Re-engineered Yeast Glycosylation System Might Replace Mammalian Cell Expression

September 7, 2006
Pharmaceutical Technology Editors

ePT--the Electronic Newsletter of Pharmaceutical Technology

Scientists from GlycoFi, Inc., a wholly owned subsidiary of Merck & Co, in collaboration with Dartmouth-Hitchcock Medical Center, have engineered yeast cells capable of producing a broad range of recombinant therapeutic proteins with fully human sugar structures (glycosylation).

Lebanon, NH (Sept. 7)-Scientists from GlycoFi, Inc. (www.glycofi.com), a wholly owned subsidiary of Merck & Co. (Whitehouse Station, NJ, www.merck.com), in collaboration with Dartmouth-Hitchcock Medical Center, have engineered yeast cells capable of producing a broad range of recombinant therapeutic proteins with fully human sugar structures (glycosylation). Until now, these sugar structures, which ensure a glycoprotein’s biological activity and half-life, required the expression of therapeutic glycoproteins from mammalian host cells.

As reported in the Sept. 8, 2006, issue of Science, the research team genetically engineered the Pichia pastoris yeast to secrete human glycoproteins with fully complex, terminally sialyated N-glycans. Recombinant erythropoietin, which stimulates the production of red blood cells, was successfully expressed using these yeast strains, purified, and its activity demonstrated in vivo.

According to GlycoFi, the work “has the potential to eliminate the need for mammalian cell culture, while improving control over glycosylation and improving performance characteristics of many therapeutic proteins.” The achievement follows a six-year study involving not only the elimination of yeast-specific glycosylation reactions but also the introduction of 14 heterologous genes.

Yeast produces higher recombinant protein titers in shorter fermentation times compared with mammalian-culture systems. Yeast systems also do not have the risk of viral contamination associated with animal-based media. Tillman Gerngross, PhD, chief scientific officer of GlycoFi and professor of Bioengineering at Dartmouth College, says the advantages of yeast-expression technology “provide improvements in product uniformity and overall production economics. 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.”