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Antibodies for Toxins: From Detection to Therapeutics

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 45374

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Dr. Stéphanie Simon

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Département Médicaments et Technologies pour la Santé, Université Paris Saclay, CEA, INRAE, SPI, 91191 Gif-sur-Yvette, France
Interests: immunoassays; diagnosis; lateral flow immunoassays; ELISA; biosensors; monoclonal antibodies; immunotherapy; neutralization assays; bacterial toxins; Botulinum neurotoxins; Staphylococcus enterotoxins; Clostridium perfringens enterotoxins; plant toxins; ricin; abrin

Dr. Eric Ezan

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Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la santé, 91191, Gif-sur-Yvette, France
Interests: pharmacology; bioanalysis; health technologies

Special Issue Information

Antibodies are key determinants in the immune response. In addition to their role in the host’s fight against infections and intoxications and thanks to their very high specificity and affinity for their targets, they are a privileged tool for the development of tests and detection methods, and for therapeutic applications. Thanks to their high selectivity, first applications had been in the design of highly sensitive immunoassays such as ELISA, plasmonic resonance assays, lateral-flow immunoassays, immuno-proteomics, and flow cytometry, among others. These methods allow toxin detection and measurements in environmental matrices as well as biological fluids with sensitivities down to the femtomolar range. In the therapeutic field, antibodies have been used as anti-toxins since the 19th century and are still the tools of choice in the fight against intoxication (bacterial toxins, plant toxins, etc.), for prophylactic and therapeutic purposes. Recombinant technologies may allow the new design of monoclonal antibodies to improve their efficacy and/or tolerance.

In this Special Issue “Antibodies for Toxins: From Detection to Therapeutics”, we wish to cover the most up-to-date research and review articles on antibody-based methods for the detection and diagnosis of different toxins in environmental or biological matrices and antibody-based therapies.

Dr. Stéphanie Simon
Dr. Eric Ezan
Guest Editors

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Keywords

antibodies
immunoassays
mass spectrometry
flow cytometry
neutralization

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

4 pages, 245 KiB

Open AccessEditorial

Introduction to the Toxins Special Issue: “Antibodies for Toxins: From Detection to Therapeutics”

by Eric Ezan and Stéphanie Simon

Toxins 2022, 14(5), 363; https://doi.org/10.3390/toxins14050363 - 23 May 2022

Viewed by 1556

Abstract

This Special Issue aims to provide an up-to-date investigation and reviews linked to antibody-based technologies for medical countermeasures and detection/diagnosis tools for toxins [...] Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

Research

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18 pages, 2480 KiB

Open AccessArticle

Antibodies against Anthrax Toxins: A Long Way from Benchlab to the Bedside

by Arnaud Avril, Jean-Nicolas Tournier, Jean-Charles Paucod, Bénédicte Fournes, Philippe Thullier and Thibaut Pelat

Toxins 2022, 14(3), 172; https://doi.org/10.3390/toxins14030172 - 25 Feb 2022

Cited by 8 | Viewed by 6248

Abstract

Anthrax is an acute disease caused by the bacterium Bacillus anthracis, and is a potential biowarfare/bioterrorist agent. Its pulmonary form, caused by inhalation of the spores, is highly lethal and is mainly related to injury caused by the toxins secretion. Antibodies neutralizing the toxins of B. anthracis are regarded as promising therapeutic drugs, and two are already approved by the Federal Drug Administration. We developed a recombinant human-like humanized antibody, 35PA83 6.20, that binds the protective antigen and that neutralized anthrax toxins in-vivo in White New Zealand rabbits infected with the lethal 9602 strain by intranasal route. Considering these promising results, the preclinical and clinical phase one development was funded and a program was started. Unfortunately, after 5 years, the preclinical development was cancelled due to industrial and scientific issues. This shutdown underlined the difficulty particularly, but not only, for an academic laboratory to proceed to clinical development, despite the drug candidate being promising. Here, we review our strategy and some preliminary results, and we discuss the issues that led to the no-go decision of the pre-clinical development of 35PA83 6.20 mAb. Our review provides general information to the laboratories planning a (pre-)clinical development. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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27 pages, 2347 KiB

