| 期刊全称 | Antibody Glycosylation | | 影响因子2023 | Marija Pezer | | 视频video | http://file.papertrans.cn/159/158475/158475.mp4 | | 发行地址 | Provides a comprehensive overview on biosynthesis, regulation, functionality, analytics, and applications of immunoglobulin glycosylation.Covers automatization and bioinformatics in high-throughput an | | 学科分类 | Experientia Supplementum | | 图书封面 |  | | 影响因子 | .This book summarizes recent advances in antibody glycosylation research. Covering major topics relevant for immunoglobulin glycosylation - analytical methods, biosynthesis and regulation, modulation of effector functions - it provides new perspectives for research and development in the field of therapeutic antibodies, biomarkers, vaccinations, and immunotherapy..Glycans attached to both variable and constant regions of antibodies are known to affect the antibody conformation, stability, and effector functions. Although it focuses on immunoglobulin G (IgG), the most explored antibody in this context, and unravels the natural phenomena resulting from the mixture of IgG glycovariants present in the human body, the book also discusses other classes of human immunoglobulins, as well as immunoglobulins produced in other species and production systems. Further, it reviews the glycoanalytical methods applied to antibodies and addresses a range of less commonly explored topics, such as automatization and bioinformatics aspects of high-throughput antibody glycosylation analysis. Lastly, the book highlights application areas ranging from the ones already benefitting from antibody glycoengin | | Pindex | Book 2021 |
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Front Matter |
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Abstract
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,Micro-Heterogeneity of Antibody Molecules, |
Yusuke Mimura,Radka Saldova,Yuka Mimura-Kimura,Pauline M. Rudd,Roy Jefferis |
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Abstract
Therapeutic monoclonal antibodies (mAbs) are mostly of the IgG class and constitute highly efficacious biopharmaceuticals for a wide range of clinical indications. Full-length IgG mAbs are large proteins that are subject to multiple posttranslational modifications (PTMs) during biosynthesis, purification, or storage, resulting in micro-heterogeneity. The production of recombinant mAbs in nonhuman cell lines may result in loss of structural fidelity and the generation of variants having altered stability, biological activities, and/or immunogenic potential. Additionally, even fully human therapeutic mAbs are of unique specificity, by design, and, consequently, of unique structure; therefore, structural elements may be recognized as non-self by individuals within an outbred human population to provoke an anti-therapeutic/anti-drug antibody (ATA/ADA) response. Consequently, regulatory authorities require that the structure of a potential mAb drug product is comprehensively characterized employing state-of-the-art orthogonal analytical technologies; the PTM profile may define a set of critical quality attributes (CQAs) for the drug product that must be maintained, employing quality by
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Abstract
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Lectin and Liquid Chromatography-Based Methods for Immunoglobulin (G) Glycosylation Analysis |
Tea Petrović,Irena Trbojević-Akmačić |
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Abstract
Immunoglobulin (Ig) glycosylation has been shown to dramatically affect its structure and effector functions. Ig glycosylation changes have been associated with different diseases and show a promising biomarker potential for diagnosis and prognosis of disease advancement. On the other hand, therapeutic biomolecules based on structural and functional features of Igs demand stringent quality control during the production process to ensure their safety and efficacy. Liquid chromatography (LC) and lectin-based methods are routinely used in Ig glycosylation analysis complementary to other analytical methods, e.g., mass spectrometry and capillary electrophoresis. This chapter covers analytical approaches based on LC and lectins used in low- and high-throughput .- and .-glycosylation analysis of Igs, with the focus on immunoglobulin G (IgG) applications. General principles and practical examples of the most often used LC methods for Ig purification are described, together with typical workflows for .- and .-glycan analysis on the level of free glycans, glycopeptides, subunits, or intact Igs. Lectin chromatography is a historical approach for the analysis of lectin-carbohydrate interaction
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Mass Spectrometry-Based Methods for Immunoglobulin G ,-Glycosylation Analysis |
Siniša Habazin,Jerko Štambuk,Jelena Šimunović,Toma Keser,Genadij Razdorov,Mislav Novokmet |
