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Antibodies
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Structure and Function of Antibodies
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Structure and Function of Antibodies

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 287584

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Roy Jefferis

E-Mail Website
Guest Editor
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Interests: antibody structure and function
Prof. Dr. Koichi Kato

E-Mail Website
Guest Editor
Department of Creative Research, Biomolecular Organization Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki 444-8787, Japan
Interests: biomolecular ordering; glycobiophysics; biomolecular NMR spectroscopy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. William R. (Bill) Strohl

E-Mail Website
Guest Editor
BiStro Biotech Consulting, Bridgewater, NJ, USA
Interests: antibodies; Fc engineering; Fc fusion proteins; bispecific antibodies; IgMs

Special Issue Information

Dear Colleagues

This Special Issue aims to review the current knowledge in the field of immunotherapy with a view to providing insight that may inform the next generation of antibody therapeutics. The design and clinical application of monoclonal antibody (mAb) therapeutics requires a comprehensive understanding of the intimate relationship between structure and function. Continued reports of adverse reactions and/or loss of efficacy are evidence of the need for a deeper and more precise understanding of sequelae following immune intervention(s); however, the unique structure of a mAb may inevitably result in elicitation of anti-drug antibodies (ADA), at least in a proportion of patients. Further insights into the mechanisms of action (MoA) in vivo require the elucidation of parameters that determine the “architecture” of the immune complexes formed, e.g., epitope specificity, affinity, isotype, etc. Advances towards the generation of structurally homogeneous mAbs, e.g., glycoforms, may be realised through cell engineering to control/regulate intracellular pathways, e.g., post-translational modifications. Next Generation Sequencing (NGS) reveals individual and population polymorphisms within immune repertoires, e.g., the antibody variable region and cellular receptor genes that may be relevant to patient stratification and the pursuit of personalized medicine. The armamentarium should be extended beyond IgG to include the other antibody isotypes, e.g., IgA, IgM, and IgE.

Prof. Dr. Roy Jefferis
Prof. Dr. William R. (Bill) Strohl
Prof. Dr. Koichi Kato
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibodies is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ig genes
  • Orthogonal physico-chemical techniques
  • IgG 3-D structure
  • Antibody paratopes
  • IgG subclasses
  • Glycoforms
  • Mechanisms of action

Published Papers (13 papers)

