Biomedical applications of yeast- a patent view, part one: yeasts as workhorses for the production of therapeutics and vaccines

ABSTRACT

Introduction: Yeasts, as Eukaryotes, offer unique features for ease of growth and genetic manipulation possibilities, making it an exceptional microbial host.

Areas covered: This review provides general and patent-oriented insights into production of biopharmaceuticals by yeasts. Patents, wherever possible, were correlated to the original or review articles. The review describes applications of major GRAS (generally regarded as safe) yeasts for the production of therapeutic proteins and subunit vaccines; additionally, immunomodulatory properties of yeast cell wall components were reviewed for use of whole yeast cells as a new vaccine platform. The second part of the review will discuss yeast- humanization strategies and innovative applications.

Expert opinion: Biomedical applications of yeasts were initiated by utilization of Saccharomyces cerevisiae, for production of leavened (fermented) products, and advanced to serve to produce biopharmaceuticals. Higher biomass production and expression/secretion yields, more similarity of glycosylation patterns to mammals and possibility of host-improvement strategies through application of synthetic biology might enhance selection of Pichia pastoris (instead of S. cerevisiae) as a host for production of biopharmaceutical in future. Immunomodulatory properties of yeast cell wall β-glucans and possibility of intracellular expression of heterologous pathogen/tumor antigens in yeast cells have expanded their application as a new platform, ‘Whole Yeast Vaccines’.

KEYWORDS:

• Saccharomyces cerevisiae
• Pichia pastoris
• Methylotrophic yeast
• heterologous expression
• whole yeast vaccine

Article highlights

• Yeasts have been the most beneficial organisms to mankind. Application of yeasts was associated to the human civilization by production of leavened (fermented) products 6-8 × 10³ years BC. S. cerevisiae, the most studied and utilized yeast, have been termed the Escherichia coli (E. coli) of the eukaryotic world.

• S. cerevisiae is a source of breakthrough discoveries in life sciences (the glycolytic pathway, genetic maps, and cell architecture), the first eukaryote whose complete genome was deciphered, and the host for the production of the first approved recombinant therapeutic protein (insulin) and subunit vaccine (HBV) for human use.

• Yeasts are considered as ‘exceptional microbial workhorses for the production of biopharmaceuticals’ due to a number of unique features, including safety (GRAS), ease of growth, a short generation time (approximately 80 minutes), the possibility of haploid maintenance, genetic manipulation possibilities similar to prokaryotes (while representing the advanced cellular features of eukaryotes), and eukaryotic type post-translational modifications (PTMs).

• Approximately 20% of biopharmaceutics are currently produced using yeast cells, mainly S. cerevisiae. However, some advantageous characteristics of other yeasts such as higher biomass production and expression/secretion yields, more similarity of glycosylation patterns to mammals and the availability of improved hosts (through application of synthetic biology) might conduct the biotech industries to prefer P. pastoris and other GRAS yeasts (rather than S. cerevisiae) for the production of biopharmaceuticals.

• The capability of VLP (virus-like particle) production (for expressed antigens) has made yeast a powerful workhorse for the production of various pathogenic antigens to formulate a variety of subunit vaccines (such as HBV and HPV).

• Attempts to humanize glycosylation patterns of yeasts might further expand their application for the production of human glycoproteins that are mostly produced using mammalian cells. Humanization of yeasts for glycosylation patterns might circumvent the limitation of their applications for only intracellular expression of biopharmaceuticals or to secrete only those proteins in which glycosylation might not be a determining functional factor.

• Immunomodulatory properties of yeasts’ cell wall β-glucans as well as the possibility of intracellular expression of heterologous pathogen/tumor antigens in yeast cells have expanded their applications as a new vaccine platform (modality), ‘Whole Yeast Vaccines (WYVs)’. The application of WYVs, especially for oral immunization strategies, is further evolving by employment of the yeast display (arming) technology for surface presentation of antigens.

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Acknowledgments

Authors apologize to all colleagues who their valuable works have not been quoted in this manuscript due to reference number limitations.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported in part by grant number 849 entitled, ‘Construction of whole yeast vaccine encoding HPV-E7 antigen’ from Pasteur Institute of Iran.