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Using Glyco-Engineering to Produce Therapeutic Proteins Assigned Reading: Using glyco-engineering to produce therapeutic proteins. Dicker M and Strasser R Expert Opin. Biol. Ther. (2015) 15:1501. Advances in the production of human therapeutic proteins in yeasts and filamentous fungi Gerngross TU, Nat. Biotech, 22:1409 (2004) Glycan Engineering for Cell and Developmental Biology Griffin ME and Hsieh-Wilson LC Cell Chem Biol, 23:108 (2016) Expert Opinion on Biological Therapy ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20 Using glyco-engineering to produce therapeutic proteins Martina Dicker & Richard Strasser To cite this article: Martina Dicker & Richard Strasser (2015) Using glyco-engineering to produce therapeutic proteins, Expert Opinion on Biological Therapy, 15:10, 1501-1516, DOI: 10.1517/14712598.2015.1069271 To link to this article: http://dx.doi.org/10.1517/14712598.2015.1069271 Published online: 14 Jul 2015. Submit your article to this journal Article views: 345 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iebt20 Download by: [University of California, San Diego] Date: 17 May 2016, At: 09:13 Review Using glyco-engineering to produce therapeutic proteins † Martina Dicker & Richard Strasser 1. Introduction University of Natural Resources and Life Sciences, Department of Applied Genetics and Cell Biology, Vienna, Austria 2. N-glycosylation of proteins 3. What are the targets for Introduction: Glycans are increasingly important in the development of N-glycan-engineering? new biopharmaceuticals with optimized efficacy, half-life, and antigenicity. 4. O-glycosylation of proteins Current expression platforms for recombinant glycoprotein therapeutics typically do not produce homogeneous glycans and frequently display non- 5. What are the targets for human glycans which may cause unwanted side effects. To circumvent these O-glycan-engineering? issues, glyco-engineering has been applied to different expression systems 6. O-glycan engineering including mammalian cells, insect cells, yeast, and plants. 7. Glyco-engineered therapeutic Areas covered: This review summarizes recent developments in glyco- glycoproteins engineering focusing mainly on in vivo expression systems for recombinant 8. Conclusion proteins. The highlighted strategies aim at producing glycoproteins with 9. Expert opinion homogeneous N- and O-linked glycans of defined composition. Expert opinion: Glyco-engineering of expression platforms is increasingly rec- 10. So what are the challenges for the future? ognized as an important strategy to improve biopharmaceuticals. A better understanding and control of the factors leading to glycan heterogeneity will allow simplified production of recombinant glycoprotein therapeutics with less variation in terms of glycosylation. Further technological advances will have a major impact on manufacturing processes and may provide a completely new class of glycoprotein therapeutics with customized functions. Keywords: biopharmaceuticals, glycosyltransferases, N-glycosylation, O-glycosylation, recombinant glycoprotein Expert Opin. Biol. Ther. (2015) 15(10):1501-1516 1. Introduction Many protein drugs are glycosylated and the attached glycan structures often influ- ence the therapeutic properties. The number and composition of the glycans play an important role for protein folding, solubility, and intracellular trafficking. Glycans can shield the protein backbone to prevent immunogenic reactions and distinct cellular recognition events depend on the presence of specific glycan structures. Downloaded by [University of California, San Diego] at 09:13 17 May 2016 Thus, glycosylation has a huge impact on the biological activity of glycoproteins and should be carefully controlled during manufacturing to achieve optimized ther- apeutic efficacy. Dependent on the species, cell-type, and physiological status of the production host, the glycosylation pattern on recombinant glycoproteins can differ significantly. Glycans on proteins are structurally quite diverse and consist of a set of monosaccharides that are assembled by different linkages. The glycosylation pro- cesses in the ER and Golgi generate the majority of rather heterogeneous glycan structures found on recombinant glycoproteins. Due to the recognized importance in therapy, substantial efforts have been made in recent years to overcome glycan heterogeneity and establish in vivo and in vitro glyco-engineering technologies for efficient production of homogeneous therapeutic glycoproteins. Such recombinant proteins with custom-made glycosylation are essential to understand glycan- mediated functions of glycoprotein therapeutics and represent a new class of next- generation drugs with enhanced biological activity. 