Herceptin, also known as Trastuzumab, is a pioneering antibody drug used in the treatment of HER2-positive breast cancer. By targeting the HER2 protein abundantly expressed on the surface of certain breast cancer cells, Herceptin serves as a beacon, marking these cells for immune system recognition and subsequent destruction. This mechanism highlights the significance of membrane proteins as drug targets not only for Herceptin but also for numerous other therapeutics under development or already in use.
In the realm of drug development, evaluating candidate molecules is pivotal, with a crucial test being the assessment of their binding affinity and kinetics. However, the inherent instability of many membrane proteins outside of their native cellular environment poses a significant challenge. Current methods for analysing binding affinity and kinetics typically require the isolation of proteins, leading to bottlenecks in therapeutic development. Alternative approaches, such as extracting and stabilizing membrane proteins, are time-consuming and complex.
To address these challenges, our project aims to adapt our existing Amperia antibody quantification system for the new application of measuring the binding affinity and kinetics of antibodies with membrane proteins. The system will seamlessly integrate with intact cells, leveraging the Redox Electrochemical Detection (RED) platform technology pioneered by HexagonFab. Through this project, we will develop the optimal sensor coating to facilitate experiments that involve whole cells.
The optimal production and storage conditions for achieving the ideal surface functionalization must be identified. This includes testing of various production methods followed by precise chemical analysis to evaluate the properties of the surface functionalization. In collaboration with NPL, this project aims to evaluate the influence of different production processes on the surface functionalization. By identifying the most effective process conditions, HexagonFab can enhance the performance of its sensors and ensure the successful development of advanced technologies.
Understanding and optimizing the surface coating process for cell assay applications will ensure that the sensors exhibit the required sensitivity and specificity. By facilitating cheaper and faster development pathways for innovative therapeutics, this technology promises to benefit patients and enhance the healthcare ecosystem.
Cell and gene therapies are promising treatments for several unmet medical needs. Most of these therapies rely on viral vectors as the delivery tool for cell modification. HEK-293 cell line is the most used platform for the manufacturing of cell and gene therapy viral vectors that have achieved successful clinical data and regulatory approval for commercialization. However, the production capacity of this platform is still inefficient to meet the current and growing future demand for viral vectors which leads to the need for large volume bioreactors and high manufacturing costs. Several attempts described in literature to genetically modify HEK-293 cells to improve viral vector titers have resulted in modest improvements in productivity.
In this project, we aim to increase viral vector productivity at least 50-100 folds higher by the genetic modification of the 293 cell line targeting genes with crucial role in viral vector production and quality. For that, functional genomics analysis will be used for the gene identification instead of a comparison gene by gene approach as previous attempts. By using functional genomic analysis, the focus will not only be on the genomic but also a combination of epigenomics, transcriptomics, proteomics and metabolomics. As a result, a HEK-293 cell line adapted to serum-free media and in suspension growth will be genetically modified using CRISPR gene editing,
At the same time, within the frame of this project, a single plasmid technology will be developed to achieve process cost-reduction and simplicity. In order to support the process development and the screening of the higher producer clones, a fully automated instrument will be developed for virus detection. Furthermore, the manufacturing process of the high-producer cell line will be established and validated at large scale bioreactors. The successful development of this project will deliver a highly productive viral vector manufacturing platform able to provide high yields and high-quality products in a cost-effective manner which will ultimately be at the service of the biotech community to accelerate the clinical translation and affordability of advanced therapies.
Antibody therapeutics are a class of drugs with synthetic antibodies as the active ingredient. They offer highly targeted and effective treatments for a wide range of diseases. The analysis of antibodies during drug development presents significant challenges due to their complexity. First, assessing their binding affinity and specificity necessitates intricate methods to ensure optimal therapeutic properties. Second, the production of antibodies demands sophisticated production and monitoring, making the entire drug development process time-consuming and resource intensive. Antibodies are predominantly analysed in central labs, which can lead to delays in obtaining results and hinder real-time decision-making. Implementing decentralized analysis closer to the point of need, will offer faster turnaround times and expedite decision-making.
HexagonFab's instrument, Bolt, is specifically designed for point-of-need analysis of antibodies. Currently, Bolt is limited to working with purified solutions. This means that any sample must undergo a process to remove unwanted substances or impurities prior to analysis. Many applications in various fields necessitate compatibility with crude media, i.e. complex samples containing mixtures of different biomolecules without undergoing extensive purification. This compatibility allows for more versatile application of the instrument in diverse settings.
HexagonFab is broadening its sensor portfolio by introducing a new generation of sensors capable of measuring crude samples. These sensors feature an electrically sensitive thin film coated with biomolecules; a process known as surface functionalization. The surface functionalization employed is a unique protein/graphene composite material, offering optimal electrical conductivity, while ensuring low non-specific binding signals.
To ensure successful product launch, the optimal production and storage conditions for achieving the ideal surface functionalization must be identified. This includes testing of various production methods followed by precise chemical analysis to evaluate the properties of the surface functionalization. In collaboration with NPL, this project aims to evaluate the influence of different production processes on the surface functionalization. By identifying the most effective process conditions, HexagonFab can enhance the performance of its sensors and ensure the successful development of advanced technologies.
Understanding and optimizing the surface coating process will ensure that the sensors exhibit the required sensitivity and specificity. With their ability to measure crude samples, these sensors can directly interface with crude media, allowing for more accurate and efficient antibody analysis without the need for extensive purification, ultimately saving time and resources.
