Marija Pezer - Antibody Glycosylation

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Antibodies are one of the main weapons in our arsenal for the eternal war against pathogens. They are an elaborate tool that can specifically recognize foreign structures in our body. This is achieved by site-specific recombination of multiple variants of the V, (D), and J sequences of the variable region followed by somatic hypermutation that induces up to a million times higher rate of mutation in this region during antibody maturation. The fact that a completely bizarre process that, against all evolutionary logic, actually induces mutations has been invented during evolution indicates how important antibodies are for our survival. But binding to antigen is only one part of what antibodies do. After binding to a foreign object, antibodies have to activate proper molecular mechanisms to deal with this foreign, non-self object. If this non-self antigen is a pathogenic virus, or a bacterium, it has to be eliminated in the most efficient way. If it is on a cell that may be transformed to a tumour cell, or infected by a virus, the entire cell should be eliminated. But if this foreign antigen is a food we eat, dust, or some antigen in the air, then this antigen should be ignored, and the activation of the immune system should be avoided.

The decision of how to react to a foreign antigen is one of the most complex decisions that have to be made, and these decisions have to be made continuously throughout our lifetime. Alternative glycosylation modulates the execution of these decisions by directing IgG to different receptors and in this way activating different branches of our immune system. Fc glycans are an integral part of the CH2 domain of antibodies and as such represent an integral structural component that participates in the interaction with Fc receptors and other proteins. Attaching a different glycan to the polypeptide backbone changes the structure of the antibody and modifies its affinity for different receptors. The best currently known example is the role of core fucose that acts as a safety switch against antibody-dependant cellular cytotoxicity (ADCC) by attenuating binding of IgG to Fc-gamma-receptor IIIA.

Contrary to the polypeptide parts of the antibody that can be changed only by inducing changes in the corresponding genes, glycans are encoded in a complex network of at least several dozen genes that are affected by both epigenetics and the environment. This enables flexible and dynamic regulation of antibody function and is extensively used to fine-tune our immune system. More than thirty years ago, the initial discovery of changes in the IgG glycome composition in diseases was made and until now over 100,000 different IgG glycomes have been analysed in different diseases and physiological states. Changes in IgG glycosylation are associated with numerous diseases, often even before any other symptoms of the disease are detectable, indicating that they might be a part of molecular pathophysiology leading to the disease. With ageing IgG glycome converts from a composition that suppresses inflammation to an inflammation-promoting glycome that seems to be an underlying risk factor in many cardiometabolic diseases.

Glycosylation is an essential element in the development of different therapeutic monoclonal antibodies, and glycoengineered drugs are already on the market. Inter-individual differences in glycosylation are large and may be an important underlying element for the response or non-response to a given drug, but this is still understudied. Hopefully, the recent progress in analytical methods will enable more studies in this direction, which would help us to better understand functional aspects of inter-individual differences in antibody glycosylation.

The book Antibody Glycosylation edited by Marija Pezer and written by an international team of accomplished scientists from academia and industry provides a comprehensive overview of biosynthesis, regulation, functionality, analytics, and applications of immunoglobulin glycosylation. By covering automatization and bioinformatics in high-throughput analytical settings, it provides new perspectives for research and development in the field of therapeutic antibodies, biomarkers, vaccinations, and immunotherapy.