10.1517/14712598.2015.1069271 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 1501 All rights reserved: reproduction in whole or in part not permitted M. Dicker & R. Strasser 3. What are the targets for N-glycan- Article highlights. engineering? . Glyco-engineering offers great potential for the generation of glycoprotein therapeutics with reduced 3.1 Avoidance of macroheterogeneity side effects and enhanced activity. Analysis of recombinant glycoproteins from different Macroheterogeneity on recombinant glycoproteins arises from mammalian and non-mammalian-based expression variations in glycosylation site occupancy. These differences in systems reveals the presence of unwanted glycan glycosylation efficiency are dependent on the manufacturing modifications that mark targets for glyco-engineering. system (e.g., organism/cell-type-specific) and protein intrinsic . Recent developments in modulation of N-glycosylation and N-glycan processing demonstrate that recombinant features. The presence of the Asn-X-Ser/Thr sequon is neces- glycoproteins with defined homogeneous N-glycans can sary but not sufficient for N-glycosylation of mammalian be efficiently produced in mammalian and non- proteins. While all eukaryotic cells have an overall conserved mammalian expression systems including insect cells, machinery for N-glycosylation and display similar structural yeast, and plants. requirements for efficient N-glycosylation, there are minor dif- . Compared to N-glycosylation, strategies and methods to produce customized O-linked glycans are still in its ferences in utilization of glycosylation sites between species [2,3]. infancy. Nonetheless, future developments in this area Consequently, glycosylation sites may be skipped leading to hold great promise for another class of improved underglycosylation of recombinant proteins or additional glycoprotein biopharmaceuticals. sites may be used leading to aberrant glycosylation. Protein . The first glyco-engineered monoclonal antibodies have intrinsic factors like the surrounding amino-acid sequence already been approved in the US and in Japan. Further biochemical and molecular understanding of and secondary structure, the positioning of the consensus cellular process will be required to optimize current sequence within the polypeptide as well as the presence of other glyco-engineering approaches and develop strategies for protein modifications like disulfide bond formation so far elusive glycan modifications. contribute to N-glycosylation efficiency [4]. Recognition of these glycoprotein-specific features depends on the presence This box summarizes key points contained in the article. and function of the different OST subunits. Mammalian cells contain two OST complexes that differ in their catalytic sub- 2. N-glycosylation of proteins unit as well as in accessory proteins. These OST complexes display partially overlapping functions, but also preferences The most prominent and best characterized form of protein for certain glycoprotein substrates [3]. Engineering of the glycosylation is the linkage of a glycan to the amide in OST complex is one possible way to overcome differences the side chain of an asparagine (N-glycosylation) on newly related to N-glycosylation site occupancy. Yet, the individual synthetized proteins. N-glycosylation of proteins starts in roles of distinct OST catalytic subunits and their accessory pro- the lumen of the endoplasmic reticulum (ER) by transfer of teins are still not fully understood in eukaryotes making ratio- a conserved preassembled oligosaccharide precursor nal approaches difficult. Moreover, a recent study has indicated that overexpression of individual subunits is not sufficient to (Glc3Man9GlcNAc2)(Figure 1A) to the consensus sequence Asn-X-Ser/Thr (where X is any amino acid except proline) restore N-glycosylation in mutant cells presumably due to the inability to form functional heteromeric OST complexes [5]. exposed on nascent polypeptide chains. This initial glycan However, in protists like Leishmania major, OST is composed transfer reaction is catalyzed by the heteromeric oligosacchar- of a single subunit that can replace the whole Saccharomyces cer- yltransferase (OST) complex and is supposed to precede Downloaded by [University of California, San Diego] at 09:13 17 May 2016 evisiae OST complex and can be used to overcome underglyco- folding of the protein in the ER [1]. Immediately after the sylation of proteins. Overexpression of the single-subunit OST oligosaccharide transfer, the two terminal glucose residues from L. major in the methylotrophic yeast Pichia pastoris are cleaved off by a-glucosidase I and II and the resulting
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