Novel tools and technologies enable the production of complex biologics
Over the past few years, research and development in the healthcare sector has been hampered by the difficulty in providing the increasingly complex biological specimens identified in assayable or druggable form. However, the toolkits developed by COMPLEXINC (New Technologies and Production Tools for Complex Protein Biologics) overcome this problem: they provide high-throughput assembly of complex biologics and metabolic pathways in eukaryotic expression systems, enabling micro- to large-scale production of high-quality protein specimens for drug discovery and bio-therapeutics. ‘Shortly after being developed, these toolkits proved their worth in unlocking protein assemblies which were hitherto inaccessible, including high-value complex targets such as influenza polymerase. The COMPLEXINC platforms have been disseminated and put to use in many laboratories worldwide, and resulted in scores of high-impact publications. Moreover, they have provided the SME partners in the consortium with numerous next-generation biologics, and a competitive edge,’ says Prof. Dr Imre Berger, Senior Investigator at Wellcome Trust and Coordinator of the project. The toolkits include innovative next-generation HT DNA assembly pipelines for automated multigene expression construct generation, a superior synthetic viral genome, genetically engineered animal and yeast cell lines with unique capabilities with respect to protein maturation and modification, as well as novel methods for bioprocessing and integrated quality control. These are expected to help meet current and future demands in academic and industrial R&D, and ultimately drug discovery and new treatments for human diseases. One of the early results, obtained through COMPLEXINC’s MultiBac technology — an advanced ‘Baculovirus expression vector system’ (BEVS) particularly tailored for protein complex production — includes the discovery of the architecture of influenza C polymerase, which was recently unveiled in Nature. Recombinant influenza C polymerase was crystallised and one of the project teams at the University of Oxford determined its structure by X-ray diffraction methods. The crystal structure reveals a new conformation adopted by influenza polymerase in the apo state, complementing earlier crystal structure analyses of influenza A and B polymerases that were determined in the presence of viral RNA substrates. Geneva Biotech: setting the benchmark ‘The next-generation tools developed in COMPLEXINC are already being validated commercially, not only by the partner SMEs but also in a number of pharma companies including globally operating TOP 10 enterprises. Applications include but are not limited to HCS, SBDD, multigene delivery, vaccinology, immune therapy, alternative scaffolds, and monoclonal antibodies,’ points out Dr Berger. A spinoff high-tech SME has been set up to commercialise COMPLEXINC technologies, something that Dr Berger considers to be the most important success of the project. ‘Geneva Biotech was a COMPLEXINC spinoff with an exclusive license for the project’s intellectual property held by EMBL. Geneva Biotech sells toolkits, reagents and licenses for the production technologies created in COMPLEXINC. Moreover, it has an in-house drug discovery programme based on the project’s technology platforms in the area of Type 2 diabetes.’ The newly founded SME has already signed licenses with numerous biotech and pharma enterprises, including global TOP 10 players. This is to be added to the collaboration agreements signed by academic partners in COMPLEXINC with several of the leading pharma giants in Europe, which include co-developments in addition to contract research. Geneva Biotech has signed licenses with numerous biotech and pharma enterprises, including global TOP 10 players. Collaboration agreements have been signed by academic partners in COMPLEXINC with several of the leading pharma giants in Europe. These agreements include co-developments in addition to contract research. ‘The founding of two further start-ups, each exploiting unique COMPLEXINC outcomes, is currently being evaluated,’ Dr Berger reveals. COMPLEXINC is set to have a dramatic impact on the availability of challenging proteins and protein complexes including those of human origin, with tailor-made properties specifically geared towards commercially available applications.
Keywords
Protein production tools, complex biologics, metabolic pathways
