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GlycoFi and Dartmouth report full humanization of yeast glycosylation pathway in Science

For the first time, scientists have engineered yeast cells capable of producing a broad repertoire of recombinant therapeutic proteins with fully human sugar structures (glycosylation). These sugar structures ensure a glycoprotein's biological activity and half-life and to date, have necessitated the expression of therapeutic glycoproteins in mammalian hosts. The accomplishment reported today has the potential to eliminate the need for mammalian cell culture, while improving control over glycosylation, and improving performance characteristics of many therapeutic proteins.

Scientists from GlycoFi, Inc., a wholly owned subsidiary of Merck & Co., Inc., and their collaborators at Dartmouth-Hitchcock Medical Center published their report detailing the genetic engineering of the yeast Pichia pastoris to secrete human glycoproteins with fully complex, terminally sialyated N-glycans today in the September 8, 2006 issue of the journal Science. To demonstrate the utility of the engineered yeast strains, recombinant erythropoietin (Epo), a protein that stimulates the production of red blood cells, was expressed, purified and its activity demonstrated in vivo.

"Re-engineering the yeast glycosylation system to fully replicate the full repertoire of human glycosylation reactions has been a challenging six year effort that many doubted could be accomplished," said Tillman Gerngross, Ph.D., chief scientific officer of GlycoFi and professor of Bioengineering at Dartmouth College.

"This achievement required both the elimination of yeast-specific glycosylation reactions and the introduction of 14 heterologous genes, making this one of the most complex cellular engineering endeavors reported to date", said Stephen Hamilton, Ph.D., the lead author of the study and a senior scientist at GlycoFi.

Yeast offers numerous advantages as a recombinant protein expression system when compared to mammalian cell culture. These include the capability of producing higher recombinant protein titers, shorter fermentation times, and the ability to grow in chemically defined media, without risk of viral contamination from animal-derived ingredients.

"Switching to this technology will also provide improvements in product uniformity and overall production economics," Dr. Gerngross said. He noted that the GlycoFi and Dartmouth research team had previously published work showing how a panel of glyco-engineered yeast cell lines, displaying a more limited repertoire of human glycosylation reactions, had allowed the scientists to study the relationship between specific glycosylation structures on antibodies and their killing activity on cancer cells. Using this technology, the team had identified glycosylation structures that significantly improved an antibodies ability to kill cancer cells compared to the same antibody manufactured using mammalian cell culture.

"By engineering yeast to perform the final and, most complex step of human glycosylation, we are now able to conduct far more extensive structure-function investigations on a much wider range of therapeutic protein targets," Dr. Gerngross commented.

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