Antibodies

12 pages, 717 KiB

Open AccessOpinion

The Roles of Autoimmunity and Biotoxicosis in Sick Building Syndrome as a “Starting Point” for Irreversible Dampness and Mold Hypersensitivity Syndrome

by Tamara Tuuminen

Antibodies 2020, 9(2), 26; https://doi.org/10.3390/antib9020026 - 22 Jun 2020

Cited by 9 | Viewed by 8630

Abstract

Background: The terminology of “sick building syndrome” (SBS), meaning that a person may feel sick in a certain building, but when leaving the building, the symptoms will reverse, is imprecise. Many different environmental hazards may cause the feeling of sickness, such as [...] Read more.

Background: The terminology of “sick building syndrome” (SBS), meaning that a person may feel sick in a certain building, but when leaving the building, the symptoms will reverse, is imprecise. Many different environmental hazards may cause the feeling of sickness, such as high indoor air velocity, elevated noise, low or high humidity, vapors or dust. The Aim: To describe SBS in connection with exposure to indoor air dampness microbiota (DM). Methods: A search through Medline/Pubmed. Results and Conclusions: Chronic course of SBS may be avoided. By contrast, persistent or cumulative exposure to DM may make SBS potentially life-threatening and lead to irreversible dampness and mold hypersensitivity syndrome (DMHS). The corner feature of DMHS is acquired by dysregulation of the immune system in the direction of hypersensitivities (types I–IV) and simultaneous deprivation of immunity that manifests as increased susceptibility to infections. DMHS is a systemic low-grade inflammation and a biotoxicosis. There is already some evidence that DMHS may be linked to autoimmunity. Autoantibodies towards, e.g., myelin basic protein, myelin-associated glycoprotein, ganglioside GM1, smooth muscle cells and antinuclear autoantibodies were reported in mold-related illness. DMHS is also a mitochondropathy and endocrinopathy. The association of autoimmunity with DMHS should be confirmed through cohort studies preferably using chip-based technology. Full article

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22 pages, 1363 KiB

Open AccessReview

Human Natural Antibodies to Mammalian Carbohydrate Antigens as Unsung Heroes Protecting against Past, Present, and Future Viral Infections

by Uri Galili

Antibodies 2020, 9(2), 25; https://doi.org/10.3390/antib9020025 - 22 Jun 2020

Cited by 30 | Viewed by 6629

Abstract

Human natural antibodies to mammalian carbohydrate antigens (MCA) bind to carbohydrate-antigens synthesized in other mammalian species and protect against zoonotic virus infections. Three such anti-MCA antibodies are: (1) anti-Gal, also produced in Old-World monkeys and apes, binds to α-gal epitopes synthesized in [...] Read more.

Human natural antibodies to mammalian carbohydrate antigens (MCA) bind to carbohydrate-antigens synthesized in other mammalian species and protect against zoonotic virus infections. Three such anti-MCA antibodies are: (1) anti-Gal, also produced in Old-World monkeys and apes, binds to α-gal epitopes synthesized in non-primate mammals, lemurs, and New-World monkeys; (2) anti-Neu5Gc binds to Neu5Gc (N-glycolyl-neuraminic acid) synthesized in apes, Old-World monkeys, and many non-primate mammals; and (3) anti-Forssman binds to Forssman-antigen synthesized in various mammals. Anti-viral protection by anti-MCA antibodies is feasible because carbohydrate chains of virus envelopes are synthesized by host glycosylation machinery and thus are similar to those of their mammalian hosts. Analysis of MCA glycosyltransferase genes suggests that anti-Gal appeared in ancestral Old-World primates following catastrophic selection processes in which parental populations synthesizing α-gal epitopes were eliminated in enveloped virus epidemics. However, few mutated offspring in which the α1,3galactosyltransferase gene was accidentally inactivated produced natural anti-Gal that destroyed viruses presenting α-gal epitopes, thereby preventing extinction of mutated offspring. Similarly, few mutated hominin offspring that ceased to synthesize Neu5Gc produced anti-Neu5Gc, which destroyed viruses presenting Neu5Gc synthesized in parental hominin populations. A present-day example for few humans having mutations that prevent synthesis of a common carbohydrate antigen (produced in >99.99% of humans) is blood-group Bombay individuals with mutations inactivating H-transferase; thus, they cannot synthesize blood-group O (H-antigen) but produce anti-H antibody. Anti-MCA antibodies prevented past extinctions mediated by enveloped virus epidemics, presently protect against zoonotic-viruses, and may protect in future epidemics. Travelers to regions with endemic zoonotic viruses may benefit from vaccinations elevating protective anti-MCA antibody titers. Full article

