in mice
• the characterisation of the infection model obtained after intratracheal instillation and oropharyngeal aspiration in terms of histopathological examination of pulmonary lesions, biomarkers of inflammation and leukocytes cells infiltration after treatment with either vehicle or with the antibiotic tigecycline efficacious into reducing lung bacterial load.

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Loss of heart myocardium is considered to be an irreversible process which can eventually lead to heart failure. Adult cardiomyocytes divide at a rate of less than 1% per year and no cardiac stem or progenitor cell type contribute significantly to the replacement of lost myocytes. One approach being pursued to replace lost heart muscle and regenerate the heart is the use of stem cell-derived cardiomyocytes.

In this publication, we focus on an in-depth review of the use of human pluripotent stem-cell derived cardiomyocytes in heart regeneration including:

• a background to cardiac regeneration and the approaches used to address this
• preclinical research and achievements in the use of cell therapy and stem cell-derived cardiomyocytes for the replacement of lost heart muscle 
• an overview of existing open questions such as how the technology works, the duration of effect, patient selection, immunological issues and how to reduce risk
• a summary of the clinical trials currently ongoing in this field

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P2X3 receptors play an important role in the sensitisation of nerve fibres and pain pathways. Involvement in pathways triggering cough and contribution to the pathophysiology of endometriosis and overactive bladder have also been reported. Development of P2X antagonists have been hampered by off‑target effects which include severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer.  

In this publication, we focus on:

• how eliapixant (BAY 1817080), a P2X3 receptor antagonist, is both highly potent and selective for P2X3 over other P2X subtypes in vitro including P2X2/3
• how eliapixant reduces inflammatory pain in relevant animal models
• experimental evidence that P2X3 antagonism reduces neurogenic inflammation and vaginal pain, and demonstration of the potential use of eliapixant in endometriosis

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Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK

As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.

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Mutant huntingtin (mHTT) protein has been implicated in neuronal degeneration in Huntington's Disease.

In this publication, we focus on:

• a background to the inherited neurodegenerative disorder, Huntington's Disease, including the impact of the mutant huntingtin (mHTT) gene
• a discussion of the use of positron emission tomography (PET) to monitor disease progression
• the identification of a novel ligand CHDI-626 which binds to mHTT aggregates

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