GlycoFi makes major advance with producing humanized protein therapeutics in fungal systems.
First hybrid N-Glycan produced in yeast points the way to "overcoming bottleneck in biopharmaceutical pipeline."
GlycoFi, Inc. based in Lebanon, New Hampshire, USA has published what is seen as a major scientific milestone in efforts to produce complex human glycoproteins using high capacity fungal production systems.
The paper, published in the Proceedings of the National Academy of Sciences, by GlycoFi researchers reports on the "Use of combinatorial genetic libraries to humanize N-linked glycosylation in the yeast Pichia pastoris."
Most proteins possessing biological activity in man that have potential use as therapeutic proteins are complex molecules with sugar structures, called glycans, which give the proteins their full biological function and human identity.
Yeasts and other fungal protein expression systems could have advantages over mammalian cell culture currently used for biopharmaceutical production. Fungal expression offers shorter fermentation time, higher productivity, simple molecular biology and does not require animal-derived growth media. However, until now, yeasts or other fungi have been unable to replicate complex human glycosylation structures, and so, they could not be used for producing therapeutic glycoproteins.
With the first reported production of "hybrid" glycosylation structures in yeast, GlycoFi has taken an important step closer to dramatically improving the capacity and cost of producing therapeutic proteins. Dr Tillman Gerngross, GlycoFi’s Chief Scientific Officer reveals his team has already gone beyond the published work to demonstrate production of much more complex glycans: "We expect to manufacture fully complex human glycoproteins -- sialylated glycoproteins -- in one of our fungal production systems before the year’s end."
The GlycoFi scientifc team genetically re-engineered the secretory pathway of P. pastoris to perform a series of sequential glycosylation steps to mimic the early processing of N-glycans in humans. They were able to eliminate non-human glycosylation from the yeast by deleting the initiating alpha-1,6-mannosyltransferase gene. Then by inserting several combinatorial genetic libraries were into the yeast in such a way that the yeast synthesized new, human-like glycosylation structures, the relevant biochemical reactions in the proper sequence and location could take place within the yeast cells.
Stefan Wildt, Ph.D., GlycoFi’s Director of Strain Development explains how it’s possible to tackle the biopharmaceutical sector’s capacity shortfall by harnessing fungal protein expression: "The glycosylation structures we are seeing in our yeast are of a purity and uniformity unprecedented in biopharmaceutical manufacturing."
GlycoFi’s fungal production systems arrive at a critical time for the biopharmaceutical sector of the life science industry. As GlycoFi’s CEO, Charles Hutchinson, Ph.D., notes: "Production capacity has led to a bottleneck within the biopharmaceutical pipeline." "The result," he observes, "is that some approved therapeutic protein drugs cannot be produced in adequate amounts, and still others are not making it into commercialization due to the cost and inefficiencies of producing them in mammalian cell culture systems."
Hutchinson is hopeful that "the push to producing homogeneous, human-like glycoproteins in yeast will eliminate the production capacity bottleneck, and allow for the production of better and safer drugs."
Link to related article More on Pichia pastoris
Further information about GlycoFi
Keywords : Therapeutic protein production Biopharmaceutical Humanized proteins Yeast fungal platform Pichia pastoris Glycosylation Hybrid N-Glycan Major Advance in Life Science Proceedings of the National Academy of Sciences