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12 pages, 553 KiB

Open AccessReview

Considerations for Optimizing Dosing of Immunoglobulins Based on Pharmacokinetic Evidence

by Iftekhar Mahmood, Million A. Tegenge and Basil Golding

Antibodies 2020, 9(2), 24; https://doi.org/10.3390/antib9020024 - 19 Jun 2020

Cited by 24 | Viewed by 5907

Abstract

Immunoglobulins (IGs) are widely used for the treatment of immunodeficiency syndromes and several autoimmune diseases. In neonates, IGs have been used for the treatment of alloimmune thrombocytopenia, in neonatal infections and in the rare cases of neonatal Kawasaki disease. This review aims to [...] Read more.

Immunoglobulins (IGs) are widely used for the treatment of immunodeficiency syndromes and several autoimmune diseases. In neonates, IGs have been used for the treatment of alloimmune thrombocytopenia, in neonatal infections and in the rare cases of neonatal Kawasaki disease. This review aims to examine the various dosing regimens of IGs following intravenous (IV) and subcutaneous (SC) administration, pharmacokinetics (PK) of IGs, and the importance of trough values for the prevention of infections in patients with primary immune deficiency (PID). The review also focuses on the mechanism of catabolism of IGs and the impact on the half-life of IGs. Data and reviews were obtained from the literature and the FDA package inserts. The authors suggest that for dosing, the PK of IGs should be evaluated on the baseline-corrected concentrations since this approach provides an accurate estimate of half-life and clearance of IGs. We also suggest employing clearance as a primary PK parameter for dosing determination of IGs. We suggest that IV dosing would be more effective if given more frequently to adjust for the increased clearance at high doses and because the baseline-corrected half-life is much shorter than the baseline-uncorrected half-life. Regarding SC administration, the dose should be adjusted based on the absolute bioavailability (determined against IV dosing) of the product. Finally, we highlight clinical and PK data gaps for optimum and individualized dosing of IGs. Full article

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15 pages, 786 KiB

Open AccessReview

Targeting Dendritic Cells with Antigen-Delivering Antibodies for Amelioration of Autoimmunity in Animal Models of Multiple Sclerosis and Other Autoimmune Diseases

by Courtney A. Iberg and Daniel Hawiger

Antibodies 2020, 9(2), 23; https://doi.org/10.3390/antib9020023 - 15 Jun 2020

Cited by 10 | Viewed by 5607

Abstract

The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as [...] Read more.

The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as in some other animal disease models. As the specific mechanisms of such induced tolerance are being investigated, the newly gained insights may also possibly help to design effective treatments for patients. Here we review approaches applied for the amelioration of autoimmunity in animal models based on antibody-mediated targeting of self-antigens to DCs. Further, we discuss relevant mechanisms of immunological tolerance that underlie such approaches, and we also offer some future perspectives for the application of similar methods in certain related disease settings such as transplantation. Full article

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20 pages, 3451 KiB

Open AccessReview

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

by Souad Boune, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli

Antibodies 2020, 9(2), 22; https://doi.org/10.3390/antib9020022 - 10 Jun 2020

Cited by 75 | Viewed by 22099

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)

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13 pages, 1647 KiB

Open AccessReview

Construction of Antibody Phage Libraries and Their Application in Veterinary Immunovirology

by Shahbaz Bashir and Jan Paeshuyse

Antibodies 2020, 9(2), 21; https://doi.org/10.3390/antib9020021 - 3 Jun 2020

Cited by 18 | Viewed by 7416

Abstract

Antibody phage display (APD) technology has revolutionized the field of immunovirology with its application in viral disease diagnostics and antiviral therapy. This robust and versatile technology allows the expression of an antibody fused to a phage coat protein on the surface of a [...] Read more.

