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Engineering cells and proteins – creating pharmaceuticals

5 September 2014  •  Author(s): Marco Casteleijn & Dominique Richardson, University of Helsinki

Protein Expression

Pharmaceutical biotechnology is big business; it currently consists of 1/6 of the total volume of the pharmaceutical market and continues to grow steadily. Expression of therapeutic proteins is mainly done in living cells, although ‘cell free protein synthesis’ (CFPS) or ‘in-vitro transcription translation’ (IVTT) is beginning to emerge as an alternative for commercial production. In this article we will highlight some of the more recent advances in protein expression systems for the production of pharmaceutical proteins. We will also discuss current trends in the engineering of pharmaceutical proteins with improved properties.

Pharmaceutical protein production
While proteins of interest are still isolated from natural extracts, the advent of modern molecular biology techniques has made recombinant protein expression the mainstream methodology for pharmaceutical production. The main drivers for the use of recombinant proteins are: low availability of native protein (e.g. the annual use of amylase and xylose isomerase is over 95,000 tons each); livestock infections for the production of vaccines and subsequent economic loss; immune responses to animal proteins after injection (e.g. insulin); and reproducibility of protein production in relation to its quality. Since the implementation of recombinant DNA in the early-1970s, proteins have been expressed in many different organisms and (derived) cell types, such as bacteria, yeasts, moulds, insects, protozoa, mammals, plants, transgenic plants and animals and with the use of cell lysate in CFPS. During recombinant protein expression a gene is introduced in an organism (or its derivative) followed by constitutive- or induced-translation and transcription. Choosing the correct expression system is protein dependent and factors such as protein quality, functionality, production speed and yield are most important. As of 2014, overall trends in recombinant protein production show an increase in the use of Chinese hamster ovary (CHO) and yeast cells, while there has been a decrease in the use of other mammalian and Escherichia coli (E. coli) systems. Production of non-glycosylated proteins is conducted mainly in bacteria or yeast (45%, May 2014), while the production of glycosylated proteins is carried out predomi – nantly in CHO cells (29% compared to mammalian cells, insect cells and transgenic-animals and -plants at 26%. More than a decade ago about 20 pharmaceutical proteins were produced by transgenic technology for clinical trials14, however the high developmental costs for these production systems clearly hindered the advancement of this method. Other emerging systems in the market include the use of P. pastoris and H. polymorpha – both of which are discussed hereafter…

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