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Abstract
Mass spectrometry and its hyphenated techniques enabled by the improvements in liquid chromatography, capillary electrophoresis, novel ionization, and fragmentation modes are truly a cornerstone of robust and reliable protein glycosylation analysis. Boost in immunoglobulin G (IgG) glycan and glycopeptide profiling demands for both applied biomedical and research applications has brought many new advances in the field in terms of technical innovations, sample preparation, improved throughput, and confidence in glycan structural characterization. This chapter summarizes mass spectrometry basics, focusing on IgG and monoclonal antibody .-glycosylation analysis on several complexity levels. Different approaches, including antibody enrichment, glycan release, labeling, and glycopeptide preparation and purification, are covered and illustrated with recent breakthroughs and examples from the literature omitting excessive theoretical frameworks. Finally, selected highly popular methodologies in IgG glycoanalytics such as liquid chromatography–mass spectrometry and matrix-assisted laser desorption ionization are discussed more thoroughly yet in simple terms making this text a practical star
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Capillary (Gel) Electrophoresis-Based Methods for Immunoglobulin (G) Glycosylation Analysis |
Samanta Cajic,René Hennig,Robert Burock,Erdmann Rapp |
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Abstract
The in-depth characterization of protein glycosylation has become indispensable in many research fields and in the biopharmaceutical industry. Especially knowledge about modulations in immunoglobulin G (IgG) .-glycosylation and their effect on immunity enabled a better understanding of human diseases and the development of new, more effective drugs for their treatment. This chapter provides a deeper insight into capillary (gel) electrophoresis-based (C(G)E) glycan analysis, addressing its impressive performance and possibilities, its great potential regarding real high-throughput for large cohort studies, as well as its challenges and limitations. We focus on the latest developments with respect to miniaturization and mass spectrometry coupling, as well as data analysis and interpretation. The use of exoglycosidase sequencing in combination with current C(G)E technology is discussed, highlighting possible difficulties and pitfalls. The application section describes the detailed characterization of .-glycosylation, utilizing multiplexed CGE with laser-induced fluorescence detection (xCGE-LIF). Besides a comprehensive overview on antibody glycosylation by comparing species-specific I
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Automation of Immunoglobulin Glycosylation Analysis |
Jenifer L. Hendel,Richard A. Gardner,Daniel I. R. Spencer |
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Abstract
The development of reliable, affordable, high-resolution glycomics technologies that can be used for many samples in a high-throughput manner are essential for both the optimization of glycosylation in the biopharmaceutical industry as well as for the advancement of clinical diagnostics based on glycosylation biomarkers. We will use this chapter to review the sample preparation processes that have been used on liquid-handling robots to obtain high-quality glycomics data for both biopharmaceutical and clinical antibody samples. This will focus on glycoprotein purification, followed by glycan or glycopeptide generation, derivatization and enrichment. The use of liquid-handling robots for glycomics studies on other sample types beyond antibodies will not be discussed here. We will summarize our thoughts on the current status of the field and explore the benefits and challenges associated with developing and using automated platforms for sample preparation. Finally, the future outlook for the automation of glycomics will be discussed along with a projected impact on the field in general.
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Bioinformatics in Immunoglobulin Glycosylation Analysis |
Frédérique Lisacek,Kathirvel Alagesan,Catherine Hayes,Steffen Lippold,Noortje de Haan |
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Abstract
Analytical methods developed for studying immunoglobulin glycosylation rely heavily on software tailored for this purpose. Many of these tools are now used in high-throughput settings, especially for the glycomic characterization of IgG. A collection of these tools, and the databases they rely on, are presented in this chapter. Specific applications are detailed in examples of immunoglobulin glycomics and glycoproteomics data processing workflows. The results obtained in the glycoproteomics workflow are emphasized with the use of dedicated visualizing tools. These tools enable the user to highlight glycan properties and their differential expression.