Antibody phage display (APD) technology has revolutionized the field of immunovirology with its application in viral disease diagnostics and antiviral therapy. This robust and versatile technology allows the expression of an antibody fused to a phage coat protein on the surface of a filamentous phage. The DNA sequence coding for the antibody is packaged within the phage, linking the phenotype to genotype. Antibody phage display inherits the ability to rapidly generate and modify or improve high-affinity monoclonal antibodies, rendering it indispensable in immunology. In the last two decades, phage-display-derived antibodies have been extensively used in human medicine as diagnostic and therapeutic modalities. Recently, they are also gaining significant ground in veterinary medicine. Even though these advancements are mainly biased towards economically important animals such as chicken, cattle, and pigs, they are laying the foundation of fulfilling the unmet needs of veterinary medicine as antibody-based biologics in viral diagnostics, therapeutics, and immunoprophylaxis. This review provides a brief overview of the construction of antibody phage libraries and their application in diagnosis, prevention, and control of infectious viral diseases in veterinary medicine in detail. Full article

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11 pages, 1655 KiB

Open AccessArticle

Study of Neuraminidase-Inhibiting Antibodies in Clinical Trials of Live Influenza Vaccines

by Yulia Desheva, Tatiana Smolonogina, Svetlana Donina and Larisa Rudenko

Antibodies 2020, 9(2), 20; https://doi.org/10.3390/antib9020020 - 29 May 2020

Cited by 9 | Viewed by 4246

Abstract

Background: Currently, the immunogenicity of influenza vaccines is assessed by detecting an increase of hemagglutination inhibition (HI) antibodies. As neuraminidase (NA)-based immunity may be significant in protecting against influenza infection, detection of neuraminidase inhibiting (NI) antibodies may improve the assessment of the immunogenicity [...] Read more.

Background: Currently, the immunogenicity of influenza vaccines is assessed by detecting an increase of hemagglutination inhibition (HI) antibodies. As neuraminidase (NA)-based immunity may be significant in protecting against influenza infection, detection of neuraminidase inhibiting (NI) antibodies may improve the assessment of the immunogenicity of influenza vaccines. Methods: We investigated the immune response to NA in people after immunization with live influenza vaccines (LAIVs). A number of A/H7NX or A/H6NX viruses were used to detect NI antibodies, using an enzyme-linked lectin assay (ELLA). Results: Seasonal LAIV immunization stimulated an increase in NI antibodies not only to homologous A/H1N1 influenza, but also to A/H1N1pdm09 and A/H5N1 influenza. After A/17/California/09/38 (H1N1) pdm09 LAIV vaccination, there was no statistical relationship between post-vaccinated antibody seroconversion and two surface glycoproteins in serum samples obtained from the same individuals (p = 0.24). Vaccination with LAIV of H5N2, H2N2, H7N3, and H7N9 subtypes led to 7%–29.6% NI antibody seroconversions in the absence of HI antibody conversions. There was relatively low coordination of hemagglutinin (HA) and NA antibody responses (r = 0.24–0.59). Conclusions: The previously noted autonomy for HI and NI immune responses was confirmed when assessing the immunogenicity of LAIVs. Combining the traditional HI test with the detection of NI antibodies can provide a more complete assessment of LAIV immunogenicity. Full article

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15 pages, 849 KiB

Open AccessFeature PaperReview

Anti-Idiotypic Agonistic Antibodies: Candidates for the Role of Universal Remedy

by Aliya K. Stanova, Varvara A. Ryabkova, Sergei V. Tillib, Vladimir J. Utekhin, Leonid P. Churilov and Yehuda Shoenfeld

Antibodies 2020, 9(2), 19; https://doi.org/10.3390/antib9020019 - 28 May 2020

Cited by 19 | Viewed by 8102

Abstract

Anti-idiotypic antibodies (anti-IDs) were discovered at the very beginning of the 20th century and have attracted attention of researchers for many years. Nowadays, there are five known types of anti-IDs: α, β, γ, ε, and δ. Due to the ability of internal-image anti-IDs [...] Read more.

Anti-idiotypic antibodies (anti-IDs) were discovered at the very beginning of the 20th century and have attracted attention of researchers for many years. Nowadays, there are five known types of anti-IDs: α, β, γ, ε, and δ. Due to the ability of internal-image anti-IDs to compete with an antigen for binding to antibody and to alter the biologic activity of an antigen, anti-IDs have become a target in the search for new treatments of autoimmune illnesses, cancer, and some other diseases. In this review, we summarize the data about anti-IDs that mimic the structural and functional properties of some bioregulators (autacoids, neurotransmitters, hormones, xenobiotics, and drugs) and evaluate their possible medical applications. The immune system is potentially able to reproduce or at least alter the effects of any biologically active endogenous or exogenous immunogenic agent via the anti-idiotypic principle, and probably regulates a broad spectrum of cell functions in the body, being a kind of universal remedy or immunacea, by analogy to the legendary ancient goddess of universal healing Panacea (Πανάκεια, Panakeia in Greek) in the treatment and prevention of diseases, possibly including non-infectious somatic and even hereditary ones. Full article