Open AccessArticle

Differentiation, Quantification and Identification of Abrin and Abrus precatorius Agglutinin

by Sylvia Worbs, Bettina Kampa, Martin Skiba, Eva-Maria Hansbauer, Daniel Stern, Hervé Volland, François Becher, Stéphanie Simon, Martin B. Dorner and Brigitte G. Dorner

Toxins 2021, 13(4), 284; https://doi.org/10.3390/toxins13040284 - 18 Apr 2021

Cited by 13 | Viewed by 4445

Abstract

Abrin, the toxic lectin from the rosary pea plant Abrus precatorius, has gained considerable interest in the recent past due to its potential malevolent use. However, reliable and easy-to-use assays for the detection and discrimination of abrin from related plant proteins such as Abrus precatorius agglutinin or the homologous toxin ricin from Ricinus communis are sparse. To address this gap, a panel of highly specific monoclonal antibodies was generated against abrin and the related Abrus precatorius agglutinin. These antibodies were used to establish two sandwich ELISAs to preferentially detect abrin or A. precatorius agglutinin (limit of detection 22 pg/mL for abrin; 35 pg/mL for A. precatorius agglutinin). Furthermore, an abrin-specific lateral flow assay was developed for rapid on-site detection (limit of detection ~1 ng/mL abrin). Assays were validated for complex food, environmental and clinical matrices illustrating broad applicability in different threat scenarios. Additionally, the antibodies turned out to be suitable for immuno-enrichment strategies in combination with mass spectrometry-based approaches for unambiguous identification. Finally, we were able to demonstrate for the first time how the developed assays can be applied to detect, identify and quantify abrin from a clinical sample derived from an attempted suicide case involving A. precatorius. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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24 pages, 3075 KiB

Open AccessArticle

Innovative and Highly Sensitive Detection of Clostridium perfringens Enterotoxin Based on Receptor Interaction and Monoclonal Antibodies

by Thea Neumann, Maren Krüger, Jasmin Weisemann, Stefan Mahrhold, Daniel Stern, Martin B. Dorner, Cécile Feraudet-Tarisse, Christopher Pöhlmann, Katharina Schulz, Ute Messelhäußer, Dagmar Rimek, Frank Gessler, Thomas Elßner, Stéphanie Simon, Andreas Rummel and Brigitte G. Dorner

Toxins 2021, 13(4), 266; https://doi.org/10.3390/toxins13040266 - 8 Apr 2021

Cited by 6 | Viewed by 3237

Abstract

Clostridium perfringens enterotoxin (CPE) regularly causes food poisoning and antibiotic-associated diarrhea; therefore, reliable toxin detection is crucial. To this aim, we explored stationary and mobile strategies to detect CPE either exclusively by monoclonal antibodies (mAbs) or, alternatively, by toxin-enrichment via the cellular receptor of CPE, claudin-4, and mAb detection. Among the newly generated mAbs, we identified nine CPE-specific mAbs targeting five distinct epitopes, among them mAbs recognizing CPE bound to claudin-4 or neutralizing CPE activity in vitro. In surface plasmon resonance experiments, all mAbs and claudin-4 revealed excellent affinities towards CPE, ranging from 0.05 to 2.3 nM. Integrated into sandwich enzyme-linked immunosorbent assays (ELISAs), the most sensitive mAb/mAb and claudin-4/mAb combinations achieved similar detection limits of 0.3 pg/mL and 1.0 pg/mL, respectively, specifically detecting recombinant CPE from spiked feces and native CPE from 30 different C. perfringens culture supernatants. The implementation of mAb- and receptor-based ELISAs into a mobile detection platform enabled the fast detection of CPE, which will be helpful in clinical laboratories to diagnose diarrhea of assumed bacterial origin. In conclusion, we successfully employed an endogenous receptor and novel high affinity mAbs for highly sensitive and specific CPE-detection. These tools will be useful for both basic and applied research. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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30 pages, 5427 KiB

Open AccessArticle

Highly Sensitive and Specific Detection of Staphylococcal Enterotoxins SEA, SEG, SEH, and SEI by Immunoassay

by Cécile Féraudet Tarisse, Céline Goulard-Huet, Yacine Nia, Karine Devilliers, Dominique Marcé, Chloé Dambrune, Donatien Lefebvre, Jacques-Antoine Hennekinne and Stéphanie Simon

