In vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies

Laustsen, Andreas Hougaard; Karatt-Vellatt, Aneesh; Masters, Edward W.; Arias, Ana Silvia; Pus, Urska; Knudsen, Carsten; Oscoz, Saioa; Slavny, Peter; Griffiths, Daniel T.; Luther, Alice M.; Leah, Rachael A.; Lindholm, Majken; Lomonte, Bruno; Gutiérrez, José Marı́a; McCafferty, John

doi:10.1038/s41467-018-06086-4

Cited by 95 publications

(162 citation statements)

References 27 publications

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“…Recombinant antivenoms containing several monoclonal antibodies or single-chain variable fragments (scFv) that target CTXs may be a promising source material for solving the problem of N. atra-induced local tissue damage. A previous study reported a situation similar to our case [56], showing that the currently used equine polyvalent antivenom exhibited a limited ability to neutralize dendrotoxin-mediated neurotoxicity. In this case, the researchers developed a cocktail of a few humanized monoclonal antibodies against this neurotoxin.…”

Section: Discussionsupporting

confidence: 86%

“…Several advanced biotechnological tools have recently been adopted for developing alternative strategies for antivenom production [53,54]. Applying expertise in synthetic biology, antibody research and immunology, a number of researchers have attempted to develop recombinant antivenoms and investigate their ability to neutralize toxins from snake venom [55][56][57][58][59]. Recombinant antivenoms containing several monoclonal antibodies or single-chain variable fragments (scFv) that target CTXs may be a promising source material for solving the problem of N. atra-induced local tissue damage.…”

Section: Discussionmentioning

confidence: 99%

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Pathogenesis of local necrosis induced by Naja atra venom: Assessment of the neutralization ability of Taiwanese freeze-dried neurotoxic antivenom in animal models

et al. 2020

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Naja atra envenomation is one of the most significant clinical snakebite concerns in Taiwan. Taiwanese freeze-dried neurotoxic antivenom (FNAV) is currently used clinically for the treatment of cobra snakebite, and has been shown to limit the mortality of cobra envenomation to less than 1%. However, more than half of victims (60%) require surgery because of local tissue necrosis, a major problem in patients with cobra envenomation. Although the importance of evaluating the neutralizing effect of FNAV on this pathology is recognized, whether FNAV is able to prevent the local necrosis extension induced by N. atra venom has not been investigated in detail. Cytotoxins (CTXs) are considered as the major components of N. atra venom that cause necrosis. In the current study, we isolated CTXs from whole cobra venom and used both whole venom and purified CTXs to develop animal models for assessing the neutralization potential of FNAV against venom necrotizing activity. Local necrotic lesions were successfully produced in mice using CTXs in place of whole N. atra venom. FNAV was able to rescue mice from a subcutaneously injected lethal dose of cobra venom; however, it was unable to prevent CTX-induced dermo-necrosis. Furthermore, using the minimal necrosis dose (MND) of CTXs and venom proteome data, we found a dose of whole N. atra venom suitable for FNAV and developed a workable protocol for inducing local necrosis in rodent models that successfully imitated the clinical circumstance of cobra envenoming. This information provides a more comprehensive understanding of PLOS Neglected Tropical Diseases | https://doi.the pathophysiology of N. atra envenomation, and serves as a guide for improving current antivenom strategies and advancing clinical snakebite management in Taiwan. Author summaryNaja atra envenomation is an important public health issue in Taiwan. Although the mortality rate of cobra snakebite is controlled using antivenom, more than half of victims develop symptoms of local necrosis and require surgical intervention. Whether the Taiwanese freeze-dried neurotoxic antivenom (FNAV) currently in clinical use is able to prevent the local necrosis extension induced by N. atra venom is still unclear. In this study, we developed a dermo-necrosis animal model using purified cytotoxins (CTXs), the major necrosis-related proteins from N. atra venom. We found that FNAV was able to neutralize the lethality of whole cobra venom, but was unable to neutralize the necrosis induced by CTXs in vivo. This finding introduced an example that supplementary quality control assays may be necessary to determine the effectiveness of antivenoms in neutralizing specific pathology induced by the venom; only evaluating the rodent lethality prevention is insufficient. Our results provide insights that should help improve current antivenoms and advance cobra snakebite management in Taiwan.Pathogenesis of local necrosis induced by Naja atra venom PLOS Neglected Tropical Diseases | https://doi.org/10.The lyophilized fractions from RP-HPLC were d...