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12 pages, 4455 KiB

Open AccessArticle

Glomerular Diseases Associated with Malignancies: Histopathological Pattern and Association with Circulating Autoantibodies

by Sophia Lionaki, Smaragdi Marinaki, Konstantinos Panagiotellis, Ioanna Tsoumbou, George Liapis, Ioanna Vlahadami, Athanasios Tzioufas, Petros Sfikakis and Ioannis Boletis

Antibodies 2020, 9(2), 18; https://doi.org/10.3390/antib9020018 - 25 May 2020

Cited by 7 | Viewed by 4361

Abstract

Aim: Glomerular diseases (GD) associated with malignancies (AM, GDAM) have unique features, which are important to recognize, in the light of the progress made in cancer therapy. We aimed to describe the clinical and histopathological characteristics of patients with GDAM in relation to [...] Read more.

Aim: Glomerular diseases (GD) associated with malignancies (AM, GDAM) have unique features, which are important to recognize, in the light of the progress made in cancer therapy. We aimed to describe the clinical and histopathological characteristics of patients with GDAM in relation to the presence of circulating autoantibodies, pointing to potential immune pathogenic pathways connecting cancer to GD. Materials and Methods: The included patients were studied retrospectively on the basis of a kidney biopsy proving GD and a related biopsy to establish the diagnosis of AM. We recorded patients’ demographics, serological and laboratory parameters, histopathological findings, and the type of malignancy, GD, and therapy. Results: In total, 41 patients with GDAM, with a mean age of 63.1 (±10.7) years, were studied. In 28 (68.3%) cases, GD was associated with a solid tumor, and in 13 (31.7%) patients with a lymphoid malignancy. The most frequent histopathological pattern was membranous nephropathy (43.9%). Overall, at the time of GD diagnosis, 17% of the patients were positive for antinuclear antibodies (ANA), and 12.2% for antineutrophil cytoplasmic autoantibodies (ANCA), all against myeloperoxidase (MPO). In addition, 93.3% of the patients who had membranous nephropathy were negative for transmembrane glycoprotein M-type phospholipase A₂ receptor (PLA₂R) antibody. Sixteen patients (39.0%) presented with acute nephritic syndrome, of whom five (31.25%) developed rapidly progressive glomerulonephritis. In a mean follow-up time of 36.1 (±28.3) months, nine (21.95%) patients ended up with end-stage kidney disease, and eight (19.5%) died. Conclusion: We found that 3.2% of patients who underwent a native kidney biopsy in our institution during the past decade, for any reason, were identified as having some type of GD associated with a malignancy. Serology indicated a significant presence of ANA or MPO-ANCA antibodies in patients with nephritic syndrome and the absence of PLA₂R antibodies in patients with membranous nephropathy. Full article

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34 pages, 2569 KiB

Open AccessFeature PaperReview

Combined Anti-Cancer Strategies Based on Anti-Checkpoint Inhibitor Antibodies

by Josée Golay and Alain E. Andrea

Antibodies 2020, 9(2), 17; https://doi.org/10.3390/antib9020017 - 20 May 2020

Cited by 20 | Viewed by 7332

Abstract

Therapeutic monoclonal antibodies for the treatment of cancer came of age in 1997, with the approval of anti-CD20 Rituximab. Since then, a wide variety of antibodies have been developed with many different formats and mechanisms of action. Among these, antibodies blocking immune checkpoint [...] Read more.

Therapeutic monoclonal antibodies for the treatment of cancer came of age in 1997, with the approval of anti-CD20 Rituximab. Since then, a wide variety of antibodies have been developed with many different formats and mechanisms of action. Among these, antibodies blocking immune checkpoint inhibitors (ICI) have revolutionized the field, based on the novelty of their concept and their demonstrated efficacy in several types of cancer otherwise lacking effective immunotherapy approaches. ICI are expressed by tumor, stromal or immune cells infiltrating the tumor microenvironment, and negatively regulate anti-tumor immunity. Antibodies against the first discovered ICI, CTLA-4, PD-1 and PD-L1, have shown significant activity in phase III studies against melanoma and other solid cancers, alone or in combination with chemotherapy or radiotherapy. However, not all cancers and not all patients respond to these drugs. Therefore, novel antibodies targeting additional ICI are currently being developed. In addition, CTLA-4, PD-1 and PD-L1 blocking antibodies are being combined with each other or with other antibodies targeting novel ICI, immunostimulatory molecules, tumor antigens, angiogenic factors, complement receptors, or with T cell engaging bispecific antibodies (BsAb), with the aim of obtaining synergistic effects with minimal toxicity. In this review, we summarize the biological aspects behind such combinations and review some of the most important clinical data on ICI-specific antibodies. Full article