Toxins 2021, 13(2), 130; https://doi.org/10.3390/toxins13020130 - 9 Feb 2021

Cited by 16 | Viewed by 4026

Abstract

Staphylococcal food poisoning (SFP) is one of the most common foodborne diseases worldwide, resulting from the ingestion of staphylococcal enterotoxins (SEs), primarily SE type A (SEA), which is produced in food by enterotoxigenic strains of staphylococci, mainly S. aureus. Since newly identified SEs have been shown to have emetic properties and the genes encoding them have been found in food involved in poisoning outbreaks, it is necessary to have reliable tools to prove the presence of the toxins themselves, to clarify the role played by these non-classical SEs, and to precisely document SFP outbreaks. We have produced and characterized monoclonal antibodies directed specifically against SE type G, H or I (SEG, SEH or SEI respectively) or SEA. With these antibodies, we have developed, for each of these four targets, highly sensitive, specific, and reliable 3-h sandwich enzyme immunoassays that we evaluated for their suitability for SE detection in different matrices (bacterial cultures of S. aureus, contaminated food, human samples) for different purposes (strain characterization, food safety, biological threat detection, diagnosis). We also initiated and described for the first time the development of monoplex and quintuplex (SEA, SE type B (SEB), SEG, SEH, and SEI) lateral flow immunoassays for these new staphylococcal enterotoxins. The detection limits in buffer were under 10 pg/mL (0.4 pM) by enzyme immunoassays and at least 300 pg/mL (11 pM) by immunochromatography for all target toxins with no cross-reactivity observed. Spiking studies and/or bacterial supernatant analysis demonstrated the applicability of the developed methods, which could become reliable detection tools for the routine investigation of SEG, SEH, and SEI. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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17 pages, 16034 KiB

Open AccessArticle

Ricin Antibodies’ Neutralizing Capacity against Different Ricin Isoforms and Cultivars

by Maria Lucia Orsini Delgado, Arnaud Avril, Julie Prigent, Julie Dano, Audrey Rouaix, Sylvia Worbs, Brigitte G. Dorner, Clémence Rougeaux, François Becher, François Fenaille, Sandrine Livet, Hervé Volland, Jean-Nicolas Tournier and Stéphanie Simon

Toxins 2021, 13(2), 100; https://doi.org/10.3390/toxins13020100 - 29 Jan 2021

Cited by 15 | Viewed by 3987

Abstract

Ricin, a highly toxic protein from Ricinus communis, is considered a potential biowarfare agent. Despite the many data available, no specific treatment has yet been approved. Due to their ability to provide immediate protection, antibodies (Abs) are an approach of choice. However, their high specificity might compromise their capacity to protect against the different ricin isoforms (D and E) found in the different cultivars. In previous work, we have shown the neutralizing potential of different Abs (43RCA-G1 (anti ricin A-chain) and RB34 and RB37 (anti ricin B-chain)) against ricin D. In this study, we evaluated their protective capacity against both ricin isoforms. We show that: (i) RB34 and RB37 recognize exclusively ricin D, whereas 43RCA-G1 recognizes both isoforms, (ii) their neutralizing capacity in vitro varies depending on the cultivar, and (iii) there is a synergistic effect when combining RB34 and 43RCA-G1. This effect is also demonstrated in vivo in a mouse model of intranasal intoxication with ricin D/E (1:1), where approximately 60% and 40% of mice treated 0 and 6 h after intoxication, respectively, are protected. Our results highlight the importance of evaluating the effectiveness of the Abs against different ricin isoforms to identify the treatment with the broadest spectrum neutralizing effect. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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9 pages, 1846 KiB

Open AccessCommunication

Development and Evaluation of an Immuno-MALDI-TOF Mass Spectrometry Approach for Quantification of the Abrin Toxin in Complex Food Matrices

by Sandrine Livet, Sylvia Worbs, Hervé Volland, Stéphanie Simon, Martin B. Dorner, François Fenaille, Brigitte G. Dorner and François Becher

