Antibody production with yeasts and filamentous fungi: on the road to large scale?

Gasser, Brigitte; Mattanovich, Diethard

doi:10.1007/s10529-006-9237-x

Cited by 70 publications

(31 citation statements)

References 58 publications

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“…yeasts and filamentous fungi are regarded as compelling alternatives to mammalian cell culture for the production of recombinant mAbs and antibody fragments. 9 The advantages of using yeast expression systems for therapeutic glycoprotein production include ease of genetic manipulation, stable expression, rapid cell growth and high yield of secreted protein, low-cost scalable fermentation processes and no risk of human pathogenic virus contamination. ALD518, a humanized IgG1 mAb that targets interleukin-6 (IL-6), is manufactured in wild type Pichia pastoris; this antibody has successfully completed Phase 2 studies.…”

Section: Introductionmentioning

confidence: 99%

Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study

Zhang¹,

Li²,

Dumitru³

et al. 2011

mAbs

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Section: Introductionmentioning

confidence: 99%

Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study

Zhang¹,

Li²,

Dumitru³

et al. 2011

mAbs

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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

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114

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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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“…Some reports have addressed the production of antibody by yeast, although in those studies, productivity was either low or not mentioned (15,20,25,30,44). For the production of antibodies in yeast, it will be necessary to increase productivity.…”

Section: Discussionmentioning

confidence: 99%

Efficient Antibody Production upon Suppression of O Mannosylation in the Yeast Ogataea minuta

Kuroda

Kobayashi

Kitagawa

et al. 2008

Appl Environ Microbiol

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When antibodies were expressed in the methylotrophic yeast Ogataea minuta, we found that abnormal O mannosylation occurred in the secreted antibody. Yeast-specific O mannosylation is initiated by the addition of mannose at serine (Ser) or threonine (Thr) residues in the endoplasmic reticulum via protein O mannosyltransferase (Pmt) activity. To suppress the addition of O-linked sugar chains on antibodies, we examined the possibility of inhibiting Pmt activity by the addition of a Pmt inhibitor during cultivation. The Pmt inhibitor was found to partially suppress the O mannosylation on the antibodies. Surprisingly, the suppression of O mannosylation was associated with an increased amount of assembled antibody (H2L2) and enhanced the antigen-binding activity of the secreted antibody. In this study, we demonstrated the expression of human antibody in O. minuta and elucidated the relationship between O mannosylation and antibody production in yeast.Antibodies for pharmaceutical applications have recently received a great deal of attention due to their specific antigenbinding activities, antibody-dependent cellular cytotoxicity, and other useful characteristics. Indeed, sales of antibodies for pharmaceuticals have grown rapidly over the past decade and are expected to exceed 30 billion U.S. dollars by 2010 (1). A large volume of antibodies is required for pharmaceuticals, as antibodies are primarily marketed for chronic conditions. Antibodies possess relatively low potency, which results in the need for accumulating doses over time (10). Although therapeutic antibodies have great potential value, they have also been viewed with some skepticism. Antibodies are expensive to produce, in part because they are commonly manufactured by using batch/fed-batch cultures of mammalian cells. The increasing demand to reduce the cost of antibody production has promoted research into the development of an antibody expression system that is more practical than expression with mammalian cells.Development of transgenic plants and animals as alternative hosts is therefore a promising field of study. Monoclonal antibodies have, thus far, been successfully produced from a number of sources, including plants, the milk of transgenic goats, the eggs of transgenic chickens, etc. (4, 12, 32). Moreover, antibodies derived from certain newly developed transgenic systems share physical characteristics that are similar to those of antibodies from mammalian cells such as Chinese hamster ovary (CHO) cells while exhibiting higher antibody-dependent cellular cytotoxicity activity due to the absence of fucose residues in N-linked sugar chains (6, 45). These alternative transgenic expression systems could reduce the cost of large-scale antibody production. However, the prolonged construction of transgenics remains a major disadvantage in terms of market demands.The production of antibodies and antibody fragments has been studied by using various microorganism expression systems, including Escherichia coli, fungus, and yeast (7,13,37,41). Since microorg...

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Antibody production with yeasts and filamentous fungi: on the road to large scale?

Cited by 70 publications

References 58 publications

Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study

Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study

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

Efficient Antibody Production upon Suppression of O Mannosylation in the Yeast Ogataea minuta

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