Production of monoclonal antibodies by glycoengineered Pichia pastoris

Potgieter, Thomas I.; Cukan, Michael; Drummond, James E.; Houston-Cummings, Nga Rewa; Jiang, Yi; Li, Fang; Lynaugh, Heather; Mallem, Muralidhar; McKelvey, Troy W.; Mitchell, Teresa; Nylen, Adam; Rittenhour, Alissa; Stadheim, Terrance A.; Zha, Dongxing; d’Anjou, Marc

doi:10.1016/j.jbiotec.2008.12.015

Cited by 147 publications

(127 citation statements)

References 54 publications

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“…With a large academic and industrial user base, human-type N-glycosylation already in place, gram-per liter monoclonal antibody production recently reported 8 and the genome now publicly available, the stage is set for Pichia pastoris to become an even more important expression system for biopharmaceutical proteins.…”

Section: Discussionmentioning

confidence: 99%

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Genome sequence of the recombinant protein production host Pichia pastoris

et al. 2009

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The methylotrophic yeast Pichia pastoris is widely used for the production of proteins and as a model organism for studying peroxisomal biogenesis and methanol assimilation. P. pastoris strains capable of human-type N-glycosylation are now available, which increases the utility of this organism for biopharmaceutical production. Despite its biotechnological importance, relatively few genetic tools or engineered strains have been generated for P. pastoris. To facilitate progress in these areas, we present the 9.43 Mbp genomic sequence of the GS115 strain of P. pastoris. We also provide manually curated annotation for its 5,313 protein-coding genes.The methylotrophic yeast Pichia pastoris is by far the most commonly used yeast species in the production of recombinant proteins 1 and is employed in laboratories around the world to produce proteins for basic research and medical applications. It is also an important model organism for the investigation of peroxisomal proliferation and methanol assimilation. The P. pastoris expression technology has been commercially available for many years. P. pastoris grows to high cell density, provides tightly controlled methanol-inducible transgene expression and efficiently secretes heterologous proteins in defined media. Several P. pastoris-produced biopharmaceuticals that are either not glycosylated (such as human serum albumin 2 ) or for which glycosylation is needed only for proper folding (such as several vaccines 3 ) are already on the market. An important recent breakthrough has been the development of P. pastoris strains with humantype N-glycosylation [4][5][6] . Humanized glycosylation will further increase the importance of P. pastoris for biopharmaceutical production; indeed, proteins produced with this system are moving into clinical development 7 . Moreover, monoclonal antibodies can be made at gramper-liter scale in the humanized glycosylation-homogenous strains 8 .For further strain engineering, a better understanding of all aspects of the yeast's protein production machinery is needed, and a number of studies relating to P. pastoris's secretory system and engineered promoters have been forthcoming 9,10 . To facilitate the investigation of P. pastoris and other methylotrophic yeasts, we present the 9.43 Mbp genomic sequence of the GS115 strain of P. pastoris.

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Section: Discussionmentioning

confidence: 99%

“…Humanized glycosylation will further increase the importance of P. pastoris for biopharmaceutical production; indeed, proteins produced with this system are moving into clinical development 7 . Moreover, monoclonal antibodies can be made at gramper-liter scale in the humanized glycosylation-homogenous strains 8 .…”

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confidence: 99%

Genome sequence of the recombinant protein production host Pichia pastoris

et al. 2009

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“…For example, the N-glycosylation pathway in P. pastoris has been engineered successfully to yield heterologous proteins with human-like N-glycan structures [15][16][17]. This makes P. pastoris invaluable for the production of heterologous proteins intended for pharmaceutical applications [18][19][20]. These characteristics make P. pastoris an ideal platform for the production of recombinant therapeutic proteins [19].…”

Section: Introductionmentioning

confidence: 99%

Genome‐scale metabolic model of methylotrophic yeast Pichia pastoris and its use for in silico analysis of heterologous protein production

Sohn

Graf

Kim

et al. 2010

Biotechnology Journal

115

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The methylotrophic yeast Pichia pastoris has gained much attention during the last decade as a platform for producing heterologous recombinant proteins of pharmaceutical importance, due to its ability to reproduce post-translational modification similar to higher eukaryotes. With the recent release of the full genome sequence for P. pastoris, in-depth study of its functions has become feasible. Here we present the first reconstruction of the genome-scale metabolic model of the eukaryote P. pastoris type strain DSMZ 70382, PpaMBEL1254, consisting of 1254 metabolic reactions and 1147 metabolites compartmentalized into eight different regions to represent organelles. Additionally, equations describing the production of two heterologous proteins, human serum albumin and human superoxide dismutase, were incorporated. The protein-producing model versions of PpaMBEL1254 were then analyzed to examine the impact on oxygen limitation on protein production.

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“…However, mAbs expressed in CHO have little or no sialylation at its Fc region due to the steric hindrance of the Fc structure (Nimmerjahn and Ravetch, 2010). On the other hand, glycoengineered Pichia provides the possibility of expressing antibody with different glycoforms in relatively more homogenous fashion (Potgieter et al, 2009). Since the engineering of the glycosylation pathway of Pichia was a sequential process, which makes it possible to generate a panel of hosts which express glycoprotein with different glycoforms.…”

Section: Selection Of Glycoengineered Pichia Expressing Mabsmentioning

confidence: 99%

Production of monoclonal antibodies by glycoengineered Pichia pastoris

Cited by 147 publications

References 54 publications

Genome sequence of the recombinant protein production host Pichia pastoris

Genome sequence of the recombinant protein production host Pichia pastoris

Genome‐scale metabolic model of methylotrophic yeast Pichia pastoris and its use for in silico analysis of heterologous protein production

Glycoengineered Yeast as an Alternative Monoclonal Antibody Discovery and Production Platform

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