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13 pages, 2816 KiB  
Article
Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations
by Saeko Yanaka, Rina Yogo, Rintaro Inoue, Masaaki Sugiyama, Satoru G. Itoh, Hisashi Okumura, Yohei Miyanoiri, Hirokazu Yagi, Tadashi Satoh, Takumi Yamaguchi and Koichi Kato
Antibodies 2019, 8(3), 39; https://doi.org/10.3390/antib8030039 - 01 Jul 2019
Cited by 26 | Viewed by 7658
Abstract
The Fc portion of immunoglobulin G (IgG) is a horseshoe-shaped homodimer, which interacts with various effector proteins, including Fcγ receptors (FcγRs). These interactions are critically dependent on the pair of N-glycans packed between the two CH2 domains. Fucosylation of these N-glycans [...] Read more.
The Fc portion of immunoglobulin G (IgG) is a horseshoe-shaped homodimer, which interacts with various effector proteins, including Fcγ receptors (FcγRs). These interactions are critically dependent on the pair of N-glycans packed between the two CH2 domains. Fucosylation of these N-glycans negatively affects human IgG1-FcγRIIIa interaction. The IgG1-Fc crystal structures mostly exhibit asymmetric quaternary conformations with divergent orientations of CH2 with respect to CH3. We aimed to provide dynamic views of IgG1-Fc by performing long-timescale molecular dynamics (MD) simulations, which were experimentally validated by small-angle X-ray scattering and nuclear magnetic resonance spectroscopy. Our simulation results indicated that the dynamic conformational ensembles of Fc encompass most of the previously reported crystal structures determined in both free and complex forms, although the major Fc conformers in solution exhibited almost symmetric, stouter quaternary structures, unlike the crystal structures. Furthermore, the MD simulations suggested that the N-glycans restrict the motional freedom of CH2 and endow quaternary-structure plasticity through multiple intramolecular interaction networks. Moreover, the fucosylation of these N-glycans restricts the conformational freedom of the proximal tyrosine residue of functional importance, thereby precluding its interaction with FcγRIIIa. The dynamic views of Fc will provide opportunities to control the IgG interactions for developing therapeutic antibodies. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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18 pages, 4772 KiB  
Article
IgG Charge: Practical and Biological Implications
by Danlin Yang, Rachel Kroe-Barrett, Sanjaya Singh and Thomas Laue
Antibodies 2019, 8(1), 24; https://doi.org/10.3390/antib8010024 - 14 Mar 2019
Cited by 55 | Viewed by 14223
Abstract
Practically, IgG charge can contribute significantly to thermodynamic nonideality, and hence to solubility and viscosity. Biologically, IgG charge isomers exhibit differences in clearance and potency. It has been known since the 1930s that all immunoglobulins carry a weak negative charge in physiological solvents. [...] Read more.
Practically, IgG charge can contribute significantly to thermodynamic nonideality, and hence to solubility and viscosity. Biologically, IgG charge isomers exhibit differences in clearance and potency. It has been known since the 1930s that all immunoglobulins carry a weak negative charge in physiological solvents. However, there has been no systematic exploration of this fundamental property. Accurate charge measurements have been made using membrane confined electrophoresis in two solvents (pH 5.0 and pH 7.4) on a panel of twelve mAb IgGs, as well as their F(ab’)2 and Fc fragments. The following observations were made at pH 5.0: (1) the measured charge differs from the calculated charge by ~40 for the intact IgGs, and by ~20 for the Fcs; (2) the intact IgG charge depends on both Fv and Fc sequences, but does not equal the sum of the F(ab)’2 and Fc charge; (3) the Fc charge is consistent within a class. In phosphate buffered saline, pH 7.4: (1) the intact IgG charges ranged from 0 to −13; (2) the F(ab’)2 fragments are nearly neutral for IgG1s and IgG2s, and about −5 for some of the IgG4s; (3) all Fc fragments are weakly anionic, with IgG1 < IgG2 < IgG4; (4) the charge on the intact IgGs does not equal the sum of the F(ab’)2 and Fc charge. In no case is the calculated charge, based solely on H+ binding, remotely close to the measured charge. Some mAbs carried a charge in physiological salt that was outside the range observed for serum-purified human poly IgG. To best match physiological properties, a therapeutic mAb should have a measured charge that falls within the range observed for serum-derived human IgGs. A thermodynamically rigorous, concentration-dependent protein–protein interaction parameter is introduced. Based on readily measured properties, interaction curves may be generated to aid in the selection of proteins and solvent conditions. Example curves are provided. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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Review

