Antibody Cross-Reactivity in Antivenom Research

Ledsgaard, Line; Jenkins, Timothy; Davidsen, Kristian; Krause, Kamille Elvstrøm; Martos-Esteban, Andrea; Engmark, Mikael; Andersen, Mikael Rørdam; Lund, Ole; Laustsen, Andreas Hougaard

doi:10.3390/toxins10100393

Cited by 46 publications

(29 citation statements)

References 102 publications

(162 reference statements)

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“…The antibody developer may piggy-back on the many scientific and technological achievements from the fields of oncology and autoimmune diseases [85], which can be exploited to reap the many technologically low-hanging fruits that exist in the field of neglected tropical diseases due to the lack of prior art. This creates an opportunity for the academic scientist who is evaluated more on his or her ability to perform and publish high impact science than on his or her ability to areas such as understanding and designing cross-reactivity for monoclonal antibodies [107], use of oligoclonal antibody cocktails for multi-target neutralization [1,17,108], novel immunization approaches [109], targeting of evasive pathogens [9,10], and exploitation of novel therapeutic mechanisms of action [41]. Such potential developments will likely be further catalyzed by advances in antibody production technologies that may enable low cost of antibody manufacture [17,110] PDB IDs were obtained from the Protein Data Bank (https://www.rcsb.org).…”

Section: Expert Opinionmentioning

confidence: 99%

How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

Laustsen

2019

Expert Opinion on Drug Discovery

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Highlights 1. Therapies based on monoclonal antibodies against bacterial and viral agents have already entered the clinic, while no monoclonal antibodies against parasites, animal envenoming, or mushroom poisonings have been tested in the clinical setting 2. Neglected tropical diseases represent a golden opportunity for antibody developers, as there are many scientifically low-hanging fruits in this field 3. An increasing number of therapeutic monoclonal antibody discoveries has been reported for neglected tropical diseases and other infectious diseases 4. Monoclonal antibodies may be particularly useful for developing therapies against intoxications caused by both animals and bacteria 5. Low cost of manufacture and selective cross-reactivity are key challenges for developing monoclonal antibodies against neglected tropical diseases and other infectious diseases 6. Treatment against snakebite envenoming and bacterial and viral infections will likely require the use of oligoclonal antibodies for multi-target neutralization Abstract Introduction: Monoclonal antibody-based therapies now represent the single-largest class of molecules undergoing clinical investigation. Although a handful of different monoclonal antibodies have been clinically approved for bacterial and viral indications, as well as rabies, therapies based on monoclonal antibodies are yet to fully enter the fields of neglected tropical diseases and other infectious diseases. Areas covered: This review presents current state-of-the-art in the development and use of monoclonal antibodies against neglected tropical diseases and other infectious diseases, including viral, bacterial, and parasitic infections, as well as envenomings by animal bites and stings. Additionally, a short section on mushroom poisonings is included. Key challenges for developing antibody-based therapeutics is discussed for each of these fields. Expert opinion: Neglected tropical diseases and other infectious diseases represent a golden opportunity for academics and technology developers for advancing our scientific capabilities within the understanding and design of antibody cross-reactivity, use of oligoclonal antibody mixtures for multi-target neutralization, novel immunization methodologies, targeting of evasive pathogens, and development of fundamentally novel therapeutic mechanisms of action. Furthermore, a huge humanitarian and societal impact is to gain by exploiting antibody technologies for the development of biotherapies against diseases, for which current treatment options are suboptimal or non-existent.

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Section: Expert Opinionmentioning

confidence: 99%

How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

Laustsen

2019

Expert Opinion on Drug Discovery

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“…Localizing the immunogenic region of toxins may allow for the synthesis of small peptides that could be used as synthetic epitopes for immunization. Generally, neutralizing antibodies target epitopes that are three-dimensional structures that may contain discontinuous epitopic elements [ 213 ]. However, some continuous epitopic elements are still able to raise a protective immune response, as extensively exemplified by the studies reported in Table 1 , Table 2 and Table 3 .…”

Section: Biochemical Bioinformatic and Omics Tools That Could Aimentioning

confidence: 99%

Innovative Immunization Strategies for Antivenom Development

Bermúdez-Méndez

Fuglsang-Madsen

Føns

et al. 2018

Toxins

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Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation antivenoms.

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“…Toxicovenomics is a proteomicsbased approach that can be used to analyze snake venoms to provide an overview of which toxins are medically relevant in envenomings, and this approach shows promise for selecting the most effective venom mixtures for immunization [7][8][9]. However, toxicovenomics needs to be combined with complementary analytical approaches, such as animal-based neutralization assays, immunochemical studies [3], and antivenomics [10]; these, together, can provide an in-depth view into the molecular reactivity and potential neutralization of these medically relevant toxins [11,12]. Nevertheless, all of these approaches fail to provide information about the specific binding interactions between venom toxin epitopes and antivenom antibody paratopes [11].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, all of these approaches fail to provide information about the specific binding interactions between venom toxin epitopes and antivenom antibody paratopes [11]. Such molecular interaction information is key towards developing a better understanding of the nature of antivenom cross-reactivity and para-specificity and, consequently, the development of improved and broadly neutralizing antivenoms [11,12].…”

Section: Introductionmentioning

confidence: 99%

An interactive database for the investigation of high-density peptide microarray guided interaction patterns and antivenom cross-reactivity

et al. 2020

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Snakebite envenoming is a major neglected tropical disease that affects millions of people every year. The only effective treatment against snakebite envenoming consists of unspecified cocktails of polyclonal antibodies purified from the plasma of immunized production animals. Currently, little data exists on the molecular interactions between venom-toxin epitopes and antivenom-antibody paratopes. To address this issue, high-density peptide microarray (hdpm) technology has recently been adapted to the field of toxinology. However, analysis of such valuable datasets requires expert understanding and, thus, complicates its broad application within the field. In the present study, we developed a userfriendly, and high-throughput web application named "Snake Toxin and Antivenom Binding Profiles" (STAB Profiles), to allow straightforward analysis of hdpm datasets. To test our tool and evaluate its performance with a large dataset, we conducted hdpm assays using all African snake toxin protein sequences available in the UniProt database at the time of study design, together with eight commercial antivenoms in clinical use in Africa, thus representing the largest venom-antivenom dataset to date. Furthermore, we introduced a novel method for evaluating raw signals from a peptide microarray experiment and a data normalization protocol enabling intra-microarray and even inter-microarray chip comparisons. Finally, these data, alongside all the data from previous similar studies by Engmark et al., were preprocessed according to our newly developed protocol and made publicly available for download through the STAB Profiles web application (http://tropicalpharmacology.com/ tools/stab-profiles/). With these data and our tool, we were able to gain key insights into toxin-antivenom interactions and were able to differentiate the ability of different antivenoms to interact with certain toxins of interest.

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Antibody Cross-Reactivity in Antivenom Research

Cited by 46 publications

References 102 publications

How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

Innovative Immunization Strategies for Antivenom Development

An interactive database for the investigation of high-density peptide microarray guided interaction patterns and antivenom cross-reactivity

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