Production, Characterisation and Testing of an Ovine Antitoxin against Ricin; Efficacy, Potency and Mechanisms of Action

Whitfield, Sarah Joanne Christine; Griffiths, Gareth; Jenner, Dominic C.; Gwyther, Robert J; Stahl, Fiona M; Cork, L; Holley, Jane L.; Green, A Christopher; Clark, Graeme C.

doi:10.3390/toxins9100329

Cited by 13 publications

(24 citation statements)

References 64 publications

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“…Although prophylactic anti-ricin vaccines are being developed [20], the only post-exposure measure found to be effective against ricin intoxications in pre-clinical settings is passive immunization with anti-ricin neutralizing antibodies [21][22][23]. In a recent study, ovine-derived anti-ricin antitoxin was shown to confer high-level protection at late time-points (24-30 h post-exposure) following exposure to aerosolized ricin, however these studies were confined to a small animal model, the mouse [24]. In another study, monoclonal anti-ricin antibodies were shown to protect nonhuman primates; however, high-level protection was reached only when treatment was given at 4 h post-exposure to a lethal dose of aerosolized ricin.…”

Section: Discussionmentioning

confidence: 99%

Post-Exposure Anti-Ricin Treatment Protects Swine against Lethal Systemic and Pulmonary Exposures

Falach

Sapoznikov

Evgy

et al. 2020

Toxins

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Ricin, a plant-derived toxin originating from the seeds of Ricinus communis (castor bean plant), is one of the most lethal toxins known. To date, there is no approved post-exposure therapy for ricin exposures. This work demonstrates for the first time the therapeutic efficacy of equine-derived anti-ricin F(ab’)2 antibodies against lethal pulmonary and systemic ricin exposures in swine. While administration of the antitoxin at 18 h post-exposure protected more than 80% of both intratracheally and intramuscularly ricin-intoxicated swine, treatment at 24 h post-exposure protected 58% of the intramuscular-exposed swine, as opposed to 26% of the intratracheally exposed animals. Quantitation of the anti-ricin neutralizing units in the anti-toxin preparations confirmed that the disparate protection conferred to swine subjected to the two routes of exposure stems from variance between the two models. Furthermore, dose response experiments showed that approximately 3 times lesser amounts of antibody are needed for high-level protection of the intramuscularly compared to the intratracheally intoxicated swine. This study, which demonstrates the high-level post-exposure efficacy of anti-ricin antitoxin at clinically relevant time-points in a large animal model, can serve as the basis for the formulation of post-exposure countermeasures against ricin poisoning in humans.

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Section: Discussionmentioning

confidence: 99%

Post-Exposure Anti-Ricin Treatment Protects Swine against Lethal Systemic and Pulmonary Exposures

Falach

Sapoznikov

Evgy

et al. 2020

Toxins

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“…Currently, there are no specific treatments for ricin intoxication, however pre-clinical studies have demonstrated the utility of polyclonal or monoclonal ricin-neutralising antibodies (anti-toxin) to treat the intoxication (Gal et al 2017;Van Slyke et al 2016;Whitfield et al 2017), although these are not yet licensed for clinical use. Data suggests that efficacy of these antibody therapies is significantly reduced if they are not given very early post exposure (Griffiths et al 2007;Pratt et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Multiple metabolic pathways are predictive of ricin intoxication in a rat model

et al. 2019

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Introduction Exposure to ricin can be lethal and treatments that are under development have short windows of opportunity for administration after exposure. It is therefore essential to achieve early detection of ricin exposure to provide the best prognosis for exposed individuals. Ricin toxin can be detected in clinical samples via several antibody-based techniques, but the efficacy of these can be limited due to the rapid processing and cellular uptake of toxin in the body and subsequent low blood ricin concentrations. Other diagnostic tools that perform, in an orthogonal manner, are therefore desirable. Objectives To determine time-dependent metabolic changes in Sprague-Dawley rats following intravenous exposure to ricin. Methods Sprague-Dawley rats were intravenously exposed to ricin and multiple blood samples were collected from each animal for up to 48 h following exposure in two independent studies. Plasma samples were analysed applying HILIC and C 18 reversed phase UHPLC-MS assays followed by univariate and multivariate analysis. Results In Sprague-Dawley rats we have demonstrated that metabolic changes measured in blood can distinguish between rats exposed intravenously to ricin and controls prior to the onset of behavioral signs of intoxication after 24 h. A total of 37 metabolites were significantly altered following exposure to ricin when compared to controls. The arginine/proline, bile acid and triacylglyceride metabolic pathways were highlighted as being important with two triacylglycerides at 8 h post exposure giving an AUROC score of 0.94. At 16 h and 24 h the AUROC score increased to 0.98 and 1.0 with the number of metabolites in the panel increasing to 5 and 7, respectively. Conclusions These data demonstrate that metabolites may be a useful tool to diagnose and detect ricin exposure, thus increasing the effectiveness of supportive therapy and future ricin-specific medical treatments.Keywords Ricin · Metabolomics · Arginine/proline metabolism · Bile acid metabolism · Triacylglyceride metabolism