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11 pages, 2846 KiB

Open AccessArticle

A Purification Strategy Utilizing Hydrophobic Interaction Chromatography to Obtain Homogeneous Species from a Site-Specific Antibody Drug Conjugate Produced by AJICAP™ First Generation

by Yutaka Matsuda, Monica Leung, Tatsuya Okuzumi and Brian Mendelsohn

Antibodies 2020, 9(2), 16; https://doi.org/10.3390/antib9020016 - 18 May 2020

Cited by 30 | Viewed by 9731

Abstract

In recent years, site-specific antibody drug conjugates (ADC)s have been in great demand because they have an expanded therapeutic index compared with conventional ADCs. AJICAP™ technology is a chemical conjugation platform to obtain site-specific ADCs through the use of a class of Fc-affinity [...] Read more.

In recent years, site-specific antibody drug conjugates (ADC)s have been in great demand because they have an expanded therapeutic index compared with conventional ADCs. AJICAP™ technology is a chemical conjugation platform to obtain site-specific ADCs through the use of a class of Fc-affinity compounds. Promising results from early technology development studies led to further investigation of AJICAP™ ADC materials to obtain site-specific and homogeneous drug antibody ratio (DAR) ADCs. Here we report site-specific conjugation followed by a preparative hydrophobic interaction chromatography (HIC) purification strategy to obtain purified “DAR = 1.0” and “DAR = 2.0” AJICAP™ ADC materials. Optimization of the mobile phase conditions and resin achieved a high recovery rate. In vitro biological assay demonstrated the target selective activity for purified homogeneous DAR ADCs. These results indicate the ability of a HIC purification strategy to provide “DAR = 1.0” and “DAR = 2.0” AJICAP™ ADCs with considerable potency and target selectivity. Full article

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3 pages, 145 KiB

Open AccessEditorial

Antibodies as Diagnostic Targets and as Reagents for Diagnostics

by Nicole H. Trier and Gunnar Houen

Antibodies 2020, 9(2), 15; https://doi.org/10.3390/antib9020015 - 18 May 2020

Cited by 6 | Viewed by 4443

Abstract

Antibodies (Abs) were discovered around the turn of the 19th century and characterized in the following decades as an essential part of the human adaptive immune system [...] Full article

(This article belongs to the Special Issue Antibody-Based Diagnostics)

15 pages, 15088 KiB

Open AccessArticle

Generation of Monoclonal Antibodies Specific for Native LL37 and Citrullinated LL37 That Discriminate the Two LL37 Forms in the Skin and Circulation of Cutaneous/Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients

by Roberto Lande, Raffaella Palazzo, Philippe Hammel, Immacolata Pietraforte, Isabelle Surbeck, Michel Gilliet, Carlo Chizzolini and Loredana Frasca

Antibodies 2020, 9(2), 14; https://doi.org/10.3390/antib9020014 - 11 May 2020

Cited by 9 | Viewed by 5267

Abstract

Human cathelicidin LL37 is a cationic antimicrobial peptide active against bacteria and viruses and exerting immune modulatory functions. LL37 can be also a target of autoreactive B- and T-lymphocytes in autoimmune settings. Irreversible post-translational modifications, such as citrullination and carbamylation, mainly occurring at [...] Read more.

Human cathelicidin LL37 is a cationic antimicrobial peptide active against bacteria and viruses and exerting immune modulatory functions. LL37 can be also a target of autoreactive B- and T-lymphocytes in autoimmune settings. Irreversible post-translational modifications, such as citrullination and carbamylation, mainly occurring at the level of cationic amino acids arginine and lysine, can affect the inflammatory properties and reduce antibacterial effects. Moreover, these modifications could be implicated in the rupture of immune tolerance to LL37 in chronic conditions such as psoriatic disease and cutaneous lupus (LE)/systemic lupus erythematosus (SLE). Here, we describe the generation and fine specificity of six recombinant antibodies (MRB137–MRB142), produced as a monovalent mouse antibody with the antigen-binding scFv portion fused to a mouse IgG2a Fc, and their ability to recognize either native or citrullinated LL37 (cit-LL37) and not cross-react to carbamylated LL37. By using these antibodies, we detected native LL37 or cit-LL37 in SLE and rheumatoid arthritis (RA) sera, and in LE skin, by ELISA and immunohistochemistry, respectively. Such antibodies represent previously unavailable and useful tools to address relationships between the presence of post-translational modified LL37 and the immune system status (in terms of innate/adaptive responses activation) and the clinical characteristics of patients affected by chronic immune-mediated diseases or infectious diseases. Full article