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35 pages, 5945 KiB  
Review
Structure, Function, and Therapeutic Use of IgM Antibodies
by Bruce A. Keyt, Ramesh Baliga, Angus M. Sinclair, Stephen F. Carroll and Marvin S. Peterson
Antibodies 2020, 9(4), 53; https://doi.org/10.3390/antib9040053 - 13 Oct 2020
Cited by 102 | Viewed by 20597
Abstract
Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) [...] Read more.
Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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30 pages, 3191 KiB  
Review
IgA: Structure, Function, and Developability
by Patrícia de Sousa-Pereira and Jenny M. Woof
Antibodies 2019, 8(4), 57; https://doi.org/10.3390/antib8040057 - 05 Dec 2019
Cited by 117 | Viewed by 24202
Abstract
Immunoglobulin A (IgA) plays a key role in defending mucosal surfaces against attack by infectious microorganisms. Such sites present a major site of susceptibility due to their vast surface area and their constant exposure to ingested and inhaled material. The importance of IgA [...] Read more.
Immunoglobulin A (IgA) plays a key role in defending mucosal surfaces against attack by infectious microorganisms. Such sites present a major site of susceptibility due to their vast surface area and their constant exposure to ingested and inhaled material. The importance of IgA to effective immune defence is signalled by the fact that more IgA is produced than all the other immunoglobulin classes combined. Indeed, IgA is not just the most prevalent antibody class at mucosal sites, but is also present at significant concentrations in serum. The unique structural features of the IgA heavy chain allow IgA to polymerise, resulting in mainly dimeric forms, along with some higher polymers, in secretions. Both serum IgA, which is principally monomeric, and secretory forms of IgA are capable of neutralising and removing pathogens through a range of mechanisms, including triggering the IgA Fc receptor known as FcαRI or CD89 on phagocytes. The effectiveness of these elimination processes is highlighted by the fact that various pathogens have evolved mechanisms to thwart such IgA-mediated clearance. As the structure–function relationships governing the varied capabilities of this immunoglobulin class come into increasingly clear focus, and means to circumvent any inherent limitations are developed, IgA-based monoclonal antibodies are set to emerge as new and potent options in the therapeutic arena. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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80 pages, 4399 KiB  
Review
Antibody Structure and Function: The Basis for Engineering Therapeutics
by Mark L. Chiu, Dennis R. Goulet, Alexey Teplyakov and Gary L. Gilliland
Antibodies 2019, 8(4), 55; https://doi.org/10.3390/antib8040055 - 03 Dec 2019
Cited by 255 | Viewed by 69060
Abstract
Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host [...] Read more.
Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. We also review the design and selection of binding arms, and avidity modulation. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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30 pages, 1875 KiB  
Review
Design and Production of Bispecific Antibodies
by Qiong Wang, Yiqun Chen, Jaeyoung Park, Xiao Liu, Yifeng Hu, Tiexin Wang, Kevin McFarland and Michael J. Betenbaugh
Antibodies 2019, 8(3), 43; https://doi.org/10.3390/antib8030043 - 02 Aug 2019
Cited by 145 | Viewed by 31991
Abstract
With the current biotherapeutic market dominated by antibody molecules, bispecific antibodies represent a key component of the next-generation of antibody therapy. Bispecific antibodies can target two different antigens at the same time, such as simultaneously binding tumor cell receptors and recruiting cytotoxic immune [...] Read more.
With the current biotherapeutic market dominated by antibody molecules, bispecific antibodies represent a key component of the next-generation of antibody therapy. Bispecific antibodies can target two different antigens at the same time, such as simultaneously binding tumor cell receptors and recruiting cytotoxic immune cells. Structural diversity has been fast-growing in the bispecific antibody field, creating a plethora of novel bispecific antibody scaffolds, which provide great functional variety. Two common formats of bispecific antibodies on the market are the single-chain variable fragment (scFv)-based (no Fc fragment) antibody and the full-length IgG-like asymmetric antibody. Unlike the conventional monoclonal antibodies, great production challenges with respect to the quantity, quality, and stability of bispecific antibodies have hampered their wider clinical application and acceptance. In this review, we focus on these two major bispecific types and describe recent advances in the design, production, and quality of these molecules, which will enable this important class of biologics to reach their therapeutic potential. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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68 pages, 4837 KiB  