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“…Although prophylactic anti-ricin vaccines are being developed [ 3 ], the only post-exposure measure found effective against ricin intoxications in pre-clinical settings, is passive immunization with anti-ricin neutralizing antibodies [ 4 , 5 , 6 , 7 ]. Anti-ricin antibodies may be elicited following vaccination of various animal species, including mice [ 8 ], rabbits [ 9 ], monkeys [ 10 ], horses [ 11 ] and sheep [ 12 ]. A variety of ricin immunogens were employed to elicit neutralizing antibody responses against ricin.…”

Section: Introductionmentioning

confidence: 99%

“…A variety of ricin immunogens were employed to elicit neutralizing antibody responses against ricin. A toxoid-based vaccine (formaldehyde-inactivated ricin) was shown to induce high titers of protective antibodies both in rabbits [ 4 ] and in sheep [ 12 ]. Anti-ricin preparations were reported to elicit potent toxin neutralization in vitro and in vivo following horse immunization with an RTA/RTB chain construct, in which the native inter-chain linking domain has been replaced by a non-cleavable linker [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Generation of Highly Efficient Equine-Derived Antibodies for Post-Exposure Treatment of Ricin Intoxications by Vaccination with Monomerized Ricin

Falach

Sapoznikov

Alcalay

et al. 2018

Toxins

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Ricin, a highly lethal toxin derived from the seeds of Ricinus communis (castor beans) is considered a potential biological threat agent due to its high availability, ease of production, and to the lack of any approved medical countermeasure against ricin exposures. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this work was to generate anti-ricin antitoxin that confers high level post-exposure protection against ricin challenge. Due to safety issues regarding the usage of ricin holotoxin as an antigen, we generated an inactivated toxin that would reduce health risks for both the immunizer and the immunized animal. To this end, a monomerized ricin antigen was constructed by reducing highly purified ricin to its monomeric constituents. Preliminary immunizing experiments in rabbits indicated that this monomerized antigen is as effective as the native toxin in terms of neutralizing antibody elicitation and protection of mice against lethal ricin challenges. Characterization of the monomerized antigen demonstrated that the irreversibly detached A and B subunits retain catalytic and lectin activity, respectively, implying that the monomerization process did not significantly affect their overall structure. Toxicity studies revealed that the monomerized ricin displayed a 250-fold decreased activity in a cell culture-based functionality test, while clinical signs were undetectable in mice injected with this antigen. Immunization of a horse with the monomerized toxin was highly effective in elicitation of high titers of neutralizing antibodies. Due to the increased potential of IgG-derived adverse events, anti-ricin F(ab’)2 antitoxin was produced. The F(ab’)2-based antitoxin conferred high protection to intranasally ricin-intoxicated mice; ~60% and ~34% survival, when administered 24 and 48 h post exposure to a lethal dose, respectively. In line with the enhanced protection, anti-inflammatory and anti-edematous effects were measured in the antitoxin treated mice, in comparison to mice that were intoxicated but not treated. Accordingly, this anti-ricin preparation is an excellent candidate for post exposure treatment of ricin intoxications.

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Production, Characterisation and Testing of an Ovine Antitoxin against Ricin; Efficacy, Potency and Mechanisms of Action

Cited by 13 publications

References 64 publications

Post-Exposure Anti-Ricin Treatment Protects Swine against Lethal Systemic and Pulmonary Exposures

Post-Exposure Anti-Ricin Treatment Protects Swine against Lethal Systemic and Pulmonary Exposures

Multiple metabolic pathways are predictive of ricin intoxication in a rat model

Generation of Highly Efficient Equine-Derived Antibodies for Post-Exposure Treatment of Ricin Intoxications by Vaccination with Monomerized Ricin

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