The Centre for Medicines Discovery (CMD), established in August 2020, comprises a number of disease focused groups and small research facilities (SRF). The Biotech facility, provides protein production services for academic and industrial customers. In this talk, our well established expression platforms for production and validation of intracellular, secreted and membrane proteins will be presented, with a highlight on production of SARS-CoV-2 proteins for serological assay development.

Buffer exchange sucks up precious hands-on time and limits the exploration of formulation conditions. This talk will cover how to accelerate a screen of 15 antibody/ formulation combinations using Big Tuna for automated buffer exchange and Uncle for in-depth stability and aggregation analysis  – all with just 1 hour of hands-on time.

We recently established a novel, end-to-end automated process for the fast generation and characterization of very large panels of multi-specific biotherapeutics (up to 10,000). Here, we report on how we apply this unique engineering platform for the identification and optimization of next-generation, multi-specific biotherapeutics addressing novel mechanisms of action.

WD-40 repeat protein-5 (WDR5) interacts specifically with a conserved arginine-containing motif, simply called the Win motif, in all six members of the SET1 family of histone 3 lysine 4 (H3K4) methyltransferases, MLL1-4 and SETd1/AB. We have developed a battery of analytical approaches, both in low- and high-throughput settings, for a comprehensive analysis of WDR5-Win motif interactions present in all six SET1 members of H3K4 methyltransferases.

The nature of Therapeutic Biologics is continuously evolving. Current trends towards empowered biologics and novel formats result in unique challenges for both Upstream and Downstream processes. Here we will discuss the approach we have taken to develop platform processes that can address the large diversity of molecules we encounter in the Discovery setting in the shortened time-lines needed to facilitate the Discovery process. We will explore the implications of empowered biologics and novel formats for Discovery Biologics support, focusing primarily on Downstream processes. We will discuss the importance of enhanced analytics with the goal of ensuring the best molecule is moving forward.

With the ever increasing demand for antibody and protein-based therapeutics, a flexible purification platform that can handle low to high sample volumes and expression levels is critical for screening. Protein purification using traditional chromatography is limited by throughput and requires time-consuming, labour-intensive sample preparation (centrifugation and filtration) processes to avoid column clogging and to achieve volumes that are amenable to this platform. Magnetic beads-based purification permits the incubation of the beads directly into cell culture (for secreted proteins) or crude lysates regardless of sample volume. This provides a simplified approach to direct target capture while eliminating much of the sample preparation steps and potentially improving the quality of the purified product. The tools and their application to simplify and significantly augment protein purification and screening cost-effectively will be described.

As biologic therapeutics continue to increase in complexity, innovative approaches to candidate screening, characterization and development are more important than ever. Our approaches to high throughput protein production incorporate advanced analytics, automation and high-quality informatics to enable robust molecule screening, selection and scale up. These enhancements improve the speed, quality and productivity of our biologics development pipeline.

There is still much cooperativity associated with domain interactions in the design of multispecific biologics agents. Empirical assessments of structure and function are critical for hit to lead selection. A review of approaches to efficiently assess different architectures will be presented.

The identification of protein-peptide networks offers attractive opportunities for drug development. We proposed the “Hold-up” assay, which has a wide potential for the identification and quantification of protein-protein and protein-peptide interactions at a pace of 1,000 interactions/day. During this session, we will present the last evolution of this assay, and how we used it to determine the affinities and specificities of various peptide drug candidates for PDZ domains.

Marginal stability and low molecular activity are the cardinal impediments to applying proteins in research and technology. We have developed a hybrid approach that combines structure-bioinformatics analyses with Rosetta atomistic design to improve protein stability, expressibility, binding affinity, catalytic rate and selectivity. Applied to very diverse biologics, this strategy has led to orders of magnitude improvement in these properties through one-shot calculations and experimental analysis, in many cases eliminating the need for painstaking and risky in vitro evolution processes. Many of our methods are enabled in web-accessible servers, providing practically useful protein design algorithms to protein scientists.

Biosensors transduce a binding event into a measurable output. I will describe a versatile biosensor platform technology based on plant hormone receptors that can be used in vitro and in vivo in application areas as diverse as screening for novel synthetic cannabinoids to developing plant sentinels that can perceive chemical warfare agents that then change plant phenotypes in a way that can be observed by drone or satellite.