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Special Issue "Discovery of Antibodies and Novel Antivenoms against Envenoming"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (31 December 2018)

Special Issue Editors

Guest Editor
Prof. Dr. Mikael Rørdam Andersen

Network Engineering of Eukaryotic Cell factories, Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, 2800, Kgs. Lyngby, Denmark
Website | E-Mail
Guest Editor
Assoc. Prof. Dr. Andreas Hougaard Laustsen

Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby DK-2800, Denmark
Website | E-Mail
Phone: +45 2988 1134
Interests: recombinant antivenom, antibody discovery, phage display, toxicovenomics, snakebite envenoming, biologics, biotherapeutics, antibody technologies, mamba venoms, toxin synergism, next-generation antivenoms, oligoclonal antibodies, Biotech entrepreneurship, commercialization of life science, biotech innovation

Special Issue Information

Dear Colleagues,

Envenomings caused by animals constitute a real threat to many people living in rural conditions across the globe. Although effective antisera have been available for more than a century, opportunities for improvement still exist. Novel approaches may deliver antivenoms against envenomings for which there is currently no treatment. Independence of venoms in the manufacturing process may be achievable through novel immunization methodologies. Costs of manufacturing may be improved via intelligent engineering approaches. Additionally, advances in biotechnology hold the promise of unlocking the next generation of recombinant antivenoms that may be based on camelid antibody fragments, human antibodies, or yet to come molecular formats. Additionally, classical medicinal chemistry approaches could aid in developing inhibitors against toxins with enzymatic function. Finally, the introduction of cutting-edge technologies utilized for investigating specificity, cross-reactivity, neutralization potential, and other important antivenom/antibody properties may help guide antivenom research and allow researchers to identify promising toxin-neutralizing molecules.

The aim of this Special Issue is to provide an overview of the different technological avenues that are being pursued within the development of novel antivenoms. Moreover, this Special Issue wishes to highlight the most recent advances within the discovery of toxin-targeting antibodies and technologies used to guide their development. We invite original research papers, reviews, short communications, commentaries, and letters to the editor.

Prof. Dr. Mikael Rørdam Andersen
Assoc. Prof. Dr. Andreas Hougaard Laustsen
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 papers will be 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 double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly 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

  • Recombinant antivenom
  • Toxin neutralization
  • Venoms monoclonal antibodies
  • Cross-reactivity
  • Omics technologies
  • Snakebite antivenom
  • Phage display technology
  • Antibody discovery
  • Neglected tropical diseases

Published Papers (8 papers)

