Glycoengineering: The effect of glycosylation on the properties of therapeutic proteins

Sinclair, Angus M.; Elliott, Steve

doi:10.1002/jps.20319

Cited by 431 publications

(309 citation statements)

References 65 publications

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“…Together, the absence of terminal sialic acids and the exposure of terminal galactose or N-acetylglucosamine residues control both the elimination of the fusion protein from blood and its extravasation properties. Low levels of terminal sialic acids can lead to unacceptably fast clearance, as previously described (5). A contribution to protein clearance of either the asialoglycoprotein receptor and of the mannose receptor would be compatible with our analytical data.…”

Section: Resultssupporting

confidence: 88%

“…Indeed, the first glyco-engineered antibody product, obinutuzumab (Gazyva), has recently been approved for chronic lymphocytic leukemia. The impact of protein glycosylation on pharmacokinetics has been extensively studied for glycoprotein hormones, including the prominent examples of recombinant erythropoietin and its glyco-engineered derivative Darbepoetin alfa (5). The introduction of additional N-glycosylation motifs into the peptide sequence of erythropoietin can result in increased serum half-lives (6).…”

mentioning

confidence: 99%

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Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies

Venetz¹,

Hess²,

Lin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The ability of antibodies to extravasate out of blood vessels is critical for therapeutic activity, because molecular targets for most diseases are located outside of the endothelial lining. By performing detailed biodistribution studies with a novel IL9-armed cancer-specific antibody, we identified a clear correlation between N-linked glycan structures and tumor-targeting efficiencies. Site-specific glycan analysis provided a detailed view of the glycan microheterogeneity present on the IL9 portion of the recombinant protein. Nonsialylated glycan structures have a negative impact on disease-homing activity, highlighting the importance of glycosylation control and characterization during process development.

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Section: Resultssupporting

confidence: 88%

mentioning

confidence: 99%

Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies

Venetz¹,

Hess²,

Lin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…This suggests that higher serum concentrations of darbepoetin alfa may be required to get similar fractions of ESA-bound receptors, which theoretically could result in reduced in-vivo-specific activity or efficacy. However, the additional carbohydrate on darbepoetin did not blunt the biological response [53], and the same signal transduction pathways were stimulated with similar kinetics and magnitude [39,53]. When in vitro and in vivo activities were compared, the shapes of the dose-response curve, maximal stimulation, and hematological response were all similar, suggesting that the different carbohydrate content can affect the specific activity but did not affect function per se.…”

Section: Successful Development Of Darbepoetin Alfamentioning

confidence: 93%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

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Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesisstimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivospecific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains.

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“…An aglycosylated but biologically active form of hEPO can be produced in E. coli, but the absence of the N-glycans strongly reduced the in vivo half-life. In contrast, engineering of an EPO variant carrying two additional N-glycan chains (Darbepoietin alfa) increased in vivo half-life and activity [5].…”

Section: Introductionmentioning

confidence: 94%

Glycoengineering of yeasts from the perspective of glycosylation efficiency

et al. 2014

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Glycoengineering: The effect of glycosylation on the properties of therapeutic proteins

Cited by 431 publications

References 65 publications

Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies

Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Glycoengineering of yeasts from the perspective of glycosylation efficiency

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