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17 pages, 1942 KiB

Open AccessConcept Paper

Network Organization of Antibody Interactions in Sequence and Structure Space: the RADARS Model

by József Prechl

Antibodies 2020, 9(2), 13; https://doi.org/10.3390/antib9020013 - 6 May 2020

Cited by 6 | Viewed by 5231

Abstract

Adaptive immunity in vertebrates is a complex self-organizing network of molecular interactions. While deep sequencing of the immune-receptor repertoire may reveal clonal relationships, functional interpretation of such data is hampered by the inherent limitations of converting sequence to structure to function. In this [...] Read more.

Adaptive immunity in vertebrates is a complex self-organizing network of molecular interactions. While deep sequencing of the immune-receptor repertoire may reveal clonal relationships, functional interpretation of such data is hampered by the inherent limitations of converting sequence to structure to function. In this paper, a novel model of antibody interaction space and network, termed radial adjustment of system resolution, RAdial ADjustment of System Resolution (RADARS), is proposed. The model is based on the radial growth of interaction affinity of antibodies towards an infinity of directions in structure space, each direction corresponding to particular shapes of antigen epitopes. Levels of interaction affinity appear as free energy shells of the system, where hierarchical B-cell development and differentiation takes place. Equilibrium in this immunological thermodynamic system can be described by a power law distribution of antibody-free energies with an ideal network degree exponent of phi square, representing a scale-free fractal network of antibody interactions. Plasma cells are network hubs, memory B cells are nodes with intermediate degrees, and B1 cells function as nodes with minimal degree. Overall, the RADARS model implies that a finite number of antibody structures can interact with an infinite number of antigens by immunologically controlled adjustment of interaction energy distribution. Understanding quantitative network properties of the system should help the organization of sequence-derived predicted structural data. Full article

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22 pages, 1400 KiB

Open AccessReview

A Review of Deep Learning Methods for Antibodies

by Jordan Graves, Jacob Byerly, Eduardo Priego, Naren Makkapati, S. Vince Parish, Brenda Medellin and Monica Berrondo

Antibodies 2020, 9(2), 12; https://doi.org/10.3390/antib9020012 - 28 Apr 2020

Cited by 47 | Viewed by 16584

Abstract

Driven by its successes across domains such as computer vision and natural language processing, deep learning has recently entered the field of biology by aiding in cellular image classification, finding genomic connections, and advancing drug discovery. In drug discovery and protein engineering, a [...] Read more.

Driven by its successes across domains such as computer vision and natural language processing, deep learning has recently entered the field of biology by aiding in cellular image classification, finding genomic connections, and advancing drug discovery. In drug discovery and protein engineering, a major goal is to design a molecule that will perform a useful function as a therapeutic drug. Typically, the focus has been on small molecules, but new approaches have been developed to apply these same principles of deep learning to biologics, such as antibodies. Here we give a brief background of deep learning as it applies to antibody drug development, and an in-depth explanation of several deep learning algorithms that have been proposed to solve aspects of both protein design in general, and antibody design in particular. Full article

(This article belongs to the Collection Computational Antibody and Antigen Design)

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9 pages, 2170 KiB

Open AccessArticle

Mapping Immunodominant Antibody Epitopes of Abrin

by Ron Alcalay, Reut Falach, Yoav Gal, Anita Sapoznikov, Tamar Sabo, Chanoch Kronman and Ohad Mazor

Antibodies 2020, 9(2), 11; https://doi.org/10.3390/antib9020011 - 27 Apr 2020

Cited by 4 | Viewed by 4321

Abstract

Abrin, a toxin isolated from the seeds of Abrus precatorius (jequirity pea) is considered a biological threat agent by the Center for Disease Control and Prevention. To date, there is no effective postexposure treatment for abrin poisoning, and efforts are being made to [...] Read more.

