Biotech firm creates improved delivery method for protein-based
therapies
Researchers at Thayer School of
Engineering, Dartmouth Medical
School, and the biotechnology firm GlycoFi Inc. report a significant advance in
the production of therapeutic proteins. In the September 8 issue of Science, the Dartmouth/GlycoFi
team announced the complete humanization of the glycosylation pathway in the
yeast Pichia pastoris.
Tillman Gerngross, chief scientific officer of GlycoFi and associate professor
of engineering. (Photo by Joseph Mehling '69)
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"We've successfully completed one of the most complex cellular
engineering endeavors undertaken to date," says
Tillman Gerngross, chief scientific officer of GlycoFi and associate
professor of engineering.
Protein-based therapies represent more than half of all the drugs currently
in development, and they have to be manufactured by living cells, which are
genetically engineered to produce a given protein of interest. However, most of
these proteins require the attachment of sugar structures, a process known as
glycosylation, to attain full biological function. To date, this has required
the expression of such proteins in mammalian cells that have the ability to
attach human-like sugar structures.
This new finding replicates all the steps of human glycosylation within a
yeast cell, eliminating the need for mammalian cells. Plus, report the
researchers, the technology offers numerous advantages over the conventional
use of mammalian cell cultures, namely reduced risk of contamination by
pathogens and infectious agents along with improved drug performance and
manufacturing efficiency.
"Humanizing glycosylation in yeast was a tour de force of genetic
engineering, requiring the knockout of four yeast genes and the introduction of
over 14 heterologous genes," says Stephen Hamilton, the lead author on the
study and a senior scientist at GlycoFi.
The study details the genetic engineering of the yeast Pichia
pastoris to secrete human glycoproteins with fully complex, terminally
sialyated N-glycans. The researchers demonstrated the effectiveness of this
approach when the glycoengineered yeast strain was used to produce functional
erythropoietin, a protein widely used in the treatment of anemia, and
considered to be the most successful biotech drug to date.
Gerngross notes that the GlycoFi/Dartmouth research team previously
demonstrated the importance of glycosylation structures on other commercially
relevant therapeutic proteins such as antibodies (published in Nature Biotechnology
earlier this year). As with most glycoproteins, the researchers were able to
show that by controlling glycosylation they could significantly improve
antibodies' ability to kill cancer cells.
"By engineering yeast to perform the final and most complex step of
human glycosylation, we will be able to conduct far more extensive
structure-function investigations on a much wider range of therapeutic protein
targets," Gerngross says.
By SUSAN KNAPP
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