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Research

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Open AccessFeature PaperArticle Vipera berus berus Venom from Russia: Venomics, Bioactivities and Preclinical Assessment of Microgen Antivenom
Received: 31 December 2018 / Revised: 27 January 2019 / Accepted: 29 January 2019 / Published: 1 February 2019
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Abstract
The common European adder, Vipera berus berus, is a medically relevant species, which is widely distributed in Russia and thus, is responsible for most snakebite accidents in Russia. We have investigated the toxic and enzymatic activities and have determined the proteomic composition [...] Read more.
The common European adder, Vipera berus berus, is a medically relevant species, which is widely distributed in Russia and thus, is responsible for most snakebite accidents in Russia. We have investigated the toxic and enzymatic activities and have determined the proteomic composition of its venom. Phospholipases A2 (PLA2, 25.3% of the venom proteome), serine proteinases (SVSP, 16.2%), metalloproteinases (SVMP, 17.2%), vasoactive peptides (bradykinin-potentiating peptides (BPPs), 9.5% and C-type natriuretic peptides (C-NAP, 7.8%), cysteine-rich secretory protein (CRISP, 8%) and L-amino acid oxidase (LAO, 7.3%) represent the major toxin classes found in V. b. berus (Russia) venom. This study was also designed to assess the in vivo and in vitro preclinical efficacy of the Russian Microgen antivenom in neutralizing the main effects of V. b. berus venom. The results show that this antivenom is capable of neutralizing the lethal, hemorrhagic and PLA2 activities. Third-generation antivenomics was applied to quantify the toxin-recognition landscape and the maximal binding capacity of the antivenom for each component of the venom. The antivenomics analysis revealed that 6.24% of the anti-V. b. berus F(ab’)2 molecules fraction are toxin-binding antibodies, 60% of which represent clinically relevant antivenom molecules. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Open AccessArticle Effects of Two Fractions of Swietenia macrophylla and Catechin on Muscle Damage Induced by Bothrops Venom and PLA2
Received: 8 November 2018 / Revised: 4 January 2019 / Accepted: 7 January 2019 / Published: 14 January 2019
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Abstract
Plant natural products can attenuate the myonecrosis caused by Bothrops snake venom and their phospholipases A2 (PLA2). In this study, we evaluated the effects of two fractions (F4 and F6) from Swietenia macrophylla and purified catechin on the muscle damage [...] Read more.
Plant natural products can attenuate the myonecrosis caused by Bothrops snake venom and their phospholipases A2 (PLA2). In this study, we evaluated the effects of two fractions (F4 and F6) from Swietenia macrophylla and purified catechin on the muscle damage caused by a myotoxic PLA2 from Colombian Bothrops asper venom (BaColPLA2) in mice and by Bothrops marmoratus venom from Brazil in mouse phrenic nerve-diaphragm muscle (PND) preparations in vitro. Male mice were injected with PLA2 (50 µg) in the absence or presence of F4, F6, and catechin, in the gastrocnemius muscle and then killed 3, 7, 14, and 28 h later for histopathological analysis of myonecrosis, leukocyte infiltration, and the presence of collagen. Fractions F4 and F6 (500 µg) and catechin (90 µg) significantly reduced the extent of necrosis at all-time intervals. These two fractions and catechin also attenuated the leukocyte infiltration on day 3, as did catechin on day 14. There was medium-to-moderate collagen deposition in all groups up to day 7, but greater deposition on days 14 and 28 in the presence of F6 and catechin. Bothrops marmoratus venom (100 µg/mL) caused slight (~25%) muscle facilitation after 10 min and weak neuromuscular blockade (~64% decrease in contractile activity after a 120-min incubation). Pre-incubation of venom with F4 or F6 abolished the facilitation, whereas catechin, which was itself facilitatory, did not. All three fractions attenuated the venom-induced decrease in muscle contractions. These findings indicate that fractions and catechin from S. macrophylla can reduce the muscle damage caused by Bothrops venom and PLA2. These fractions or their components could be useful for treating venom-induced local damage. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Open AccessArticle Generation of a Broadly Cross-Neutralizing Antibody Fragment against Several Mexican Scorpion Venoms
Received: 11 December 2018 / Revised: 3 January 2019 / Accepted: 3 January 2019 / Published: 10 January 2019
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Abstract
The recombinant antibody fragments generated against the toxic components of scorpion venoms are considered a promising alternative for obtaining new antivenoms for therapy. Using directed evolution and site-directed mutagenesis, it was possible to generate a human single-chain antibody fragment with a broad cross-reactivity [...] Read more.