Abrin, a toxin isolated from the seeds of Abrus precatorius (jequirity pea) is considered a biological threat agent by the Center for Disease Control and Prevention. To date, there is no effective postexposure treatment for abrin poisoning, and efforts are being made to develop an efficient vaccine and measures for postexposure therapy. Epitope mapping is widely applied as an efficient tool for discovering the antigenic moieties of toxins, thus providing invaluable information needed for the development of vaccines and therapies. Aiming to identify the immunodominant epitopes of abrin, several neutralizing antiabrin polyclonal antibodies were screened using a set of 15-mer peptides spanning the amino acid sequence of either the A or B subunits of abrin. Analysis of the antibody-binding pattern revealed 11 linear epitopes for the A subunit and 14 epitopes for the B subunit that are located on the surface of the toxin and thus accessible for antibody interactions. Moreover, the spatial location of several of these epitopes suggests they may block the galactose-binding pockets or the catalytic domain, thus neutralizing the toxin. These findings provide useful information and suggest a possible strategy for the development and design of an improved abrin-based vaccine and therapeutic antibodies. Full article

(This article belongs to the Special Issue Development of Therapeutic Antibodies against Toxins and Pathogens)

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17 pages, 2390 KiB

Open AccessArticle

Ion Binding Properties of a Naturally Occurring Metalloantibody

by Elinaz Farokhi, Jonathan K. Fleming, M. Frank Erasmus, Aaron D. Ward, Yunjin Wu, Maria G. Gutierrez, Jonathan M. Wojciak and Tom Huxford

Antibodies 2020, 9(2), 10; https://doi.org/10.3390/antib9020010 - 16 Apr 2020

Cited by 1 | Viewed by 5446

Abstract

LT1009 is a humanized version of murine LT1002 IgG1 that employs two bridging Ca²⁺ ions to bind its antigen, the biologically active lipid sphingosine-1-phosphate (S1P). We crystallized and determined the X-ray crystal structure of the LT1009 Fab fragment in 10 mM CaCl [...] Read more.

LT1009 is a humanized version of murine LT1002 IgG1 that employs two bridging Ca²⁺ ions to bind its antigen, the biologically active lipid sphingosine-1-phosphate (S1P). We crystallized and determined the X-ray crystal structure of the LT1009 Fab fragment in 10 mM CaCl₂ and found that it binds two Ca²⁺ in a manner similar to its antigen-bound state. Flame atomic absorption spectroscopy (FAAS) confirmed that murine LT1002 also binds Ca²⁺ in solution and inductively-coupled plasma-mass spectrometry (ICP-MS) revealed that, although Ca²⁺ is preferred, LT1002 can bind Mg²⁺ and, to much lesser extent, Ba²⁺. Isothermal titration calorimetry (ITC) indicated that LT1002 binds two Ca²⁺ ions endothermically with a measured dissociation constant (K_D) of 171 μM. Protein and genome sequence analyses suggested that LT1002 is representative of a small class of confirmed and potential metalloantibodies and that Ca²⁺ binding is likely encoded for in germline variable chain genes. To test this hypothesis, we engineered, expressed, and purified a Fab fragment consisting of naïve murine germline-encoded light and heavy chain genes from which LT1002 is derived and observed that it binds Ca²⁺ in solution. We propose that LT1002 is representative of a class of naturally occurring metalloantibodies that are evolutionarily conserved across diverse mammalian genomes. Full article

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17 pages, 3794 KiB

Open AccessArticle

Exploration and Modulation of Antibody Fragment Biophysical Properties by Replacing the Framework Region Sequences

by Thomas Cnudde, Zineb Lakhrif, Justine Bourgoin, Fanny Boursin, Catherine Horiot, Corinne Henriquet, Anne di Tommaso, Matthieu Olivier Juste, Isabella Gizzi Jiacomini, Isabelle Dimier-Poisson, Martine Pugnière, Marie-Nöelle Mévélec and Nicolas Aubrey

Antibodies 2020, 9(2), 9; https://doi.org/10.3390/antib9020009 - 15 Apr 2020

Cited by 3 | Viewed by 4600

Abstract

In order to increase the successful development of recombinant antibodies and fragments, it seems fundamental to enhance their expression and/or biophysical properties, such as the thermal, chemical, and pH stabilities. In this study, we employed a method bases on replacing the antibody framework [...] Read more.

