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Cited by 100Lysosomal Storage Disorders ResearchGlycosylation and Glycoproteins ResearchViral Infectious Diseases and Gene Expression in Insects

Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems

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Tekoah, Yoram, Tzaban, Salit, Kizhner, Tali, Hainrichson, Mariana, Gantman, Anna, Golembo, Myriam, Aviezer, David, Shaaltiel, Yoseph·2013·Bioscience Reports
DOI 10.1042/bsr20130081PMC PMC3782720
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Abstract

The glycosylation of recombinant β-glucocerebrosidase, and in particular the exposure of mannose residues, has been shown to be a key factor in the success of ERT (enzyme replacement therapy) for the treatment of GD (Gaucher disease). Macrophages, the target cells in GD, internalize β-glucocerebrosidase through MRs (mannose receptors). Three enzymes are commercially available for the treatment of GD by ERT. Taliglucerase alfa, imiglucerase and velaglucerase alfa are each produced in different cell systems and undergo various post-translational or post-production glycosylation modifications to expose their mannose residues. This is the first study in which the glycosylation profiles of the three enzymes are compared, using the same methodology and the effect on functionality and cellular uptake is evaluated. While the major differences in glycosylation profiles reside in the variation of terminal residues and mannose chain length, the enzymatic activity and stability are not affected by these differences. Furthermore, the cellular uptake and in-cell stability in rat and human macrophages are similar. Finally, in vivo studies to evaluate the uptake into target organs also show similar results for all three enzymes. These results indicate that the variations of glycosylation between the three regulatory-approved β-glucocerebrosidase enzymes have no effect on their function or distribution.

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  • Velaglucerase alfa and other β-glucocerebrosidases produced in CHO and carrot cells show diverse glycan profiles but similar macrophage uptake, in vitro enzymatic activity, stability, and efficacy.

    “Even though these three products show diverse glycan profiles, they showed similar macrophage uptake, in vitro enzymatic activity, stability and efficacy (Ben Turkia et al., 2013;Tekoah et al., 2013).”

    From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Tekoah et al., 2013

    The Introduction table identifies the three enzymes as produced in human fibrosarcoma, CHO, and carrot cells. The Discussion reports different glycan profiles but comparable enzymatic activity, stability, and macrophage uptake. It says clinical trial data *suggest* no significant differences in clinical improvement, rather than establishing similar efficacy as a finding of this study. (LLM, conf=0.83)

