Science Pool

A recent publication in Nature Medicine further validates Just – Evotec Biologics’ J.MD^TM Molecular Design suite. 

Children under the age of 5 years account for more than 75% of deaths attributable to malaria. The World Health Organization (WHO) has recommended the vaccine Morsquirix for paediatric use, but it has modest efficacy. Monoclonal antibodies and other complementary strategies are critically important in efforts to eradicate this disease. 
 
A multi-disciplinary team of scientists from multiple organizations collaborated on a project to select and engineer a potent and long-lasting antibody drug with anti-malaria activity. Key to this mission was to develop an antibody with developability properties amenable for cost-effective manufacturing and dosing in paediatric populations. 
 
Scientists from Just – Evotec Biologics played a crucial role in the project. They helped with the lead candidate selection by ranking a panel of human-derived potential antibody candidates for developability using Just - Evotec Biologics’ in silico Abacus tool. Abacus is a component of our J.MD^TM Molecular Design suite of tools for antibody research and development. Once the team had selected a lead and backup candidates, Just - Evotec Biologics scientists designed optimized variants of the candidate antibodies with greatly improved developability properties informed by stability violations found with the Abacus tool. 
 
Scientists used stable pools to express the optimized designs and generate material for biophysical characterization and activity assays. This enabled the final lead selection of AB000224 and AB007088 for advancement as a clinical lead and backup. The team engineered the variable domains of both antibodies to enable low-cost manufacturing at scale for distribution to paediatric populations. 
 
Just-Evotec Biologics scientists identified the best-producing clonal cell line, expressing the candidate molecule in continuous-perfusion bioreactors at twice the original titre. They advanced the candidate into production following good manufacturing practices. The material generated from this production run is being used to support studies for clinical development of an antimalaria drug suitable for use in paediatric populations living in Low to Middle Income Countries. 

Learn more in the following article published in the prestigious journal, Nature Medicine. 

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Antimicrobial resistance (AMR) is one of the biggest health threats worldwide. Key to countering AMR is the development of novel anti-infective drugs. The limitations of animal models and clinical trial design have emphasised the importance of nonclinical pharmacokinetics/pharmacodynamics (PK/PD) platforms which provide a detailed understanding of the relationship between the fate of the antimicrobial compound in the body (PK) and the impact of exposure to the compound on the target microbes (PD). This allows us to optimise dosing regimens to maximise the efficacy of antimicrobial compounds (microbial killing) while minimising toxicity and the risk of the emergence of AMR.

What is the HFIM?

The HFIM is a system of pumps, tubing and microfibers that mimics the body, allowing in vitro assessment of anti-infective compounds under more relevant conditions. It consists of a central reservoir and tubing used as a circulating system, and a hollow fibre cartridge with thousands of permeable capillaries. The extra capillary space (ECS) outside the fibres within the cartridge contains the target organism. During operation, the drug-infused growth medium in the central reservoir is continuously pumped to the hollow fibre cartridge, rapidly passing through the capillaries into the ECS. This continuous flow ensures that nutrients, oxygen, and test compounds are continuously refreshed while waste products are removed. To simulate drug clearance, fresh medium is added to the central reservoir effectively diluting the drug from the system. Accordingly, this balance of drug supply/clearance can effectively simulate the drug’s PK profile.

Why choose the HFIM as PK/PD model?

It is the most capable in vitro system for PK/PD determination for anti-infective compounds, against bacteria and fungi. It is a dynamic model capable of simulating almost any given concentration-time profile for one or more compounds, even if they have very different half-lives.. The Hollow Fibre Infection Model is not limited by in vivo model availability, compatibility of PK profiles, dosing or sampling frequency, or study duration, which is extremely important for understanding PK/PD relationships and the risk of AMR over clinically relevant treatment times. Various cartridges with fibres manufactured from different materials are available to optimise the HFIM for microbial growth and compound performance.

In conclusion, the HFIM is a versatile in vitro PK/PD platform which can accelerate the development of antibacterial and antifungal compounds, contributing to the fight against AMR. 

If you’d like to learn more about the uses of the Hollow Fibre Infection Model you can download our white paper here

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The tuberculosis lesion environment is highly complex. Mycobacterium tuberculosis (M.tb) reside in various niches and their metabolism and other characteristics, including drug tolerance depend on the specific environmental characteristics of those niches. So-called persister bacteria refer to those that are difficult to eradicate with drug treatment and that may contribute to the long durations of TB treatment required for cure. Many in vitro models have been developed in attempts to mimic these niches with the objective of determining potential anti-TB compound activity in models that reflect M.tb’s characteristics in vivo.
Foamy macrophages Foam-M are characterized by lipid body accumulation induced by Mtb infection and they may be an important niche for Mtb during infection.