Toxins 2021, 13(1), 52; https://doi.org/10.3390/toxins13010052 - 13 Jan 2021

Cited by 5 | Viewed by 3515

Abstract

The toxin abrin found in the seeds of Abrus precatorius has attracted much attention regarding criminal and terroristic misuse over the past decade. Progress in analytical methods for a rapid and unambiguous identification of low abrin concentrations in complex matrices is essential. Here, we report on the development and evaluation of a MALDI-TOF mass spectrometry approach for the fast, sensitive and robust abrin isolectin identification, differentiation and quantification in complex food matrices. The method combines immunoaffinity-enrichment with specific abrin antibodies, accelerated trypsin digestion and the subsequent MALDI-TOF analysis of abrin peptides using labeled peptides for quantification purposes. Following the optimization of the workflow, common and isoform-specific peptides were detected resulting in a ~38% sequence coverage of abrin when testing ng-amounts of the toxin. The lower limit of detection was established at 40 ng/mL in milk and apple juice. Isotope-labeled versions of abundant peptides with high ionization efficiency were added. The quantitative evaluation demonstrated an assay variability at or below 22% with a linear range up to 800 ng/mL. MALDI-TOF mass spectrometry allows for a simple and fast (<5 min) analysis of abrin peptides, without a time-consuming peptide chromatographic separation, thus constituting a relevant alternative to liquid chromatography-tandem mass spectrometry. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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7 pages, 939 KiB

Open AccessCommunication

Phage Display Selection of an Anti-Idiotype-Antibody with Broad-Specificity to Deoxynivalenol Mycotoxins

by Janne Leivo, Markus Vehniäinen and Urpo Lamminmäki

Toxins 2021, 13(1), 18; https://doi.org/10.3390/toxins13010018 - 28 Dec 2020

Cited by 12 | Viewed by 2726

Abstract

The use of synthetic antibody libraries and phage displays provides an efficient and robust method for the generation of antibodies against a wide range of targets with highly specific binding properties. As the in vitro selection conditions can be easily controlled, these methods enable the rapid generation of binders against difficult targets such as toxins and haptens. In this study, we used deoxynivalenol mycotoxin as a target to generate anti-idiotype-antibodies with unique binding properties from synthetic antibody libraries. The binding of the selected anti-idiotype antibodies can be efficiently inhibited with the addition of free isoforms of deoxynivalenol. The antibody was consecutively used to develop deoxynivalenol-specific ELISA and TRF-immunoassays, which can detect deoxynivalenol and two of the most common metabolic isoforms in the range of 78–115 ng/mL. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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13 pages, 3180 KiB

Open AccessArticle

A Monoclonal Antibody against the C-Terminal Domain of Bacillus cereus Hemolysin II Inhibits HlyII Cytolytic Activity

by Natalia Rudenko, Alexey Nagel, Anna Zamyatina, Anna Karatovskaya, Vadim Salyamov, Zhanna Andreeva-Kovalevskaya, Alexander Siunov, Alexander Kolesnikov, Anna Shepelyakovskaya, Khanafiy Boziev, Bogdan Melnik, Fedor Brovko and Alexander Solonin

Toxins 2020, 12(12), 806; https://doi.org/10.3390/toxins12120806 - 19 Dec 2020

Cited by 9 | Viewed by 2477

Abstract

Bacillus cereus is the fourth most common cause of foodborne illnesses that produces a variety of pore-forming proteins as the main pathogenic factors. B. cereus hemolysin II (HlyII), belonging to pore-forming β-barrel toxins, has a C-terminal extension of 94 amino acid residues designated as HlyIICTD. An analysis of a panel of monoclonal antibodies to the recombinant HlyIICTD protein revealed the ability of the antibody HlyIIC-20 to inhibit HlyII hemolysis. A conformational epitope recognized by HlyIIC-20 was found. by the method of peptide phage display and found that it is localized in the N-terminal part of HlyIICTD. The HlyIIC-20 interacted with a monomeric form of HlyII, thus suppressing maturation of the HlyII toxin. Protection efficiencies of various B. cereus strains against HlyII were different and depended on the epitope amino acid composition, as well as, insignificantly, on downstream amino acids. Substitution of L324P and P324L in the hemolysins ATCC14579^T and B771, respectively, determined the role of leucine localized to the epitope in suppressing the hemolysis by the antibody. Pre-incubation of HlyIIC-20 with HlyII prevented the death of mice up to an equimolar ratio. A strategy of detecting and neutralizing the toxic activity of HlyII could provide a tool for monitoring and reducing B. cereus pathogenicity. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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14 pages, 2904 KiB