The goal of HexagonFab is to unlock the secrets of biomolecules and shed light on how they interact. The protein analysis instrument BOLT created by HexagonFab helps the pharmaceutical industry to develop the medicine of the future, to find the best practice to produce drugs and to ensure their efficacy and safety through convenient and accelerated quality control (QC). The current systems used in drug discovery and development to perform QC measurements are hitting their limits with laborious protocols and significant hands-on-time. HexagonFab has developed a novel sensor platform tailored for convenient and rapid QC measurements, based on nearly a decade of research at the University of Cambridge, thereby offering a solution for the drug development process in the pharmaceutical industry.
As the novel sensor technology is crucial for HexagonFab's BOLT, the goal of the project is to optimise the sensor surface functionalization to bring BOLT to the market. The high specificity and sensitivity of the sensor combined with its unique technology will help the drug development industry significantly to accelerate their research and development processes, leading to safer and more efficacious drugs.
The goal of HexagonFab is to unlock the secrets of biomolecules and shed light on how they interact. The tools created by HexagonFab help researchers to develop the medicine of the future, to find the best ways to produce novel biomolecules and to assure that medicine is always safe and efficacious. The current systems used in drug discovery and development to analyse traditional molecules like proteins and small molecules are hitting their limits with the new generation of advanced drugs.
HexagonFab has developed a novel sensor platform based on nearly a decade of research at the University of Cambridge, thereby offering a solution for drug developers. The goal of the project is to create the foundation for the development of a version of the HexagonFab Bolt sensor, which will enable its application towards new classes of molecules such as Ribonucleic acid (RNA) or peptides.
RNA therapeutics represent a rapidly growing category of drugs that creates a new paradigm for personalized medicine and treatment of many diseases. Given the challenge of small molecules such as RNA to traditional analysis instrumentation, the HexagonFab Bolt could become the perfect solution to answer this industry need.
The influenza burden
Each year more than 800'000 people in the UK see their GP for suspected influenza infection and 20'000-30'000 people are admitted to hospitals. Hospitals face the daily risk that incoming patients (110,000 annually in the Emergency Room in Addenbrooke's Hospital in Cambridge 2017/2018) will lead to Influenza outbreaks in the hospital. Indeed, there were more 2200 confirmed influenza outbreaks in the UK last year in hospitals, care homes, and schools.
To prevent outbreaks, patients must be tested for influenza before antiviral treatment is initiated. Unfortunately, this testing process can take several hours, resulting in delayed diagnosis and treatment. The current established and trusted "gold standard" method of testing for influenza in hospitals can take up to 12 hours. A delay of half a day is highly costly to the patient and hospital: patients must wait longer to be seen by the correct department, wards become congested with patients waiting for test results and the risk of viral outbreaks increases as potential carriers of the virus wait for results.
Clinicians have expressed a need for rapid influenza detection tests that can be carried out by non-medically trained personnell in the Emergency Room. A selection of currently existing rapid diagnostic tests (RDTs) has been tried. The sensitivity of most have been shown to be insufficient, thus often resulting in false negatives. There is an urgent need for a novel rapid diagnostic test for influenza virus that can be used in hospital emergency rooms.
What can be done
At HexagonFab, a biosensor has been developed and built from novel nanomaterials, which will bring the sensitivity of laboratory based tests to the emergency room. The technology gains its outstanding sensitivity through the unique surface of the nanomaterial, which is the core sensing element. In order to improve the sensor, it is necessary to investigate in detail how the nanomaterial interacts with its environment and how it can be tailored to be even more sensitive and specific. This continued InnovateUK A4I project brings the unique expertise of NPL, one of the leading research organisations of the UK, to investigate the surface of the nanomaterial and how the sensor can be optimised to achieve the sensitivity of current laboratory-based tests, while allowing use at the patient in the emergency room.
Each year more than 800'000 people in the UK see their GP for suspected influenza infection and 20-30'000 hospital people are admitted to hospitals. Hospitals face the daily risk that incoming patients (100,000 in the Emergency Room 2017 in Addenbrooke's Hospital in Cambridge) will lead to Influenza outbreaks in the hospital. Indeed, there were more 700 confirmed influenza cases last year at Addenbrooke's hospital, and three ward closures due to Influenza outbreaks.
To prevent outbreaks, patients must be tested for influenza before antiviral treatment is initiated. Unfortunately, this testing process can take several hours, resulting in delayed diagnosis and treatment. The current established and trusted "gold standard" method of testing for influenza in hospitals can take up to 12 hours. A delay of half a day is highly costly to the patient and hospital: patients must wait longer to be seen by the correct department, wards become congested with patients waiting for test results and the risk of viral outbreaks increases as potential carriers of the virus wait for results. Clinicians have expressed a need for rapid detection influenza tests that can be carried out by non-medically trained personal in the Emergency Room. A selection of currently existing rapid diagnostic tests (RDTs) has been tried. The sensitivity of most have been shown to be insufficient, thus often resulting in false negatives.
There is an urgent need for a novel rapid diagnostic test for influenza virus that can be used in hospital emergency rooms. At HexagonFab, a biosensor has been developed and built from novel nanomaterials, which will bring the sensitivity of laboratory based tests to the emergency room. The technology gains its outstanding sensitivity through the unique surface of the nanomaterial, which is the core sensing element. In order to optimise the sensor, it is necessary to gain a deep understanding of how the nanomaterial interacts with its environment and how it can be tailored to be even more sensitive and specific. The InnovateUK A4I project brings the unique expertise of leading research organisations in the UK to investigate the surface of the nanomaterial and how the sensor can be optimised to achieve the sensitivity of current laboratory-based tests, while allowing use at the patient in the emergency room.