The recombinant antibody fragments generated against the toxic components of scorpion venoms are considered a promising alternative for obtaining new antivenoms for therapy. Using directed evolution and site-directed mutagenesis, it was possible to generate a human single-chain antibody fragment with a broad cross-reactivity that retained recognition for its original antigen. This variant is the first antibody fragment that neutralizes the effect of an estimated 13 neurotoxins present in the venom of nine species of Mexican scorpions. This single antibody fragment showed the properties of a polyvalent antivenom. These results represent a significant advance in the development of new antivenoms against scorpion stings, since the number of components would be minimized due to their broad cross-neutralization capacity, while at the same time bypassing animal immunization. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Open AccessArticle Antivenom Production against Bothrops jararaca and Bothrops erythromelas Snake Venoms Using Cross-Linked Chitosan Nanoparticles as an Immunoadjuvant
Received: 12 March 2018 / Revised: 3 April 2018 / Accepted: 5 April 2018 / Published: 16 April 2018
Cited by 2 | PDF Full-text (15530 KB) | HTML Full-text | XML Full-text
Abstract
In Brazil, envenomation by snakes of the genus Bothrops is clinically relevant, particularly for the species Bothrops jararaca and B. erythromelas. The most effective treatment for envenomation by snakes is the administration of antivenoms associated with adjuvants. Novel adjuvants are required to [...] Read more.
In Brazil, envenomation by snakes of the genus Bothrops is clinically relevant, particularly for the species Bothrops jararaca and B. erythromelas. The most effective treatment for envenomation by snakes is the administration of antivenoms associated with adjuvants. Novel adjuvants are required to reduce side effects and maximize the efficiency of conventional serum and vaccine formulations. The polymer chitosan has been shown to have immunoadjuvant properties, and it has been used as a platform for delivery systems. In this context, we evaluated the potential immunoadjuvant properties of chitosan nanoparticles (CNPs) loaded with B. jararaca and B. erythromelas venoms in the production of sera against these venoms. Stable CNPs were obtained by ionic gelation, and mice were immunized subcutaneously for 6 weeks with 100 µL of each snake venom at concentrations of 5.0 or 10.0% (w/w), encapsulated in CNPs or associated with aluminium hydroxide (AH). The evaluation of protein interactions with the CNPs revealed their ability to induce antibody levels equivalent to those of AH, even with smaller doses of antigen. In addition, the CNPs were less inflammatory due to their modified release of proteins. CNPs provide a promising approach for peptide/protein delivery from snake venom and will be useful for new vaccines. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Open AccessFeature PaperArticle Camelid Single-Domain Antibodies (VHHs) against Crotoxin: A Basis for Developing Modular Building Blocks for the Enhancement of Treatment or Diagnosis of Crotalic Envenoming
Received: 1 February 2018 / Revised: 11 March 2018 / Accepted: 16 March 2018 / Published: 29 March 2018
Cited by 2 | PDF Full-text (39312 KB) | HTML Full-text | XML Full-text
Abstract
Toxic effects triggered by crotalic envenoming are mainly related to crotoxin (CTX), composed of a phospholipase A2 (CB) and a subunit with no toxic activity (CA). Camelids produce immunoglobulins G devoid of light chains, in which the antigen recognition domain is called [...] Read more.
Toxic effects triggered by crotalic envenoming are mainly related to crotoxin (CTX), composed of a phospholipase A2 (CB) and a subunit with no toxic activity (CA). Camelids produce immunoglobulins G devoid of light chains, in which the antigen recognition domain is called VHH. Given their unique characteristics, VHHs were selected using Phage Display against CTX from Crotalus durissus terrificus. After three rounds of biopanning, four sequence profiles for CB (KF498602, KF498603, KF498604, and KF498605) and one for CA (KF498606) were revealed. All clones presented the VHH hallmark in FR2 and a long CDR3, with the exception of KF498606. After expressing pET22b-VHHs in E. coli, approximately 2 to 6 mg of protein per liter of culture were obtained. When tested for cross-reactivity, VHHs presented specificity for the Crotalus genus and were capable of recognizing CB through Western blot. KF498602 and KF498604 showed thermostability, and displayed affinity constants for CTX in the micro or nanomolar range. They inhibited in vitro CTX PLA2 activity, and CB cytotoxicity. Furthermore, KF498604 inhibited the CTX-induced myotoxicity in mice by 78.8%. Molecular docking revealed that KF498604 interacts with the CA–CB interface of CTX, seeming to block substrate access. Selected VHHs may be alternatives for the crotalic envenoming treatment. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Review

