Impact of N-Linked Glycosylation on Therapeutic Proteins

Abstract

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.

Eptacog beta for the management of patients with haemophilia A and B with inhibitors: A European perspective

“…24 Differences in N-glycosylation profiles have also been shown to have an impact on the therapeutic properties and stability of human antibodies. 24 For eptacog beta, the major Nglycosylation structures are complex biantennary structures sialylated at the α 2−6 position, among which 57% are monosialylated and 12% are bisialylated. In contrast, eptacog alfa presents approximately 50% bisialylated and 18% monosialylated biantennary N-glycans that are sialylated at the α 2−3 position.…”

“…This difference is due to their different production techniques: eptacog alfa is expressed in baby hamster kidney cells and secreted into a cultured media containing foetal bovine serum; 11 whereas eptacog beta (Figure 1) is expressed in the rabbit mammary gland and secreted in the milk of transgenic rabbits 11 . N‐glycosylation profile can influence the molecular stability, pharmacokinetic and pharmacodynamic properties of therapeutic proteins and can lead to improved performance 24 . Differences in N‐glycosylation profiles have also been shown to have an impact on the therapeutic properties and stability of human antibodies 24 .…”

The Hexosamine Biosynthesis Pathway: Regulation and Function

“…At the same time, N -glycan branching subdues negative selection by diminishing the induction of Nur77, a marker of negative selection. There is considerable interest in engineering antibody glycosylation due to the many therapeutic applications of antibodies in diseases [ 251 , 252 ]. How modulating the HBP could affect antibody generation and glycosylation would be important to pursue.…”

Study on antibody Fc-glycosylation for optimal effector functions

“…Therefore, the IgG-Fc N-glycans exhibit tremendous diversity and heterogeneity, with 4400 different glyco-variants when pairing the two CH2 domains, and each of the glycoforms potentially modulates the effector functions in a slightly different manner. 14 Type I and type II FcgRs are categorized by their capacity to bind the IgG Fc-domain with specific glycoforms. 15 Type I FcgRs such as FcgRI, FcgRIIa, FcgRIIb, FcgRIIc, FcgRIIIa, and FcgRIIIb are members of the immunoglobulin superfamily, 16 while type II FcgRs are represented by C-type lectin receptors such as the human dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN/CD209) and CD23, which specifically bind to the sialylated Fc domains within immune complexes.…”

“…Therefore, the IgG-Fc N-glycans exhibit tremendous diversity and heterogeneity, with >400 different glyco-variants when pairing the two CH2 domains, and each of the glycoforms potentially modulates the effector functions in a slightly different manner. 14…”