This talk will demonstrate how hydrogen–deuterium exchange mass spectrometry (HDX-MS), supported by tailored protein purification strategies, enabled mechanistic insights into TEAD1 modulation by lipid and synthetic ligands. It will be shown how different P-site binders impact TEAD1 conformational dynamics and TEAD1/YAP interfaces behaviour. The presentation will also highlight the strategies and technical caveats employed to obtain the protein samples needed to interrogate the dynamics of the different TEAD1 states.

At Protein Sciences, GSK, our focus is on producing high-quality, multivariant recombinant proteins swiftly, meeting the evolving demands and supporting various stages of drug discovery and beyond. The talk will showcase our commitment to advancing this field by exploring novel ways to implement and enhance automation and platform technologies. This is with the aim to optimise and increase throughput for high quality recombinant protein generation.

With the exception of mRNA, most expression platforms rely on the host cell's endogenous transcription machinery, where the rate-limiting step in recombinant protein production arises from limited processivity, nuclear accessibility, and competition with host transcription. We present the C3P3 system, a biologically inspired artificial expression platform enabling high-yield, autonomous synthesis of exogenous mRNA, bypassing host machinery. Utilising a DNA-dependent RNA polymerase, C3P3 ensures both transcription and post-transcriptional modifications (e.g., capping, polyadenylation). In its current fourth generation, this system demonstrates up to 7-fold enhanced expression in HEK-293 and CHO-K1 cells, offering an efficient and versatile alternative for biologic production.

Targets for drug discovery projects are becoming more diverse and challenging. They are chosen based on evidence linking them to human disease and not on the challenges, which need to be overcome to express these proteins in suitable quantity and quality to support drug discovery projects. A number of examples of recent AstraZeneca projects will be presented, in which difficult expression/purification challenges have been overcome.

As antibody formats get more complex, it is easy to focus on the biology and neglect the expression and scale up. CreaTap is a hinge modification of antibodies to improve their penetration into solid tumours. Our proof-of-concept data put expression and manufacturing at the forefront of our proof of concept, emphasising the biological action alongside the manufacturing considerations. 

The coenzyme biotin binds with very high affinity to streptavidin, and this is exploited in a variety of assay formats such as SPR and HTRF, commonly used in drug discovery screening. Recombinant proteins can be selectively and covalently biotinylated using bacterial biotin ligase (BirA), and whilst biotinylation of proteins can be carried out using exogenous BirA, co-expressing with BirA may lead to significant advantages. These include reduced processing times and more complete modification, accelerating workflows using labelled proteins. Here we discuss approaches for co-expression of BirA in three common protein expression platforms.

Alchemab's target-agnostic and patient-oriented drug discovery platform identifies novel disease-relevant antibody therapeutics and antigens by screening patients resilient to disease. Our approach allows us to build new therapies for challenging disease areas such as neurodegeneration. Rapid antibody production is critical for biotechs advancing novel therapies from research into clinical stages. This presentation explores strategies for optimising early high-quality antibody production and achieving cost-effective, rapid development of lead candidates.

The rapid advancements of automation and digitalisation have the potential to transform every step in the complex process of biopharmaceutical research and development. This presentation highlights the recent innovations within Roche's pharma research and early development unit (pRED), focusing on a fully E2E automated MS analytics workflow, which is an integral component of a broader, modular, and interconnected automation network that spans the entire biopharmaceutical R&ED value chain.

Optimising microbial production strains remains challenging due to scale differences between screening and industrial processes. Miniaturised, high-throughput systems enable cost-effective testing of strain-condition combinations but require improved mimicry of production conditions. We developed a unified scale-down model to evaluate the cultivation parameter to yield dependencies. Central to this is a workflow management system ensuring reproducible, traceable data flows across scales and facilitating model-based analysis of microbial physiology and process conditions.

In the evolving field of antibody-drug discovery, accelerating the identification of therapeutic molecules while ensuring precision is crucial. This presentation will explore our innovative workflow, highlighting improvements in speed, data quality, and scalability that enhance molecule discovery and pipeline success. We will discuss the transition from traditional high-throughput screening to in silico-assisted processes and the integration of next-generation sequencing and machine learning to expand antibody diversity and reduce wet-lab characterisation. Furthermore, we will demonstrate how Bayer's “virtual Biotech” model, has enabled a faster and more cost-effective early-stage process.