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Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
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Author to whom correspondence should be addressed.
Received: 13 May 2020 / Revised: 29 May 2020 / Accepted: 3 June 2020 / Published: 10 June 2020
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
The development of recombinant therapeutic proteins has been a major revolution in modern medicine. Therapeutic-based monoclonal antibodies (mAbs) are growing rapidly, providing a potential class of human pharmaceuticals that can improve the management of cancer, autoimmune diseases, and other conditions. Most mAbs are typically of the immunoglobulin G (IgG) subclass, and they are glycosylated at the conserved asparagine position 297 (Asn-297) in the CH2 domain of the Fc region. Post-translational modifications here account for the observed high heterogeneity of glycoforms that may or not impact the stability, pharmacokinetics (PK), efficacy, and immunogenicity of mAbs. These modifications are also critical for the Fc receptor binding, and consequently, key antibody effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Moreover, mAbs produced in non-human cells express oligosaccharides that are not normally found in serum IgGs might lead to immunogenicity issues when administered to patients. This review summarizes our understanding of the terminal sugar residues, such as mannose, sialic acids, fucose, or galactose, which influence therapeutic mAbs either positively or negatively in this regard. This review also discusses mannosylation, which has significant undesirable effects on the PK of glycoproteins, causing a decreased mAbs’ half-life. Moreover, terminal galactose residues can enhance CDC activities and Fc–C1q interactions, and core fucose can decrease ADCC and Fc–FcγRs binding. To optimize the therapeutic use of mAbs, glycoengineering strategies are used to reduce glyco-heterogeneity of mAbs, increase their safety profile, and improve the therapeutic efficacy of these important reagents. View Full-Text
Keywords: glycosylation; post-translational modifications; pharmacokinetics; effector functions; antibody-dependent cell-mediated cytotoxicity; complement-dependent cytotoxicity; immunogenicity; pharmacodynamics; glycoengineering; antibody-drug conjugates glycosylation; post-translational modifications; pharmacokinetics; effector functions; antibody-dependent cell-mediated cytotoxicity; complement-dependent cytotoxicity; immunogenicity; pharmacodynamics; glycoengineering; antibody-drug conjugates
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MDPI and ACS Style

Boune, S.; Hu, P.; Epstein, A.L.; Khawli, L.A. Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations. Antibodies 2020, 9, 22. https://0-doi-org.brum.beds.ac.uk/10.3390/antib9020022

AMA Style

Boune S, Hu P, Epstein AL, Khawli LA. Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations. Antibodies. 2020; 9(2):22. https://0-doi-org.brum.beds.ac.uk/10.3390/antib9020022

Chicago/Turabian Style

Boune, Souad, Peisheng Hu, Alan L. Epstein, and Leslie A. Khawli. 2020. "Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations" Antibodies 9, no. 2: 22. https://0-doi-org.brum.beds.ac.uk/10.3390/antib9020022

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