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  1. [1]Zimran A. How I treat Gaucher disease Blood 2011 118 1463 1471 21670466
  2. [2]Dekker N. van Dussen L. Hollak C. E. M. Overkleeft H. Scheij S. Ghauharali K. van Breemen M. J. Ferraz M. J. Groener J. E. M. Maas M. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response Blood 2011 118 118 127 PMC3685900 21868580
  3. [3]Sato Y. Beutler E. Binding, internalization, and degradation of mannose-terminated glucocerebrosidase by macrophages J. Clin. Invest. 1993 91 1909 1917 8486762 PMC288185
  4. [4]Friedman B. Vaddi K. Preston C. Mahon E. Cataldo J. R. McPherson J. M. A comparison of the pharmacological properties of carbohydrate remodeled recombinant and placental-derived beta-glucocerebrosidase: implications for clinical efficacy in treatment of Gaucher disease Blood 1999 93 2807 2816 10216074
  5. [5]Grabowski G. A. Barton N. W. Pastores G. Dambrosia J. M. Banerjee T. K. McKee M. A. Parker C. Schiffmann R. Hill S. C. Brady R. O. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources Ann. Intern. Med. 1995 122 33 39 7985893
  6. [6]Weinreb N. J. Charrow J. Andersson H. C. Kaplan P. Kolodny E. H. Mistry P. Pastores G. Rosenbloom B. E. Scott C. R. Wappner R. S. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry Am. J. Med. 2002 113 112 119 12133749
  7. [7]Jmoudiak M. Futerman A. H. Gaucher disease: pathological mechanisms and modern management Br. J. Haematol. 2005 129 178 188 15813845
  8. [8]Brumshtein B. Salinas P. Peterson B. Peterson B. Chan V. Silman I. Sussman J. L. Savickas P. J. Robinson G. S. Futerman A. H. Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages Glycobiology 2010 20 24 32 19741058 PMC2782181
  9. [9]Shaaltiel Y. Bartfield D. Hashmueli S. Baum G. Brill-Almon E. Galili G. Dym O. Boldin-Adamsky S. A. Silman I. Sussman J. L. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system Plant Biotechnol. J. 2007 5 579 590 17524049
  10. [10]Sturm A. Heterogeneity of the complex N-linked oligosaccharides at specific glycosylation sites of two secreted carrot glycoproteins Eur. J. Biochem. 1991 199 169 179 2065672
  11. [11]Erickson A. H. Ginns E. I. Barranger J. A. Biosynthesis of the lysosomal enzyme glucocerebrosidase Biol. Chem. 1985 260 14319 14324 3932353
  12. [12]Berger J. Stirnemann J. Bourgne C. Pereira B. Pigeon P. Heraoui D. Froissart R. Rapatel C. Rose C. Belmatoug N. The uptake of recombinant glucocerebrosidases by blood monocytes from type 1 Gaucher disease patients is variable Br. J. Haematol. 2012 157 274 277 22224474
  13. [13]Van Patten S. M. Hughes H. Huff M. R. Piepenhagen P. A. Waire J. Huawei Q. Ganesa C. Reczek D. Ward P. V. Kutzko J. P. Effect of mannose chain length on targeting of glucocerebrosidase for enzyme replacement therapy of Gaucher disease Glycobiology 2007 17 467 478 17251309
  14. [14]Tekoah Y. Ko K. Koprowski H. Harvey D. J. Wormald M. R. Dwek R. A. Rudd P. M. Controlled glycosylation of therapeutic antibodies in plants Arch. Biochem. Biophys. 2004 426 266 278 15158677
  15. [15]Kuster B. Wheeler S. F. Hunter A. P. Dwek R. A. Harvey D. J. Sequencing of N-linked oligosaccharides directly from protein gels: in-gel deglycosylation followed by matrix-assisted laser desorption/ionization mass spectrometry and normal-phase high-performance liquid chromatography Anal. Biochem. 1997 250 82 101 9234902
  16. [16]Urban D. J. Zheng W. Goker-Alpan O. Jadhav A. Lamarca M. E. Inglese J. Sidransky E. Austin C. P. Optimization and validation of two miniaturized glucocerebrosidase enzyme assays for high throughput screening Comb. Chem. High Throughput Screen. 2008 11 817 824 19075603 PMC2668958
  17. [17]Zhu Y. Li X. Schuchman E. H. Desnick R. J. Cheng S. H. Dexamethasone-mediated up-regulation of the mannose receptor improves the delivery of recombinant glucocerebrosidase to Gaucher macrophages J. Pharmacol. Exp. Ther. 2004 308 705 711 14610228
  18. [18]Kirchhausen T. Macia E. Pelish H. E. Use of Dynasore, the small molecule inhibitor of dynamin, in the regulation of endocytosis Methods Enzymol. 2008 438 77 93 18413242 PMC2796620
  19. [19]Zhu Y. Li X. Schuchman E. H. Desnick R. J. Cheng S. H. Dexamethasone-mediated up-regulation of the mannose receptor improves the delivery of recombinant glucocerebrosidase to Gaucher macrophages JPET 2004 308 705 711 14610228
  20. [20]Sundström C. Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U937) Int. J. Cancer 1976 17 565 577 178611
  21. [21]Dvir H. Harel M. McCarthy A. A. Toker L. Silman I. Futerman A. H. Sussman J. L. X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease EMBO Rep. 2003 4 704 709 12792654 PMC1326319
  22. [22]Berg-Fussman A. Grace M. E. Ioannou Y. Grabowski G. A. Human acid beta-glucosidase. N-glycosylation site occupancy and the effect of glycosylation on enzymatic activity J. Biol. Chem. 1993 268 14861 14866 8325864
  23. [23]Taylor M. E. Recognition of complex carbohydrates by the macrophage mannose receptor Biochem. Soc. Trans. 1993 21 468 473 8359512
  24. [24]Stahl P. D. The macrophage mannose receptor: current status Am. J. Respir. Cell Mol. Biol. 1990 2 317 318 2182080
  25. [25]Takasaki S. Murray G. J. Furbish F. S. Brady R. O. Barranger J. A. Kobata A. Structure of the N-asparagine-linked oligosaccharide units of human placental beta-glucocerebrosidase J. Biol. Chem. 1984 259 10112 10117 6469957
  26. [26]Brumshtein B. Greenblatt H. M. Butters T. D. Shaaltiel Y. Aviezer D. Silman I. Futerman A. H. Sussman J. L. Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid β-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease J. Biol. Chem. 2007 282 29052 29058 17666401
  27. [27]Geissmann F. Manz M. G. Jung S. Sieweke M. H. Merad M. Ley K. Development of monocytes, macrophages, and dendritic cells Science. 2010 327 656 661 20133564 PMC2887389
  28. [28]Naito M. Macrophage differentiation and function in health and disease Pathol. Int. 2008 58 143 155 18251777
  29. [30]Zimran A. Elstein D. Levy-Lahad E. Zevin S. Hadas-Halpern I. Bar-Ziv Y. Foldes J. Schwartz A. J. Abrahamov A. Replacement therapy with imiglucerase for type 1 Gaucher's disease Lancet 1995 345 1479 1480 7769903
  30. [31]Zimran A. Altarescu G. Philips M. Attias D. Jmoudiak M. Deeb M. Wang N. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience Blood 2010 115 4651 4656 20299511
  31. [32]Zimran A. Brill-Almon E. Chertkoff R. Petakov M. Blanco-Favela F. Muñoz E. T. Solorio-Meza S. E. Amato D. Duran G. Giona F. Heitner R. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease Blood 2011 118 5767 5773 21900191

