Microbial factories for recombinant pharmaceuticals

Abstract

Most of the hosts used to produce the 151 recombinant pharmaceuticals so far approved for human use by the Food and Drug Administration (FDA) and/or by the European Medicines Agency (EMEA) are microbial cells, either bacteria or yeast. This fact indicates that despite the diverse bottlenecks and obstacles that microbial systems pose to the efficient production of functional mammalian proteins, namely lack or unconventional post-translational modifications, proteolytic instability, poor solubility and activation of cell stress responses, among others, they represent convenient and powerful tools for recombinant protein production. The entering into the market of a progressively increasing number of protein drugs produced in non-microbial systems has not impaired the development of products obtained in microbial cells, proving the robustness of the microbial set of cellular systems (so far Escherichia coli and Saccharomyces cerevisae) developed for protein drug production. We summarize here the nature, properties and applications of all those pharmaceuticals and the relevant features of the current and potential producing hosts, in a comparative way.

Figure 1

Number (and percentage values siding the bars) of recombinant proteins approved as biopharmaceuticals in different production systems. Data has been adapted from Table 1 in [3]. Exubera, an inhalated recombinant human insulin produced in E. coli has been omitted since Pfizer stopped its marketing in January 2008. Two recently FDA approved products Xyntha and Recothrom produced both in CHO cells have also been added.

Figure 2

Number of recombinant biopharmaceuticals in different production systems, grouped by WHO therapeutic indications (see the legend of Additional file for nomenclature). Products from E. coli and S. cerevisae are also presented together under the category of microbial cells.

Figure 3

Accumulated number of recombinant biopharmaceuticals obtained in different production systems, in front of year of their first time approval (either in US or EU). Products from E. coli and S. cerevisae are presented together under the category of microbial cells.