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Pathogenesis of local necrosis induced by Naja atra venom: Assessment of the neutralization ability of Taiwanese freeze-dried neurotoxic antivenom in animal models

et al. 2020

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“…Consequently, new strategies capable of circumventing variation in snake venom composition to deliver broad neutralization across snake species, while simultaneously improving the safety, affordability and storage logistics of treatment, are urgently needed 3,47 . Approaches showing signs of promise include the rational design of immunogens to improve the neutralizing breadth of conventional products 48 , the selection of human or humanized toxin-specific monoclonal or oligoclonal antibodies 49,50 , and the use of small molecule inhibitors specific to certain toxin families 12 , such as the PLA 2 -inhibitor varespladib 22,26,27 and the metal chelator DMPS 28 23 , we found both drugs to be equipotent in vitro. We selected marimastat as our candidate for in vivo efficacy experiments due to a number of desirable characteristics that make it amenable for a future field intervention for snakebite, specifically its oral vs.…”

Section: Discussionmentioning

confidence: 85%

“…To better mimic a real-life envenoming scenario, we next tested the marimastat and varespladib inhibitor mixture in a preclinical 'challenge then treat' model of envenoming, where the venom is first administered intraperitoneally and then the test therapy is administered intraperitoneally separately after the venom challenge 28 . To this end, we injected venom from each of the five viper species in doses equivalent to at least 5 x the intravenous (iv) LD 50 'envenomed' mice. This observation was noted for both the 'intravenous preincubation' and 'intraperitoneal challenge then treat' models of envenoming ( Fig.…”

Section: Administration Of the Marimastat And Varespladib (Mv) Dual Tmentioning

confidence: 99%

A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite

Albulescu

Xie²,

Ainsworth³

et al. 2020

Preprint

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Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and fiscal snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using multiple in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings strongly support the translation of

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“…Such studies have stimulated much research into the development of novel therapeutic approaches to tackle snakebite. These include the use of monoclonal antibody technologies to target key pathogenic toxins found in certain snake species (Laustsen et al, 2018;Silva et al, 2018), pathology rather than geographically-focused approaches to neutralizing venom toxins (Ainsworth et al, 2018), and the use of small molecule inhibitors designed to generically target specific toxin classes (Arias et al, 2017;Bryan-Quiros et al, 2019). The priority targets for these "next generation" snakebite therapeutics are the multifunctional toxins described herein (PLA2s, SVMP, SVSP, 3FTX) because of the major pathologies that they cause in snakebite victims.…”

Section: Therapeutic Implications Treating Snake Envenomationmentioning

confidence: 99%

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

et al. 2019

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Animal venoms have evolved over millions of years for prey capture and defense from predators and rivals. Snake venoms, in particular, have evolved a wide diversity of peptides and proteins that induce harmful inflammatory and neurotoxic effects including severe pain and paralysis, hemotoxic effects, such as hemorrhage and coagulopathy, and cytotoxic/myotoxic effects, such as inflammation and necrosis. If untreated, many envenomings result in death or severe morbidity in humans and, despite advances in management, snakebite remains a major public health problem, particularly in developing countries. Consequently, the World Health Organization recently recognized snakebite as a neglected tropical disease that affects ∼2.7 million p.a. The major protein classes found in snake venoms are phospholipases, metalloproteases, serine proteases, and three-finger peptides. The mechanisms of action and pharmacological properties of many snake venom toxins have been elucidated, revealing a complex multifunctional cocktail that can act synergistically to rapidly immobilize prey and deter predators. However, despite these advances many snake toxins remain to be structurally and pharmacologically characterized. In this review, the multifunctional features of the peptides and proteins found in snake venoms, as well as their evolutionary histories, are discussed with the view to identifying novel modes of action and improving snakebite treatments.

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In vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies

Cited by 95 publications

References 27 publications

Pathogenesis of local necrosis induced by Naja atra venom: Assessment of the neutralization ability of Taiwanese freeze-dried neurotoxic antivenom in animal models

Pathogenesis of local necrosis induced by Naja atra venom: Assessment of the neutralization ability of Taiwanese freeze-dried neurotoxic antivenom in animal models

A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

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