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  • Review Article
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Glycosylation as a strategy to improve antibody-based therapeutics

Nature Reviews Drug Discovery volume 8, pages 226–234 (2009)Cite this article

Key Points

  • Natural and recombinant immunoglobulin G (IgG) antibodies consist of an IgG Fab (antigen-binding fragment) region and IgG Fc (crystallizable fragment) regions. On antigen binding, antibodies form multimeric complexes that can initiate inflammatory processes leading to their elimination and destruction.

  • Glycosylation of the IgG Fc region is essential for the activation of downstream effector functions. There is heterogeneity in the oligosaccharides that are attached, resulting in multiple glycoforms that can differ from each other in biological efficacy.

  • Production cell lines may be engineered to produce selected glycoforms with enhanced biological properties and to provide maximum efficacy for a given disease indication.

  • It may be possible to further improve the effector function of currently approved therapeutic antibodies, without increasing their immunogenicity, by generating particular glycoforms.

  • Improved production vehicles can offer lower cost of goods and contribute to lower cost of treatment.

Abstract

To date, more than 20 recombinant immunoglobulin G (IgG) antibody therapeutics are licensed for the treatment of various diseases. The mechanism of action of recombinant monoclonal antibodies (rMAbs) has been extensively investigated and several distinct pathways have been defined; selective activation of specific pathways may optimize clinical outcomes for different diseases, such as cancer and chronic inflammation. Human IgG is a glycoprotein with oligosaccharides attached at a single site. These are essential to the mode of action of rMAbs, and the antibody efficacy can vary depending on the particular oligosaccharide that is attached. Methods are now becoming available that allow the production of rMAbs bearing pre-selected oligosaccharides — glycoforms — to provide maximum efficacy for a given disease indication. This Review summarizes current knowledge of these methods and avenues for their exploitation in the clinic.

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Figure 1: The α-carbon backbone structure of the immunoglobulin G (IgG) molecule.
Figure 2: IgG Fc diantennary-complex oligosaccharide composition.

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Authors and Affiliations

  1. Division of Immunity and Infection, University of Birmingham, School of Medicine, Edgbaston, B15 2TT, Birmingham, UK

    Roy Jefferis

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  1. Roy Jefferis
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Roy Jefferis has consultancy contracts with Novartis, Merck and Gilde.

Glossary

Diantennary oligosaccharide

An oligosaccharide that has two mannose 'arms'; as opposed to triantennary, tetra-antennary and so on.

Differential scanning micro-calorimetry

A thermoanalytic technique in which the difference in the amount of heat required to increase the temperature of a sample and a reference is measured as a function of temperature.

Alanine scanning

A genetic manipulation that sequentially replaces wild-type amino acids with alanine to determine the impact on the protein's structure and function.

Conformer

A discrete, defined conformation in three-dimensional space.

Antibody-dependent cellular cytotoxicity

(ADCC). Cell death that results when the Fc fragment of an antibody bound to a target cell interacts with Fc receptors on monocytes, macrophages or natural killer cells that are consequently activated to kill the target.

Complement-dependent cytotoxicity

(CDC). Cell death that results when the IgG Fc regions of an antibody bound to a target cell activate the C1 component of complement, initiating a cascade of reactions that lead to the formation of a complex that disrupts the cell membrane.

Granzyme

An apoptosis-inducing serine protease released from cytoplasmic granules by cytotoxic T cells and NK cells.

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Jefferis, R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov 8, 226–234 (2009). https://doi.org/10.1038/nrd2804

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