WEHI Special Centre for Biologic Therapies Seminar hosted by Dr Jonathan Siah

Associate Professor Daniel Scott
Co-head of the Drug Discovery Innovation group at The Florey, A/Prof in Biochemistry & Pharmacology at the Dept of Biochemistry and Pharmacology, The University of Melbourne, and is co-founder and CEO of Alkira Bio

A LASEREDD® focus on next-generation GPCR-targeting antibody therapeutics

Davis Auditorium | Bundoora large boardroom

Join via TEAMS

Including Q&A session

G protein-coupled receptors (GPCRs) are the largest class of drug targets, yet identifying and developing selective GPCR-targeting drugs is challenging. Peptides and antibodies are emerging as superior modalities to achieve selective GPCR modulation compared to small molecules. Class A GPCRs comprise the largest number of drug targets, but present several challenges for novel biologics discovery, including: low expression levels; protein instability; limited extracellular accessible epitopes and the need to present the entire receptor as an intact antigen (i.e. not just a soluble ectodomain). Existing methods to stabilise GPCR antigens are not generically applicable to improving GPCR expression, and often result in non-functional mutant GPCRs, leading to ineffective biologics discovery. We have developed a novel and superior method called Lentiviral-Assisted Selection Enabling Receptor Engineering and Drug Discovery (LASEREDD®). LASEREDD® accelerates the preparation of GPCR samples for biologics discovery by rapidly engineering high-expressing GPCR variants from diverse, minimally mutated gene libraries. The LASEREDD® approach uses directed evolution in human cells and detailed structural and pharmacological evaluation to ensure our engineered GPCRs maintain their natural structure and function. LASEREDD®-engineered GPCR variants allow the preparation of: cell lines; virus-like particles; liposomes; and homogeneously purified protein samples with high GPCR protein content/activity, enabling biophysical and structural studies of challenging GPCRs and facilitating biologics discovery. The application of LASEREDD® to several challenging GPCR targets will be presented, along with the use of LASEREDD®-optimised GPCRs for alpaca VHH antibody (nanobody) discovery campaigns. Overall, the LASEREDD® approach promises to overcome the significant barriers that have hindered biologics discovery and optimisation at GPCR targets, paving the way for more efficient & effective discovery of GPCR biologics.

Associate Professor Daniel Scott is co-head of the Drug Discovery Innovation group at The Florey, A/Prof in Biochemistry & Pharmacology at the Dept of Biochemistry and Pharmacology, The University of Melbourne, and is co-founder and CEO of Alkira Bio. G protein-coupled receptors (GPCRs) serve as the principal method through which human cells detect and react to their surroundings. Consequently, the GPCR gene family stands as the largest within the human genome and constitutes the focus of over 30% of FDA-approved drugs. Despite their pivotal role, studying GPCRs and discerning their precise functions in physiology and pathology presents significant challenges. Consequently, many GPCRs remain inadequately characterized and lack targeted therapeutic interventions. Daniel has over 20 years’ experience researching all aspects of GPCR molecular function, with a focus on developing new methods to further GPCR research and drug discovery. Daniel completed his PhD at The University of Melbourne in 2007. In 2008 he was awarded an NHMRC CJ Martin Fellowship, allowing him to work as a postdoctoral researcher in the laboratory of Prof. Andreas Plückthun in Zurich, Switzerland. While in Zurich he invented a novel method, called CHESS, which enabled the rapid engineering of stabilized GPCRs through directed evolution for structural biology and drug discovery. The CHESS technology was spun out into a company, called G7 therapeutics, co-founded by Daniel in 2013. In 2016 G7 was acquired by Sosei Heptares, who continue to use CHESS for drug discovery. Daniel took up a group leader position at The Florey in 2011, with the lab being continuously funded by the NHMRC and others funding bodies since 2014, allowing the team to mature into the current Drug Discovery Innovation group, co-led by Dr Christopher Draper-Joyce. The Drug Discovery Innovation group uses protein engineering, protein design, directed evolution, NMR and Cryo-EM to facilitate study of molecular aspects of GPCR function and for drug discovery. Daniel has published over 70 research articles and is an inventor on six patents. Daniel is passionate about research commercialization having collaborated with many commercial entities throughout his career and co-founded three biotech startups to date.

All Welcome!