Review
Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells
by William R. Strohl and Michael Naso
Antibodies 2019, 8(3), 41; https://doi.org/10.3390/antib8030041 - 03 Jul 2019
Cited by 85 | Viewed by 23647
Abstract
The concepts for T-cell redirecting bispecific antibodies (TRBAs) and chimeric antigen receptor (CAR)-T cells are both at least 30 years old but both platforms are just now coming into age. Two TRBAs and two CAR-T cell products have been approved by major regulatory [...] Read more.
The concepts for T-cell redirecting bispecific antibodies (TRBAs) and chimeric antigen receptor (CAR)-T cells are both at least 30 years old but both platforms are just now coming into age. Two TRBAs and two CAR-T cell products have been approved by major regulatory agencies within the last ten years for the treatment of hematological cancers and an additional 53 TRBAs and 246 CAR cell constructs are in clinical trials today. Two major groups of TRBAs include small, short-half-life bispecific antibodies that include bispecific T-cell engagers (BiTE®s) which require continuous dosing and larger, mostly IgG-like bispecific antibodies with extended pharmacokinetics that can be dosed infrequently. Most CAR-T cells today are autologous, although significant strides are being made to develop off-the-shelf, allogeneic CAR-based products. CAR-Ts form a cytolytic synapse with target cells that is very different from the classical immune synapse both physically and mechanistically, whereas the TRBA-induced synapse is similar to the classic immune synapse. Both TRBAs and CAR-T cells are highly efficacious in clinical trials but both also present safety concerns, particularly with cytokine release syndrome and neurotoxicity. New formats and dosing paradigms for TRBAs and CAR-T cells are being developed in efforts to maximize efficacy and minimize toxicity, as well as to optimize use with both solid and hematologic tumors, both of which present significant challenges such as target heterogeneity and the immunosuppressive tumor microenvironment. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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18 pages, 1149 KiB  
Review
The Ligands for Human IgG and Their Effector Functions
by Steven W. de Taeye, Theo Rispens and Gestur Vidarsson
Antibodies 2019, 8(2), 30; https://doi.org/10.3390/antib8020030 - 25 Apr 2019
Cited by 104 | Viewed by 20459
Abstract
Activation of the humoral immune system is initiated when antibodies recognize an antigen and trigger effector functions through the interaction with Fc engaging molecules. The most abundant immunoglobulin isotype in serum is Immunoglobulin G (IgG), which is involved in many humoral immune responses, [...] Read more.
Activation of the humoral immune system is initiated when antibodies recognize an antigen and trigger effector functions through the interaction with Fc engaging molecules. The most abundant immunoglobulin isotype in serum is Immunoglobulin G (IgG), which is involved in many humoral immune responses, strongly interacting with effector molecules. The IgG subclass, allotype, and glycosylation pattern, among other factors, determine the interaction strength of the IgG-Fc domain with these Fc engaging molecules, and thereby the potential strength of their effector potential. The molecules responsible for the effector phase include the classical IgG-Fc receptors (FcγR), the neonatal Fc-receptor (FcRn), the Tripartite motif-containing protein 21 (TRIM21), the first component of the classical complement cascade (C1), and possibly, the Fc-receptor-like receptors (FcRL4/5). Here we provide an overview of the interactions of IgG with effector molecules and discuss how natural variation on the antibody and effector molecule side shapes the biological activities of antibodies. The increasing knowledge on the Fc-mediated effector functions of antibodies drives the development of better therapeutic antibodies for cancer immunotherapy or treatment of autoimmune diseases. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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21 pages, 2380 KiB  
Review
IMGT® and 30 Years of Immunoinformatics Insight in Antibody V and C Domain Structure and Function
by Marie-Paule Lefranc and Gérard Lefranc
Antibodies 2019, 8(2), 29; https://doi.org/10.3390/antib8020029 - 11 Apr 2019
Cited by 22 | Viewed by 9512
Abstract
At the 10th Human Genome Mapping (HGM10) Workshop, in New Haven, for the first time, immunoglobulin (IG) or antibody and T cell receptor (TR) variable (V), diversity (D), joining (J), and constant (C) genes were officially recognized as ‘genes’, as were the conventional [...] Read more.
