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Proteins are fundamental to life and to many drugs, vaccines and new types of applied medicine with engineered cells. For this work, it is often essential to tag proteins to enable their identification and purification. The V5 tag, which was developed in St Andrews, is used very widely in this role and has some key advantages over alternatives.
Key impacts are:
This case study describes the impact of the discovery by Tuite and Freedman that elevating the levels of the enzyme protein disulphide isomerase (PDI) significantly increases the efficiency with which eukaryotic cells secrete disulphide-bonded proteins. This discovery led to the development of a patented, generic technology for improving both the yield and authenticity of high value, recombinant protein-based biopharmaceuticals. The patent has been used in the safe, animal free production of several FDA and EMEA approved biopharmaceuticals (e.g. recombinant human albumin; Recombumin®), generating multi-million dollar revenues. It has been sub-licensed to four major pharmaceutical companies (Novozymes, Pfizer, Glaxo, Repligen) to aid the safe production of biopharmaceuticals for a range of major human diseases (e.g. Type 2 diabetes).
Professor Neil Barclay and Dr Nick Hutchings established Everest Biotech Ltd in 2000 in response to the increasing demand for high quality antibodies within the research community. This successful spin-out company has since become a major power in antibody research and production, a position reflected by its portfolio of more than 6,000 antibodies recognising human, mouse and rat proteins, and the generation of 60 new antibodies each month. With offices in the UK and Nepal, Everest Biotech Ltd also benefits one of the poorest communities in the world by providing additional income to hundreds of farmers in the Nepalese foothills.
Impact: EaStCHEM spin out Albachem (1994), subsequently incorporated into the Almac group, enabling the latter company to become a world leader in the provision of chemically synthesised proteins.
Significance: Chemical synthesis is competitive with recombinant methods for commercial production of the therapeutic polypeptides that represent ~50% of drugs in big pharma pipelines and have a market value in 2008 of over $13B. The value attributable to Ramage's methods for polypeptide syntheses over the REF period is estimated at approximately £6M.
Beneficiaries: Drug manufacturers, contract research organisations, patients, clinicians.
Research: Studies (1993-6) led by Ramage (at the University of Edinburgh) on new methods for high-yield total syntheses and purification of long polypeptides.
Reach: Almac's protein-manufacturing team remains in the UK with 24 staff members. The Almac Group, headquartered in N. Ireland, has 3300 employees globally (1300 outside UK) and sells to 600 companies worldwide.
Protein modification represents a highly significant and growing source of new products for the biopharmaceuticals market. This case study outlines the development of PolyTherics, a highly successful spin-out company from the UCL School of Pharmacy, and the impact that their enabling technology has had on the pharmaceutical and biotechnology industries. The company was developed as a direct result of new conjugate technology developed by Professor Steve Brocchini and coworkers at the School. The company moved to independent premises in 2006 and now manages a portfolio of over 100 granted and pending patents. Several licensing agreements are in place, including with Celtic Pharma Holdings for haemophilia treatments and Nuron for a multiple sclerosis treatment based on PEGylation conjugation technology. Revenue is expected to be £8m in 2013. The impact of Polytherics is therefore as a significant and effective technology provider to the pharmaceutical and biotechnology industries.
Oxford Expression Technologies (OET) is a spin out company launched jointly by Oxford Brookes University (Brookes) and the Natural Environment Research Council (NERC) to exploit Intellectual Property (IP) in the field of protein expression using novel insect virus vectors. OET generates revenue through sale of kits, services & licences to a range of global customers including academia, research institutes, pharmaceutical and biotechnology companies. OET provides employment, invests in in-house Research and Development including funding collaborative PhD students, and generates royalty income streams for Brookes and NERC. Customers are able to produce multiple recombinant proteins to higher yields and quality than was otherwise possible and a number of companies are using the developments for the commercial production of vaccines and other uses.
Research at the University of Oxford's Glycobiology Institute (OGBI) has led to the development of `state-of-the-art' platform technologies for the analysis of oligosaccharides (sugars) that are linked to proteins and lipids. These enabling technologies have had major impacts worldwide on drug discovery programmes, have enabled robust procedures to be developed for the quality control of biopharmaceutical production, and have been widely adopted by the pharmaceutical industry.
Bacillus species constitute an industrially-important group of bacteria that are used worldwide to produce carbohydrate and protein-digesting enzymes on a large scale. While the bacteria secrete native enzymes at an economically viable rate, generating strains of bacteria that could do the same for non-native enzymes has been an industry challenge. Researchers at Newcastle University have collaborated with industry since the early 1990s to study the mechanism of protein secretion in Bacillus. They discovered bottlenecks in the protein secretion pathway and used that knowledge to engineer more productive strains of bacteria. Since 2008, companies, including Novozymes (the world's largest manufacturer of industrial enzymes), have developed strains of bacteria, based on the Newcastle findings, for use in their manufacturing processes improving yields by more than four orders of magnitude in some cases.
Stem cells play an important role in drug discovery and development of therapeutic interventions. Differentiation (and maintenance) of stem cells into specialised cells is achieved by controlled application of specific, expensive growth factors.
Dr Hyvönen has developed an efficient method for producing highly purified, bioactive human growth factors from E.coli, reducing costs by up to 10-FOLD. tHE TECHNOLOGY HAS BEEN LICENSED TO A major international manufacturer of growth factors (PeproTech Inc.), and to a UK-based specialist stem cell company (CellGS Ltd), enabling them to implement new products and business strategies. Through a departmental facility, material is also being sold to external companies and Cambridge Stem Cell Consortium members. In addition, Dr Hyvönen has made his expertise available to biotech companies through consultancy.
Combinatorial Domain Hunting (CDH) technology is a technique for producing fragments of proteins that are soluble and tractable for biophysical analysis. It was developed between 1999 and 2008 at Birkbeck College, in the laboratory of Dr Renos Savva. This technology was patented in 2001 and the biotech company Domainex Ltd was then formed to commercialise it. In 2007, Domainex merged with a UCL spinout company, NCE Discovery Ltd. The company has attracted over £3m in investment and employs about 31 people. In addition to its contract research programme, it has developed an in-house drug discovery programme utilising CDH. Early in 2012 a patent was filed on a series of inhibitors of the protein kinases IKK03b5 and TBK1, which are validated drug targets for cancer and inflammation, and the first of these are expected to begin clinical trials in 2014.