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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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While their ability to carry out post-translational modifications renders their use desirable/ essential for producing many biopharmaceuticals, animal cell-based systems do suffer from a number of disadvantages. When compared to E. coli, animal cells display very complex nutritional requirements, grow more slowly and are far more susceptible to physical damage. In industrial terms, this translates into increased production costs.
In addition to recombinant biopharmaceuticals, animal cell culture is used to produce various other biologically-based pharmaceuticals. Chief amongst these are a variety of vaccines and hybridoma cell-produced monoclonal antibodies (Chapter 10). Earlier interferon preparations were also produced in culture by a particular lymphoblastoid cell line (the Namalwa cell line), which was found to naturally synthesize high levels of several interferon-as (Chapter 4).
Additional production systems: yeasts
Attention has also focused upon a variety of additional production systems for recombinant biopharmaceuticals. Yeast cells (particularly Saccharomyces cerevisiae) display a number of characteristics that make them attractive in this regard. These characteristics include:
• their molecular biology has been studied in detail, facilitating their genetic manipulation;
• most are GRAS-listed organisms (‘generally regarded as safe’), and have a long history of industrial application (e.g. in brewing and baking);
• they grow relatively quickly in relatively inexpensive media, and their tough outer cell wall protects them from physical damage;
• suitable industrial scale fermentation equipment/technology is already available;
• they possess the ability to carry out post-translational modifications of proteins.
The practical potential of yeast-based production systems has been confirmed by the successful expression of a whole range of proteins of therapeutic interest in such systems. However, a number of disadvantages relating to heterologous protein production in yeast have been recognized. These include:
• although capable of glycosylating heterologous human proteins, the glycosylation pattern usually varies somewhat from the pattern observed in the native glycoprotein (when isolated from its natural source, or when expressed in recombinant animal cell culture systems);
• in most instances, expression levels of heterologous proteins remain less than 5% of total cellular protein. This is significantly lower than expression levels typically achieved in recombinant E. coli systems.
Despite such potential disadvantages, several recombinant biopharmaceuticals now approved for general medical use are produced in yeast (S. cerevisiae)-based systems (Table 3.12). Interestingly, most such products are not glycosylated. The oligosaccharide component of glycoproteins produced in yeasts generally contain high levels of mannose. Such high mannose-type glycosylation patterns generally trigger their rapid clearance from the blood stream. Such products, therefore, would be expected to display a short half-life when parenterally administered to man.
Fungal production systems
Fungi have elicited interest as heterologous protein producers, as many have a long history of use in the production of various industrial enzymes, such as a-amylase and glucoamylase. Suitable fermentation technology therefore already exists. In general, fungi are capable of high-level expression of various proteins, many of which they secrete into their extracellular media. The extracellular production of a biopharmaceutical would be distinctly advantageous in terms of subsequent downstream processing. Fungi also possess the ability to carry out
Table 3.12. Recombinant therapeutic proteins approved for general medical use that are produced in Saccharomycese cerevisiae. All are subsequently discussed in the chapter indicated
Trade name Description Use Refer to
Novolog Engineered short-acting insulin Diabetes mellitus 8
Leukine Colony stimulating factor (GM-CSF) Bone marrow 6
Recombivax, Comvax, Engerix B, All vaccine preparations containing Vaccination 10
Tritanrix-HB, Infanrix, Twinrix, rHBsAg as one component
Primavax, Hexavax
Revasc, Refludan Hirudin Anticoagulant 9
Fasturtec Urate oxidase Hyperuricaemia 9
Regranex Platelet-derived growth factor Diabetic ulcers 7
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