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Open AccessFeature PaperReview Antibody Cross-Reactivity in Antivenom Research
Toxins 2018, 10(10), 393; https://doi.org/10.3390/toxins10100393
Received: 13 August 2018 / Revised: 21 September 2018 / Accepted: 25 September 2018 / Published: 27 September 2018
Cited by 3 | PDF Full-text (2427 KB) | HTML Full-text | XML Full-text
Abstract
Antivenom cross-reactivity has been investigated for decades to determine which antivenoms can be used to treat snakebite envenomings from different snake species. Traditionally, the methods used for analyzing cross-reactivity have been immunodiffusion, immunoblotting, enzyme-linked immunosorbent assay (ELISA), enzymatic assays, and in vivo neutralization [...] Read more.
Antivenom cross-reactivity has been investigated for decades to determine which antivenoms can be used to treat snakebite envenomings from different snake species. Traditionally, the methods used for analyzing cross-reactivity have been immunodiffusion, immunoblotting, enzyme-linked immunosorbent assay (ELISA), enzymatic assays, and in vivo neutralization studies. In recent years, new methods for determination of cross-reactivity have emerged, including surface plasmon resonance, antivenomics, and high-density peptide microarray technology. Antivenomics involves a top-down assessment of the toxin-binding capacities of antivenoms, whereas high-density peptide microarray technology may be harnessed to provide in-depth knowledge on which toxin epitopes are recognized by antivenoms. This review provides an overview of both the classical and new methods used to investigate antivenom cross-reactivity, the advantages and disadvantages of each method, and examples of studies using the methods. A special focus is given to antivenomics and high-density peptide microarray technology as these high-throughput methods have recently been introduced in this field and may enable more detailed assessments of antivenom cross-reactivity. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Open AccessReview Current Advances in Immunological Studies on the Vespidae Venom Antigen 5: Therapeutic and Prophylaxis to Hypersensitivity Responses
Received: 12 June 2018 / Revised: 3 July 2018 / Accepted: 5 July 2018 / Published: 24 July 2018
Cited by 1 | PDF Full-text (1867 KB) | HTML Full-text | XML Full-text
Abstract
Although systemic reactions caused by allergenic proteins present in venoms affect a small part of the world population, Hymenoptera stings are among the main causes of immediate hypersensitivity responses, with risk of anaphylactic shock. In the attempt to obtain therapeutic treatments and prophylaxis [...] Read more.
Although systemic reactions caused by allergenic proteins present in venoms affect a small part of the world population, Hymenoptera stings are among the main causes of immediate hypersensitivity responses, with risk of anaphylactic shock. In the attempt to obtain therapeutic treatments and prophylaxis to hypersensitivity responses, interest in the molecular characterization of these allergens has grown in the scientific community due to the promising results obtained in immunological and clinical studies. The present review provides an update on the knowledge regarding the immune response and the therapeutic potential of Antigen 5 derived from Hymenoptera venom. The results confirm that the identification and topology of epitopes, associated with molecular regions that interact with antibodies, are crucial to the improvement of hypersensitivity diagnostic methods. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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Open AccessFeature PaperReview Basics of Antibody Phage Display Technology
Received: 31 May 2018 / Revised: 7 June 2018 / Accepted: 8 June 2018 / Published: 9 June 2018
Cited by 4 | PDF Full-text (4086 KB) | HTML Full-text | XML Full-text
Abstract
Antibody discovery has become increasingly important in almost all areas of modern medicine. Different antibody discovery approaches exist, but one that has gained increasing interest in the field of toxinology and antivenom research is phage display technology. In this review, the lifecycle of [...] Read more.
Antibody discovery has become increasingly important in almost all areas of modern medicine. Different antibody discovery approaches exist, but one that has gained increasing interest in the field of toxinology and antivenom research is phage display technology. In this review, the lifecycle of the M13 phage and the basics of phage display technology are presented together with important factors influencing the success rates of phage display experiments. Moreover, the pros and cons of different antigen display methods and the use of naïve versus immunized phage display antibody libraries is discussed, and selected examples from the field of antivenom research are highlighted. This review thus provides in-depth knowledge on the principles and use of phage display technology with a special focus on discovery of antibodies that target animal toxins. Full article
(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)
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