In order to increase the successful development of recombinant antibodies and fragments, it seems fundamental to enhance their expression and/or biophysical properties, such as the thermal, chemical, and pH stabilities. In this study, we employed a method bases on replacing the antibody framework region sequences, in order to promote more particularly single-chain Fragment variable (scFv) product quality. We provide evidence that mutations of the VH- C-C′ loop might significantly improve the prokaryote production of well-folded and functional fragments with a production yield multiplied by 27 times. Additional mutations are accountable for an increase in the thermal (+19.6 °C) and chemical (+1.9 M) stabilities have also been identified. Furthermore, the hereby-produced fragments have shown to remain stable at a pH of 2.0, which avoids molecule functional and structural impairments during the purification process. Lastly, this study provides relevant information to the understanding of the relationship between the antibodies amino acid sequences and their respective biophysical properties. Full article

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17 pages, 4716 KiB

Open AccessArticle

Fast Confirmation of Antibody Identity by MALDI-TOF MS Fingerprints

by Georg Tscheuschner, Timm Schwaar and Michael G. Weller

Antibodies 2020, 9(2), 8; https://doi.org/10.3390/antib9020008 - 26 Mar 2020

Cited by 7 | Viewed by 7363

Abstract

Thousands of antibodies for diagnostic and other analytical purposes are on the market. However, it is often difficult to identify duplicates, reagent changes, and to assign the correct original publications to an antibody. This slows down scientific progress and might even be a [...] Read more.

Thousands of antibodies for diagnostic and other analytical purposes are on the market. However, it is often difficult to identify duplicates, reagent changes, and to assign the correct original publications to an antibody. This slows down scientific progress and might even be a cause of irreproducible research and a waste of resources. Recently, activities were started to suggest the sole use of recombinant antibodies in combination with the open communication of their sequence. In this case, such uncertainties should be eliminated. Unfortunately, this approach seems to be rather a long-term vision since the development and manufacturing of recombinant antibodies remain quite expensive in the foreseeable future. Nearly all commercial antibody suppliers also may be reluctant to publish the sequence of their antibodies, since they fear counterfeiting. De novo sequencing of antibodies is also not feasible today for a reagent user without access to the hybridoma clone. Nevertheless, it seems to be crucial for any scientist to have the opportunity to identify an antibody undoubtedly to guarantee the traceability of any research activity using antibodies from a third party as a tool. For this purpose, we developed a method for the identification of antibodies based on a MALDI-TOF MS fingerprint. To circumvent lengthy denaturation, reduction, alkylation, and enzymatic digestion steps, the fragmentation was performed with a simple formic acid hydrolysis step. Eighty-nine unknown monoclonal antibodies were used for this study to examine the feasibility of this approach. Although the molecular assignment of peaks was rarely possible, antibodies could be easily recognized in a blinded test, simply from their mass-spectral fingerprint. A general protocol is given, which could be used without any optimization to generate fingerprints for a database. We want to propose that, in most scientific projects relying critically on antibody reagents, such a fingerprint should be established to prove and document the identity of the used antibodies, as well as to assign a specific reagent to a datasheet of a commercial supplier, public database record, or antibody ID. Full article

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17 pages, 3535 KiB

Open AccessCommunication

Molecular Interaction Characterization Strategies for the Development of New Biotherapeutic Antibody Modalities

by Xiangdan Wang, Minh Michael Phan, Ji Li, Herman Gill, Simon Williams, Nidhi Gupta, Valerie Quarmby and Jihong Yang

Antibodies 2020, 9(2), 7; https://doi.org/10.3390/antib9020007 - 25 Mar 2020

Cited by 6 | Viewed by 6735

Abstract

The characterization of target binding interactions is critical at each stage of antibody therapeutic development. During early development, it is important to design fit-for-purpose in vitro molecular interaction characterization (MIC) assays that accurately determine the binding kinetics and the affinity of therapeutic antibodies [...] Read more.

The characterization of target binding interactions is critical at each stage of antibody therapeutic development. During early development, it is important to design fit-for-purpose in vitro molecular interaction characterization (MIC) assays that accurately determine the binding kinetics and the affinity of therapeutic antibodies for their targets. Such information enables PK/PD (pharmacokinetics/pharmacodynamics) modeling, estimation of dosing regimens, and assessment of potency. While binding kinetics and affinities seem to be readily obtained, there is little discussion in the literature on how the information should be generated and used in a systematic manner along with other approaches to enable key drug development decisions. The introduction of new antibody modalities poses unique challenges to the development of MIC assays and further increases the need to discuss the impact of developing context-appropriate MIC assays to enable key decision making for these programs. In this paper, we discuss for the first time the challenges encountered when developing MIC assays supporting new antibody modalities. Additionally, through the presentation of several real case studies, we provide strategies to overcome these challenges to enable investigational new drug (IND) filings. Full article

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Antibodies, Volume 9, Issue 2 (June 2020) – 20 articles

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