Development and preclinical evaluation of a new F(ab′)2 antitoxin against botulinum neurotoxin serotype A

Yu, Yun-Zhou; Zhang, Shuming; Wang, Wenbing; Du, Yinan; Zhu, Heng-Qi; Zhou, Xiaowei; Lin, Jianbo; Wang, Shuang; Yu, Wei-Yuan; Huang, Pei-Tang; Sun, Zhiwei

doi:10.1016/j.biochi.2010.06.010

Cited by 13 publications

(18 citation statements)

References 25 publications

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“…al. (2010) used incomplete Freund’s adjuvant to immunize horses with a recombinant botulinum antigen [35]. We adopted an approach to combine each botulinum toxoid with Al(OH) 3 followed by emulsification with an oil-based adjuvant, Titermax Gold™.…”

Section: Discussionmentioning

confidence: 99%

“…Comparing the magnitude of the equine titers elicited by our antigen and regimen to equine titers elicited in horses immunized with a recombinant antigen, we see that our Anti-A pool of about 1000 IU/mL obtained by using 0.36 mg of formalin toxoid was much lower than the 27,000 IU/mL obtained by immunizing with 32 mg of recombinant antigen using incomplete Freund’s adjuvant [35]. Although schedules, adjuvants and dosages were different between the two approaches, the final ratio of IU:antigen shows that the formalin toxoid had an efficiency of 1000 IU/0.36 mg ≈ 2,700 IU/mg whereas the recombinant antigen efficiency was 27,000 IU/32 mg ≈ 840 IU/mg.…”

Section: Discussionmentioning

confidence: 99%

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New equine antitoxins to botulinum neurotoxins serotypes A and B

Mattoo

Keller

2012

Biologicals

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Hyperimmune monovalent antitoxins to botulinum neurotoxin serotypes A and B have been produced by immunizing horses with newly developed formalin toxoids. After primary immunization horses were found to have developed acceptable prophylactic antibody titers (1–5 IU/mL). Three horses received additional toxoid booster injections to induce hyperimmune antibody titers with antitoxin-A and antitoxin-B titers reaching peaks of approximately 2000 IU/mL and 150–625 IU/mL, respectively. Titers were quantified throughout the process by antigen-capture ELISA and by in-vivo neutralization. ELISA titers and neutralization titers correlated (R2 ~0.62–0.92), however, unique correlations between in-vitro and in-vivo titers were observed for each animal. Monovalent antitoxin pools were made by combining plasma that had been collected twice via plasmapheresis several months after primary immunization. Neutralizing units were established for each pool relative to the current US and WHO reference standards. Titers were determined at the L+/10 and L+/40 toxin dose for Toxin types A and B, respectively, and both U.S. and international units assigned to each monovalent antitoxin. Avidity of the new Anti-A pool was equivalent to the WHO Anti-A reference at the L+, L+/10 and L+/30 dose. Each monovalent plasma pool failed to cross-neutralize other botulinum neurotoxin serotypes indicating a high degree of specificity of each antitoxin for the toxin serotype used during immunization.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

New equine antitoxins to botulinum neurotoxins serotypes A and B

Mattoo

Keller

2012

Biologicals

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“…While antitoxin is administered to patients only after symptom onset, its use in animal studies has been related mostly to time postintoxication regardless of symptoms (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). To evaluate antitoxin efficacy in a more clinically relevant timeline of treatment, we recently developed a mouse model for postsymptom, antibotulinum therapy (33).…”

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confidence: 99%

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

Diamant

Pass

Rosen

et al. 2018

Antimicrob Agents Chemother

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Botulinum neurotoxins (BoNTs), the most poisonous substances known in nature, pose significant concern to health authorities. The only approved therapeutic for botulism is antitoxin. While administered to patients only after symptom onset, antitoxin efficacy is evaluated in animals mostly in relation to time postintoxication regardless of symptoms. This is most likely due to the difficulty in measuring early symptoms of botulism in animals. In this study, a rabbit spirometry model was developed to quantify early respiratory symptoms of type E botulism that were further used as a trigger for treatment. Impaired respiration, in the form of a reduced minute volume, was detected as early as 18.1 ± 2.9 h after intramuscular exposure to 2 rabbit 50% lethal doses (LD) of BoNT serotype E (BoNT/E), preceding any visible symptoms. All rabbits treated with antitoxin immediately following symptom onset survived. Postsymptom antitoxin efficacy was further evaluated in relation to toxin and antitoxin dosages as well as delayed antitoxin administration. Our system enabled us to demonstrate, for the first time, full antitoxin protection of animals treated with antitoxin after the onset of objective and quantitative type E botulism symptoms. This model may be utilized to evaluate the efficacy of antitoxins for additional serotypes of BoNT as well as that of next-generation anti-BoNT drugs that enter affected cells and act when antitoxin is no longer effective.

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“…Botulinum antitoxin is currently the treatment of choice for botulinum toxin intoxication. The efficacy of antitoxin treatment decreases with time postexposure and higher doses, which may induce adverse effects, are required to confer protection (53,54).…”

mentioning

confidence: 99%

The Receptor Binding Domain of Botulinum Neurotoxin Serotype A (BoNT/A) Inhibits BoNT/A and BoNT/E Intoxications In Vivo

David

Diamant

Barnea

et al. 2013

Clin Vaccine Immunol

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The receptor binding domain of botulinum neurotoxin (BoNT), also designated the C terminus of the heavy chain (H C ), is a promising vaccine candidate against botulism. In this study, a highly efficient expression system for the protein was developed in Escherichia coli, which provided yields that were 1 order of magnitude higher than those reported to date (350 mg H C per liter). The product was highly immunogenic, protecting mice from a challenge with 10 5 50% lethal dose (LD 50 ) after a single vaccination and generating a neutralizing titer of 49.98 IU/ml after three immunizations. In addition, a single boost with H C increased neutralizing titers by up to 1 order of magnitude in rabbits hyperimmunized against toxoid. Moreover, we demonstrate here for the first time in vivo inhibition of BoNT/A intoxication by H C /A, presumably due to a blockade of the neurotoxin protein receptor SV2. Administration of H C /A delayed the time to death from 10.4 to 27.3 h in mice exposed to a lethal dose of BoNT/A (P ‫؍‬ 0.0005). Since BoNT/A and BoNT/E partially share SV2 isoforms as their protein receptors, the ability of H C /A to cross-inhibit BoNT/E intoxication was evaluated. The administration of H C /A together with BoNT/E led to 50% survival and significantly delayed the time to death for the nonsurviving mice (P ‫؍‬ 0.003). Furthermore, a combination of H C /A and a subprotective dose of antitoxin E fully protected mice against 850 mouse LD 50 of BoNT/E, suggesting complementary mechanisms of protection consisting of toxin neutralization by antibodies and receptor blocking by H C /A.

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Development and preclinical evaluation of a new F(ab′)2 antitoxin against botulinum neurotoxin serotype A

Cited by 13 publications

References 25 publications

New equine antitoxins to botulinum neurotoxins serotypes A and B

New equine antitoxins to botulinum neurotoxins serotypes A and B

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

The Receptor Binding Domain of Botulinum Neurotoxin Serotype A (BoNT/A) Inhibits BoNT/A and BoNT/E Intoxications In Vivo

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