At the 10th Human Genome Mapping (HGM10) Workshop, in New Haven, for the first time, immunoglobulin (IG) or antibody and T cell receptor (TR) variable (V), diversity (D), joining (J), and constant (C) genes were officially recognized as ‘genes’, as were the conventional genes. Under these HGM auspices, IMGT®, the international ImMunoGeneTics information system®, was created in June 1989 at Montpellier (University of Montpellier and CNRS). The creation of IMGT® marked the birth of immunoinformatics, a new science, at the interface between immunogenetics and bioinformatics. The accuracy and the consistency between genes and alleles, sequences, and three-dimensional (3D) structures are based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts: IMGT standardized keywords (IDENTIFICATION), IMGT gene and allele nomenclature (CLASSIFICATION), IMGT standardized labels (DESCRIPTION), IMGT unique numbering and IMGT Collier de Perles (NUMEROTATION). These concepts provide IMGT® immunoinformatics insights for antibody V and C domain structure and function, used for the standardized description in IMGT® web resources, databases and tools, immune repertoires analysis, single cell and/or high-throughput sequencing (HTS, NGS), antibody humanization, and antibody engineering in relation with effector properties. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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31 pages, 5433 KiB  
Review
David vs. Goliath: The Structure, Function, and Clinical Prospects of Antibody Fragments
by Adam Bates and Christine A. Power
Antibodies 2019, 8(2), 28; https://doi.org/10.3390/antib8020028 - 09 Apr 2019
Cited by 132 | Viewed by 19425
Abstract
Since the licensing of the first monoclonal antibody therapy in 1986, monoclonal antibodies have become the largest class of biopharmaceuticals with over 80 antibodies currently approved for a variety of disease indications. The development of smaller, antigen binding antibody fragments, derived from conventional [...] Read more.
Since the licensing of the first monoclonal antibody therapy in 1986, monoclonal antibodies have become the largest class of biopharmaceuticals with over 80 antibodies currently approved for a variety of disease indications. The development of smaller, antigen binding antibody fragments, derived from conventional antibodies or produced recombinantly, has been growing at a fast pace. Antibody fragments can be used on their own or linked to other molecules to generate numerous possibilities for bispecific, multi-specific, multimeric, or multifunctional molecules, and to achieve a variety of biological effects. They offer several advantages over full-length monoclonal antibodies, particularly a lower cost of goods, and because of their small size they can penetrate tissues, access challenging epitopes, and have potentially reduced immunogenicity. In this review, we will discuss the structure, production, and mechanism of action of EMA/FDA-approved fragments and of those in clinical and pre-clinical development. We will also discuss current topics of interest surrounding the potential use of antibody fragments for intracellular targeting and blood–brain barrier (BBB) penetration. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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10 pages, 221 KiB  
Review
Immunogenicity of Innovative and Biosimilar Monoclonal Antibodies
by Erik Doevendans and Huub Schellekens
Antibodies 2019, 8(1), 21; https://doi.org/10.3390/antib8010021 - 05 Mar 2019
Cited by 55 | Viewed by 9918
Abstract
The development of hybridoma technology for producing monoclonal antibodies (mAbs) by Kohler and Milstein (1975) counts as one of the major medical breakthroughs, opening up endless possibilities for research, diagnosis and for treatment of a whole variety of diseases. Therapeutic mAbs were introduced [...] Read more.
The development of hybridoma technology for producing monoclonal antibodies (mAbs) by Kohler and Milstein (1975) counts as one of the major medical breakthroughs, opening up endless possibilities for research, diagnosis and for treatment of a whole variety of diseases. Therapeutic mAbs were introduced three decades ago. The first generation of therapeutic mAbs of murine origin showed high immunogenicity, which limited efficacy and was associated with severe infusion reactions. Subsequently chimeric, humanized, and fully human antibodies were introduced as therapeutics, these mAbs were considerably less immunogenic. Unexpectedly humanized mAbs generally show similar immunogenicity as chimeric antibodies; based on sequence homology chimeric mAbs are sometimes more “human” than humanized mAbs. With the introduction of the regulatory concept of similar biological medicines (biosimilars) a key concern is the similarity in terms of immunogenicity of these biosimilars with their originators. This review focuses briefly on the mechanisms of induction of immunogenicity by biopharmaceuticals, mAbs in particular, in relation to the target of the immune system. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