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Authors
Tekoah, Y., Tzaban, S., Kizhner, T., Hainrichson, M., Gantman, A., Golembo, M., Aviezer, D., & Shaaltiel, Y.
Affiliations
  • Protalix BioTherapeutics (Israel) (IL)
  • Bar-Ilan University (IL)
Corresponding author
  • Tekoah, Yoram
  • Tzaban, Salit
  • Kizhner, Tali
  • Hainrichson, Mariana
  • Gantman, Anna
  • Golembo, Myriam
  • Aviezer, David
  • Shaaltiel, Yoseph
ORCID
Venue
Bioscience Reports
Publisher
Portland Press Ltd.
Published
2013-09-25
Volume
33
Issue
5
ISSN
  • 0144-8463 (ISSN-L)
  • 1573-4935
DOI
10.1042/bsr20130081
PMC
PMC3782720
OpenAlex
W2080070582
Cited by
100
References
1
Citations by year
2026: 5 · 2025: 6 · 2024: 6 · 2023: 11 · 2022: 4 · 2021: 3 · 2020: 8 · 2019: 8 · 2018: 12 · 2017: 6 · 2016: 7 · 2015: 13 · 2014: 10 · 2013: 1
FWCI
7.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Bioscience Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Pfizer
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
beta-glucocerebrosidase, Gaucher disease, enzyme replacement therapy, glycosylation, mannose residues, CD206, taliglucerase alfa, imiglucerase, velaglucerase alfa, macrophage uptake, enzyme stability
MeSH terms
Animals, Biological Transport, Carbohydrate Conformation, Carbohydrate Sequence, Cell Line, Enzyme Stability, Glucosylceramidase, Glycosylation, Humans, Kinetics, Male, Mice, Inbred ICR, Molecular Sequence Data, Protein Processing, Post-Translational, Recombinant Proteins, Tissue Distribution, Macrophages, Alveolar, Mice, Rats

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