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Abstract
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-Glycan Biosynthesis: Basic Principles and Factors Affecting Its Outcome |
Teemu Viinikangas,Elham Khosrowabadi,Sakari Kellokumpu |
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Abstract
Carbohydrate chains are the most abundant and diverse of nature’s biopolymers and represent one of the four fundamental macromolecular building blocks of life together with proteins, nucleic acids, and lipids. Indicative of their essential roles in cells and in multicellular organisms, genes encoding proteins associated with glycosylation account for approximately 2% of the human genome. It has been estimated that 50–80% of all human proteins carry carbohydrate chains—glycans—as part of their structure. Despite cells utilize only nine different monosaccharides for making their glycans, their order and conformational variation in glycan chains together with chain branching differences and frequent post-synthetic modifications can give rise to an enormous repertoire of different glycan structures of which few thousand is estimated to carry important structural or functional information for a cell. Thus, glycans are immensely versatile encoders of multicellular life. Yet, glycans do not represent a random collection of unpredictable structures but rather, a collection of predetermined but still dynamic entities that are present at defined quantities in each glycosylation site of a giv
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Genetic Regulation of Immunoglobulin G Glycosylation |
Azra Frkatovic,Olga O. Zaytseva,Lucija Klaric |
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Abstract
Defining the genetic components that control glycosylation of the human immunoglobulin G (IgG) is an ongoing effort, which has so far been addressed by means of heritability, linkage and genome-wide association studies (GWAS). Unlike the synthesis of proteins, .-glycosylation biosynthesis is not a template-driven process, but rather a complex process regulated by both genetic and environmental factors. Current heritability studies have shown that while up to 75% of the variation in levels of some IgG glycan traits can be explained by genetics, some glycan traits are completely defined by environmental influences. Advances in both high-throughput genotyping and glycan quantification methods have enabled genome-wide association studies that are increasingly used to estimate associations of millions of single-nucleotide polymorphisms and glycosylation traits. Using this method, 18 genomic regions have so far been robustly associated with IgG .-glycosylation, discovering associations with genes encoding glycosyltransferases, but also transcription factors, co-factors, membrane transporters and other genes with no apparent role in IgG glycosylation. Further computational analyses have s
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Epigenetics of Immunoglobulin G Glycosylation |
Marija Klasić,Vlatka Zoldoš |
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Abstract
Alternative glycosylation of immunoglobulin G (IgG) affects its effector functions during the immune response. IgG glycosylation is altered in many diseases, but also during a healthy life of an individual. Currently, there is limited knowledge of factors that alter IgG glycosylation in the healthy state and factors involved in specific IgG glycosylation patterns associated with pathophysiology. Genetic background plays an important role, but epigenetic mechanisms also contribute to the alteration of IgG glycosylation patterns in healthy life and in disease. It is known that the expression of many glycosyltransferases is regulated by DNA methylation and by microRNA (miRNA) molecules, but the involvement of other epigenetic mechanisms, such as histone modifications, in the regulation of glycosylation-related genes (glycogenes) is still poorly understood. Recent studies have identified several differentially methylated loci associated with IgG glycosylation, but the mechanisms involved in the formation of specific IgG glycosylation patterns remain poorly understood.
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Immunoglobulin G Glycosylation Changes in Aging and Other Inflammatory Conditions |
Fabio Dall’Olio,Nadia Malagolini |
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Abstract
Among the multiple roles played by protein glycosylation, the fine regulation of biological interactions is one of the most important. The asparagine 297 (Asn.) of IgG heavy chains is decorated by a diantennary glycan bearing a number of galactose and sialic acid residues on the branches ranging from 0 to 2. In addition, the structure can present core-linked fucose and/or a bisecting GlcNAc. In many inflammatory and autoimmune conditions, as well as in metabolic, cardiovascular, infectious, and neoplastic diseases, the IgG Asn.-linked glycan becomes less sialylated and less galactosylated, leading to increased expression of glycans terminating with GlcNAc. These conditions alter also the presence of core-fucose and bisecting GlcNAc. Importantly, similar glycomic alterations are observed in aging. The common condition, shared by the above-mentioned pathological conditions and aging, is a low-grade, chronic, asymptomatic inflammatory state which, in the case of aging, is known as inflammaging. Glycomic alterations associated with inflammatory diseases often precede disease onset and follow remission. The aberrantly glycosylated IgG glycans associated with inflammation and aging can s
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Estrogen-Driven Changes in Immunoglobulin G Fc Glycosylation |
Kaitlyn A. Lagattuta,Peter A. Nigrovic |
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Abstract
Glycosylation within the immunoglobulin G (IgG) Fc region modulates its ability to engage complement and Fc receptors, affording the opportunity to fine-tune effector functions. Mechanisms regulating IgG Fc glycans remain poorly understood. Changes accompanying menarche, menopause, and pregnancy have long implicated hormonal factors. Intervention studies now confirm that estrogens enhance IgG Fc galactosylation, in females and also in males, defining the first pathway modulating Fc glycans and thereby a new link between sex and immunity. This mechanism may participate in fetal-maternal immunity, antibody-mediated inflammation, and other aspects of age- and sex-specific immune function. Here we review the changes affecting the IgG Fc glycome from childhood through old age, the evidence establishing a role for estrogens, and research directions to uncover associated mechanisms that may inform therapeutic intervention.