Open AccessArticle

Establishment of a Novel Oral Murine Model of Ricin Intoxication and Efficacy Assessment of Ovine Ricin Antitoxins

by Sarah J. Whitfield, Debbie B. Padgen, Simon Knight, Robert J. Gwyther, Jane L. Holley, Graeme C. Clark and A. Christopher Green

Toxins 2020, 12(12), 784; https://doi.org/10.3390/toxins12120784 - 8 Dec 2020

Cited by 4 | Viewed by 2607

Abstract

Ricin, produced from the castor beans of Ricinus communis, is a cytotoxin that exerts its action by inactivating ribosomes and causing cell death. Accidental (e.g., ingestion of castor beans) and/or intentional (e.g., suicide) exposure to ricin through the oral route is an area of concern from a public health perspective and no current licensed medical interventions exist to protect from the action of the toxin. Therefore, we examined the oral toxicity of ricin in Balb/C mice and developed a robust food deprivation model of ricin oral intoxication that has enabled the assessment of potential antitoxin treatments. A lethal oral dose was identified and mice were found to succumb to the toxin within 48 h of exposure. We then examined whether a despeciated ovine F(ab′)₂ antibody fragment, that had previously been demonstrated to protect mice from exposure to aerosolised ricin, could also protect against oral intoxication. Mice were challenged orally with an LD₉₉ of ricin, and 89 and 44% of mice exposed to this otherwise lethal exposure survived after receiving either the parent anti-ricin IgG or F(ab′)₂, respectively. Combined with our previous work, these results further highlight the benefit of ovine-derived polyclonal antibody antitoxin in providing post-exposure protection against ricin intoxication. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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Review

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44 pages, 1244 KiB

Open AccessReview

Immunoaffinity Extraction and Alternative Approaches for the Analysis of Toxins in Environmental, Food or Biological Matrices

by Nathalie Delaunay, Audrey Combès and Valérie Pichon

Toxins 2020, 12(12), 795; https://doi.org/10.3390/toxins12120795 - 13 Dec 2020

Cited by 26 | Viewed by 3547

Abstract

The evolution of instrumentation in terms of separation and detection allowed a real improvement of the sensitivity and analysis time. However, the analysis of ultra-traces of toxins in complex samples requires often a step of purification and even preconcentration before their chromatographic analysis. Therefore, immunoaffinity sorbents based on specific antibodies thus providing a molecular recognition mechanism appear as powerful tools for the selective extraction of a target molecule and its structural analogs to obtain more reliable and sensitive quantitative analysis in environmental, food or biological matrices. This review focuses on immunosorbents that have proven their efficiency in selectively extracting various types of toxins of various sizes (from small mycotoxins to large proteins) and physicochemical properties. Immunosorbents are now commercially available, and their use has been validated for numerous applications. The wide variety of samples to be analyzed, as well as extraction conditions and their impact on extraction yields, is discussed. In addition, their potential for purification and thus suppression of matrix effects, responsible for quantification problems especially in mass spectrometry, is presented. Due to their similar properties, molecularly imprinted polymers and aptamer-based sorbents that appear to be an interesting alternative to antibodies are also briefly addressed by comparing their potential with that of immunosorbents. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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32 pages, 3060 KiB

Open AccessReview

Multiplex Immunoassay Techniques for On-Site Detection of Security Sensitive Toxins

by Christopher Pöhlmann and Thomas Elßner

Toxins 2020, 12(11), 727; https://doi.org/10.3390/toxins12110727 - 20 Nov 2020

Cited by 19 | Viewed by 5767

Abstract

Biological toxins are a heterogeneous group of high molecular as well as low molecular weight toxins produced by living organisms. Due to their physical and logistical properties, biological toxins are very attractive to terrorists for use in acts of bioterrorism. Therefore, among the group of biological toxins, several are categorized as security relevant, e.g., botulinum neurotoxins, staphylococcal enterotoxins, abrin, ricin or saxitoxin. Additionally, several security sensitive toxins also play a major role in natural food poisoning outbreaks. For a prompt response to a potential bioterrorist attack using biological toxins, first responders need reliable, easy-to-use and highly sensitive methodologies for on-site detection of the causative agent. Therefore, the aim of this review is to present on-site immunoassay platforms for multiplex detection of biological toxins. Furthermore, we introduce several commercially available detection technologies specialized for mobile or on-site identification of security sensitive toxins. Full article

(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)

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