41 pages, 19173 KiB  
Review
IgE Antibodies: From Structure to Function and Clinical Translation
by Brian J. Sutton, Anna M. Davies, Heather J. Bax and Sophia N. Karagiannis
Antibodies 2019, 8(1), 19; https://doi.org/10.3390/antib8010019 - 22 Feb 2019
Cited by 61 | Viewed by 19937
Abstract
Immunoglobulin E (IgE) antibodies are well known for their role in mediating allergic reactions, and their powerful effector functions activated through binding to Fc receptors FcεRI and FcεRII/CD23. Structural studies of IgE-Fc alone, and when bound to these receptors, surprisingly revealed not only [...] Read more.
Immunoglobulin E (IgE) antibodies are well known for their role in mediating allergic reactions, and their powerful effector functions activated through binding to Fc receptors FcεRI and FcεRII/CD23. Structural studies of IgE-Fc alone, and when bound to these receptors, surprisingly revealed not only an acutely bent Fc conformation, but also subtle allosteric communication between the two distant receptor-binding sites. The ability of IgE-Fc to undergo more extreme conformational changes emerged from structures of complexes with anti-IgE antibodies, including omalizumab, in clinical use for allergic disease; flexibility is clearly critical for IgE function, but may also be exploited by allosteric interference to inhibit IgE activity for therapeutic benefit. In contrast, the power of IgE may be harnessed to target cancer. Efforts to improve the effector functions of therapeutic antibodies for cancer have almost exclusively focussed on IgG1 and IgG4 subclasses, but IgE offers an extremely high affinity for FcεRI receptors on immune effector cells known to infiltrate solid tumours. Furthermore, while tumour-resident inhibitory Fc receptors can modulate the effector functions of IgG antibodies, no inhibitory IgE Fc receptors are known to exist. The development of tumour antigen-specific IgE antibodies may therefore provide an improved immune functional profile and enhanced anti-cancer efficacy. We describe proof-of-concept studies of IgE immunotherapies against solid tumours, including a range of in vitro and in vivo evaluations of efficacy and mechanisms of action, as well as ex vivo and in vivo safety studies. The first anti-cancer IgE antibody, MOv18, the clinical translation of which we discuss herein, has now reached clinical testing, offering great potential to direct this novel therapeutic modality against many other tumour-specific antigens. This review highlights how our understanding of IgE structure and function underpins these exciting clinical developments. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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22 pages, 281 KiB  
Review
Macro- and Micro-Heterogeneity of Natural and Recombinant IgG Antibodies
by Alain Beck and Hongcheng Liu
Antibodies 2019, 8(1), 18; https://doi.org/10.3390/antib8010018 - 19 Feb 2019
Cited by 77 | Viewed by 13662
Abstract
Recombinant monoclonal antibodies (mAbs) intended for therapeutic usage are required to be thoroughly characterized, which has promoted an extensive effort towards the understanding of the structures and heterogeneity of this major class of molecules. Batch consistency and comparability are highly relevant to the [...] Read more.
Recombinant monoclonal antibodies (mAbs) intended for therapeutic usage are required to be thoroughly characterized, which has promoted an extensive effort towards the understanding of the structures and heterogeneity of this major class of molecules. Batch consistency and comparability are highly relevant to the successful pharmaceutical development of mAbs and related products. Small structural modifications that contribute to molecule variants (or proteoforms) differing in size, charge or hydrophobicity have been identified. These modifications may impact (or not) the stability, pharmacokinetics, and efficacy of mAbs. The presence of the same type of modifications as found in endogenous immunoglobulin G (IgG) can substantially lower the safety risks of mAbs. The knowledge of modifications is also critical to the ranking of critical quality attributes (CQAs) of the drug and define the Quality Target Product Profile (QTPP). This review provides a summary of the current understanding of post-translational and physico-chemical modifications identified in recombinant mAbs and endogenous IgGs at physiological conditions. Full article
(This article belongs to the Special Issue Structure and Function of Antibodies)
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