In this poster we:

• We describe the development of a robust 96 well plate Foamy macrophages assay designed to mimic this niche, and suitable for medium-high throughput evaluation of compound activity during drug discovery.
• We describe TB compounds activity in the foamy macrophage assay compared to other TB current assays
• We show that infection of foamy macrophage does not trigger an anti-inflammatory response in host cells

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Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV). It is still a major public health problem with 250 million chronically HBV-infected patients worldwide with none of the current treatments leading to a cure.
More effective treatments are needed to achieve HBV cure in a large proportion of patients.
We aim to develop a treatment, combining simultaneous stimulation of CD40 and IFN-I pathway, which leads to a strong anti-HBV effect with minimal inflammation.

In this poster we:

• Present the key results that demonstrated the potential of such combination to induce anti-HBV effects in vitro and in vivo
• Introduce the design of our new antibody-based therapeutic that combine the two modalities in one single molecule
• Demonstrate the efficacy of the molecule in HBV infection system in Primary Human Hepatocytes
• Show key results from our preclinical safety assessment in vitro and in vivo in Non-Human Primate

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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.

Hope you enjoy the webinar

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Chemoprophylaxis is a well-known strategy to prevent infectious diseases in populations at risk, e.g., in malaria, tuberculosis, or Neisseria meningitidis. Therefore, it is also being discussed for other diseases, such as Chikungunya virus (CHIKV) infection. This disease is spread by Aedes mosquitoes and leads to acute febrile illness, as well as to inflammation and disabling pain in the joints. While the acute fever often resolves within days, musculoskeletal, arthritis-like symptoms can persist for months and years, leading to a substantial burden of disease in tropical and subtropical areas.

There is a need not only for therapeutic, but also prophylactic treatments against Chikungunya disease – like those available for malaria. However, the design of clinical trials is complex as Chikungunya outbreaks are challenging for studying interventions: They are unpredictable in time and place, spreading rapidly, but with usually short life-spans and differential diagnosis is complex, so that there is a high risk that the outbreak is over before a trial can be conducted.

However, there is a potential solution, following evidence on the risk of secondary household infections in chikungunya outbreaks. Household transmission is well-known from respiratory viruses transmitted via aerosols. At first glance the transmission via a mosquito seems not comparable to the transmission mode of airborne viruses, but it is known that the main vector, Aedes mosquitos, has a very limited flying range, resulting in spatial microclustering of CHIKV outbreaks: household members and near neighbors have the highest risk of secondary infections. Therefore, enrolling such a high-risk population could allow for a more feasible, smaller, shorter and conclusive trial.

Evotec teamed up with scientists from Aarhus University (Denmark), the Institut Pasteur du Cambodge (Phnom Penh, Cambodia), the Fundação Oswaldo Cruz, (Salvador, Bahia, Brazil), and the Instituto Nacional de Infectologia Evandro Chagas-Fiocruz (Rio de Janeiro, Brazil) to develop an innovative chemoprophylaxis trial design for CHIKV.

As a first step, such a trial requires a surveillance study design to determine household secondary attack rate. For this study, index cases need to be identified by RT-PCR to confirm a CHIKV infection, followed by serosurveillance of household members. There is a caveat as household secondary attack rates may not be accurately predicted from one chikungunya outbreak to another. Therefore, estimates of household secondary attack rates from different countries and cultural environments are needed.

The objective of such a study will be first to establish a range of estimates around which the feasibility of prophylaxis trials can be evaluated and a sample size calculated. Subsequently, evidence-based prophylaxis trials can be conducted based on the estimated rate of secondary household infections.

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Watch the webinar to learn more about exciting new developments in predictive toxicology!

About the Webinar

In this webinar, John Barker, SVP Global Head of Protein Sciences discusses bacterial infections and global health within anti-infectives. John gave this talk at the Oxford Global Discovery UK event in October 2021.

About the Speaker

John Barker, PhD FRSB Senior Vice President, Global Head of Protein Sciences | Evotec Currently responsible for more than 150 scientists across four sites, Princeton NJ, Abingdon UK, Toulouse and Hamburg. Team delivering Protein Production, Structural Biology and Cellular Sciences both internally and to Evotec’s partnerships. Over the past 18 years built from the ground up the current Evotec structural biology unit, now with more than 30 PhD scientists, one of the largest units in industry. Supporter of UK industry as the Industrial Life Science representative on the Diamond Scientific Advisory Board. John has worked on more than 40 collaborations across a range of drug discovery projects including multiple structure and fragment guided programmes in all therapeutic areas.

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Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19.

Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories.

• In this paper we describe strategies used to prioritize thousands of β-lactams from multiple companies into a small test set for further characterization.
• In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor.
• One potent cephaloporin was active in Mtb-infected mice.

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With more then 15 years of screening experience in anti-infectives, including antibacterials and antivirals, Evotec's medium throughput and high throughput screening expertise extends to BSL2⁺ and BSL3 containment level. 

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