New Opportunities in Glycan Engineering for Therapeutic Proteins

Zhong, Xiaotian; D’Antona, Aaron M.; Scarcelli, John J.; Rouse, Jason C.

doi:10.3390/antib11010005

Cited by 9 publications

(7 citation statements)

References 129 publications

(179 reference statements)

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“…These carbohydrates are present as a branched oligosaccharide chain, conservatively linked to the asparagine-297 residue (Asn297, N297, Figure 2) in the C H 2 region of the Fc heavy chain of the immunoglobulin fragment [110]. The localization of carbohydrates on a serine or threonine residue of IgG is rare [111]. As a result, oligosaccharides are consistently located at a significant distance from the antigen-binding center [112].…”

Section: Periodate Oxidation Of Glycansmentioning

confidence: 99%

“…As a result, oligosaccharides are consistently located at a significant distance from the antigen-binding center [112]. Numerous reviews have been devoted to the properties and functions of immunoglobulin glycans and their structure [110,111,[113][114][115][116][117][118][119][120][121][122][123][124][125]. Hence, the oxidation of oligosaccharide fragments of anti-bodies to form carbonyl groups appears to be a promising method for initial modification, which can then be followed by the conjugation of the desired molecule [112,126].…”

Section: Periodate Oxidation Of Glycansmentioning

confidence: 99%

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Introduction of Carbonyl Groups into Antibodies

Gulyak,

Alferova,

Korshun

et al. 2023

Molecules

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Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery. Currently, one of the most promising endeavors in this field is the development of molecular diagnostic tools and antibody-based therapeutic agents, including antibody–drug conjugates (ADCs). To meet this challenge, it is imperative to advance methods for modifying antibodies. A particularly promising strategy involves the introduction of carbonyl groups into the antibody that are amenable to further modification by biorthogonal reactions, namely aliphatic, aromatic, and α-oxo aldehydes, as well as aliphatic and aryl–alkyl ketones. In this review, we summarize the preparation methods and applications of site-specific antibody conjugates that are synthesized using this approach.

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Section: Periodate Oxidation Of Glycansmentioning

confidence: 99%

Section: Periodate Oxidation Of Glycansmentioning

confidence: 99%

Introduction of Carbonyl Groups into Antibodies

Gulyak,

Alferova,

Korshun

et al. 2023

Molecules

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“…Post-translational modifications (PTMs) in mammalian cells provide de novo synthesized proteins with an additional level of structural diversity beyond their primary sequences [1][2][3][4]. These PTMs impose new biological functions and activity modulations as well as further physiological consequences [3][4][5][6][7]. For the discovery and development of protein therapeutics, PTMs are critical quality attributes for final clinical products, and the dependence on the biological systems for producing intended PTMs is a unique challenge for biologics drugs.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine Sulfation at Antibody Light Chain CDR-1 Increases Binding Affinity and Neutralization Potency to Interleukine-4

D’Antona,

Lee,

Zhang

et al. 2024

IJMS

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Structure and function of therapeutic antibodies can be modulated by a variety of post-translational modifications (PTM). Tyrosine (Tyr) sulfation is a type of negatively charged PTM that occurs during protein trafficking through the Golgi. In this study, we discovered that an anti-interleukin (IL)-4 human IgG1, produced by transiently transfected HEK293 cells, contained a fraction of unusual negatively charged species. Interestingly, the isolated acidic species exhibited a two-fold higher affinity to IL-4 and a nearly four-fold higher potency compared to the main species. Mass spectrometry (MS) showed the isolated acidic species possessed an +80-Dalton from the expected mass, suggesting an occurrence of Tyr sulfation. Consistent with this hypothesis, we show the ability to control the acidic species during transient expression with the addition of Tyr sulfation inhibitor sodium chlorate or, conversely, enriched the acidic species from 30% to 92% of the total antibody protein when the IL-4 IgG was co-transfected with tyrosylprotein sulfotransferase genes. Further MS and mutagenesis analysis identified a Tyr residue at the light chain complementarity-determining region-1 (CDRL-1), which was sulfated specifically. These results together have demonstrated for the first time that Tyr sulfation at CDRL-1 could modulate antibody binding affinity and potency to a human immune cytokine.

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“…In addition to these two representative examples, there are many coagulation factors, cytokines, and hormone-based therapeutic proteins whose properties have been reported to be affected by glycosylation. A detailed description of these reported findings is beyond the scope of this mini review, and the interested reader is referred to the excellent recent review articles for more comprehensive information [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Impact of N-Linked Glycosylation on Therapeutic Proteins

Chen

Liu

et al. 2022

Molecules

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Therapeutic proteins have unique advantages over small-molecule drugs in the treatment of various diseases, such as higher target specificity, stronger pharmacological efficacy and relatively low side effects. These advantages make them increasingly valued in drug development and clinical practice. However, although highly valued, the intrinsic limitations in their physical, chemical and pharmacological properties often restrict their wider applications. As one of the most important post-translational modifications, glycosylation has been shown to exert positive effects on many properties of proteins, including molecular stability, and pharmacodynamic and pharmacokinetic characteristics. Glycoengineering, which involves changing the glycosylation patterns of proteins, is therefore expected to be an effective means of overcoming the problems of therapeutic proteins. In this review, we summarize recent efforts and advances in the glycoengineering of erythropoietin and IgG monoclonal antibodies, with the goals of illustrating the importance of this strategy in improving the performance of therapeutic proteins and providing a brief overview of how glycoengineering is applied to protein-based drugs.

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New Opportunities in Glycan Engineering for Therapeutic Proteins

Cited by 9 publications

References 129 publications

Introduction of Carbonyl Groups into Antibodies

Introduction of Carbonyl Groups into Antibodies

Tyrosine Sulfation at Antibody Light Chain CDR-1 Increases Binding Affinity and Neutralization Potency to Interleukine-4

Impact of N-Linked Glycosylation on Therapeutic Proteins

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