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Abstract
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Sweet Rules: Linking Glycosylation to Antibody Function |
Falk Nimmerjahn,Anja Werner |
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Abstract
Antibodies produced upon infections with pathogenic microorganisms are essential for clearing primary infections and for providing the host with long-lasting immunity. Moreover, antibodies have become the most widely used platform for developing novel therapies against cancer and autoimmunity, requiring an in-depth understanding of how antibodies mediate their activity in vivo and which factors modulate pro- or anti-inflammatory antibody activities. Since the discovery that select residues present in the sugar domain attached to the immunoglobulin G (IgG) fragment crystallizable (Fc) region can modulate both, pro- and anti-inflammatory effector functions, a wealth of studies has focused on understanding how IgG glycosylation is regulated and how this knowledge can be used to optimize therapeutic antibody activity. With the introduction of glycoengineered afucosylated antibodies in cancer therapy and the initiation of clinical testing of highly sialylated anti-inflammatory antibodies the proof-of-concept that understanding antibody glycosylation can lead to clinical innovation has been provided. The focus of this review is to summarize recent insights into how antibody glycosylation
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Immunoglobulin G Glycosylation in Diseases |
Marija Pezer |
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Abstract
Changes in immunoglobulin G (IgG) glycosylation pattern have been observed in a vast array of auto- and alloimmune, infectious, cardiometabolic, malignant, and other diseases. This chapter contains an updated catalog of over 140 studies within which IgG glycosylation analysis was performed in a disease setting. Since the composition of IgG glycans is known to modulate its effector functions, it is suggested that a changed IgG glycosylation pattern in patients might be involved in disease development and progression, representing a predisposition and/or a functional effector in disease pathology. In contrast to the glycopattern of bulk serum IgG, which likely relates to the systemic inflammatory background, the glycosylation profile of antigen-specific IgG probably plays a direct role in disease pathology in several infectious and allo- and autoimmune antibody-dependent diseases. Depending on the specifics of any given disease, IgG glycosylation read-out might therefore in the future be developed into a useful clinical biomarker or a supplementary to currently used biomarkers.
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Immunoglobulin A Glycosylation and Its Role in Disease |
Alyssa L. Hansen,Colin Reily,Jan Novak,Matthew B. Renfrow |
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Abstract
Human IgA is comprised of two subclasses, IgA1 and IgA2. Monomeric IgA (mIgA), polymeric IgA (pIgA), and secretory IgA (SIgA) are the main molecular forms of IgA. The production of IgA rivals all other immunoglobulin isotypes. The large quantities of IgA reflect the fundamental roles it plays in immune defense, protecting vulnerable mucosal surfaces against invading pathogens. SIgA dominates mucosal surfaces, whereas IgA in circulation is predominately monomeric. All forms of IgA are glycosylated, and the glycans significantly influence its various roles, including antigen binding and the antibody effector functions, mediated by the Fab and Fc portions, respectively. In contrast to its protective role, the aberrant glycosylation of IgA1 has been implicated in the pathogenesis of autoimmune diseases, such as IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). Furthermore, detailed characterization of IgA glycosylation, including its diverse range of heterogeneity, is of emerging interest. We provide an overview of the glycosylation observed for each subclass and molecular form of IgA as well as the range of heterogeneity for each site of glycosylation. In many ways, th
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Importance and Monitoring of Therapeutic Immunoglobulin G Glycosylation |
Yusuke Mimura,Radka Saldova,Yuka Mimura-Kimura,Pauline M. Rudd,Roy Jefferis |
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Abstract
The complex diantennary-type oligosaccharides at Asn297 residues of the IgG heavy chains have a profound impact on the safety and efficacy of therapeutic IgG monoclonal antibodies (mAbs). Fc glycosylation of a mAb is an established critical quality attribute (CQA), and its oligosaccharide profile is required to be thoroughly characterized by state-of-the-art analytical methods. The Fc oligosaccharides are highly heterogeneous, and the differentially glycosylated species (glycoforms) of IgG express unique biological activities. Glycoengineering is a promising approach for the production of selected mAb glycoforms with improved effector functions, and non- and low-fucosylated mAbs exhibiting enhanced antibody-dependent cellular cytotoxicity activity have been approved or are under clinical evaluation for treatment of cancers, autoimmune/chronic inflammatory diseases, and infection. Recently, the chemoenzymatic glycoengineering method that allows for the transfer of structurally defined oligosaccharides to Asn-linked GlcNAc residues with glycosynthase has been developed for remodeling of IgG-Fc oligosaccharides with high efficiency and flexibility. Additionally, various glycoengineeri
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