Botulinum Neurotoxins (BoNTs)—Antibody and Vaccine

Lou, Jianlong; Marks, James D.

doi:10.3390/toxins10120495

Cited by 7 publications

(8 citation statements)

References 15 publications

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“…Their production is highly reproducible compared to animal hyperimmune sera thereby preventing batch to batch variations in antibody affinity 50 . Over the last decade, several neutralizing mAbs against the distinct BoNT types have been generated 17,18,54 . However, mAbs are specific of single epitopes only and extended protective coverage most often requires the combination of several mAbs.…”

Section: Discussionmentioning

confidence: 99%

“…50 Over the last decade, several neutralizing mAbs against the distinct BoNT types have been generated. 17,18,54 However, mAbs are specific of single epitopes only and extended protective coverage most often requires the combination of several mAbs. For example, the association of three distinct mAbs targeting F I G U R E 2 TA12 blocks BoNT/A1 binding to SV2C-LD by targeting a common area on H C A1.…”

Section: Discussionmentioning

confidence: 99%

“…17 Monoclonal antibodies (mAbs) represent, therefore, a promising alternative strategy to treat botulism with the advantage of being better tolerated by patients and produced in a more reproducible and safer way than animal hyperimmune serum. Various murine or humanized mAbs raised against whole BoNTs or BoNT subdomains have been evaluated for their neutralizing potency and their possible therapeutic use (review in17, 18). Most often, efficient toxin neutralization requires a combination of several mAbs.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A

et al. 2021

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Compared to conventional antisera strategies, monoclonal antibodies (mAbs) represent an alternative and safer way to treat botulism, a fatal flaccid paralysis due to botulinum neurotoxins (BoNTs). In addition, mAbs offer the advantage to be produced in a reproducible manner. We previously identified a unique and potent mouse mAb (TA12) targeting BoNT/A1 with high affinity and neutralizing activity. In this study, we characterized the molecular basis of TA12 neutralization by combining Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS) with site-directed mutagenesis and functional studies. We found that TA12 recognizes a conformational epitope located at the interface between the H CN and H CC subdomains of the BoNT/A1 receptor-binding domain (H C ). The TA12-binding interface shares common structural features with the ciA-C2 VHH epitope and lies on the face opposite recognized by ciA-C2-and the CR1/CR2-neutralizing mAbs. The single substitution of N1006 was sufficient to affect TA12 binding to H C confirming the position of the epitope. We further uncovered that the TA12 epitope overlaps with the BoNT/ A1-binding site for both the neuronal cell surface receptor synaptic vesicle glycoprotein 2 isoform C (SV2C) and the GT1b ganglioside. Hence, TA12 potently blocks the entry of BoNT/A1 into neurons by interfering simultaneously with the binding of SV2C and to a lower extent GT1b. Our study reveals the unique neutralization mechanism of TA12 and emphasizes on the potential of using single mAbs for the treatment of botulism type A.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A

et al. 2021

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“…Currently, in order to circumvent this problem several other serotypes of BTX than BTX-A or BTX-B have been explored as potential therapeutic agents in humans. BTX-E and BTX-F seem to be alternative serotypes in patients who had become resistant to BTX-A and found to be effective in dystonic patients (44,60,61).…”

Section: Antibody Development Against Botulinum Toxinmentioning

confidence: 99%

Pharmacology of Botulinum Toxins: From Poison to Remedy

Büyükafşar

2020

Düzce Tıp Fakültesi Dergisi

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Botulinum toxin (BTX) is produced by autolysis of several strains of Clostridium botulinum, a gram-positive, spore-forming, rod-shaped, strictly anaerobic bacterium. However there are also non-clostridial microorganisms that are enable to produce the toxin. As some other beneficial poison, BTX also fits well the quotations by old scientists and philosophers like "Almost every substance can become a poison but only thing is the dose discriminating the difference" (Paracelsus, XVI century) or "Poisons can be employed as a means for the destruction of life or as agents for the treatment of the sick" (Claude Bernard, XIX century) or "Poison is a medicine, medicine is a poison" (Ahi Evran, XIII century). In the 1980's, Alan Scott first published articles on the use of BTX for the treatment of strabismus. The Food and Drug Administration of the USA (FDA) first approved botulinum toxin for the treatment of strabismus (crossed eye) blepharospasm (uncontrollable eye blinking) in 1989 and for glabellar rhytides in 2002, the first cosmetic indication. Since then BTX has been used for a verity of indications not only dermatological but also non-dermatological indications including onlabelled as well as off-labelled uses. In this review you will find the pharmacological profile of botulinum toxins, i.e., mode of action, pharmacokinetics, adverse effects, indications and contrindications, drug interactions, duration and site of action, etc. Furthermore, current commercial products and novel dosage forms as well as new perspective of BTX use will also be discussed.

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“…A novel vaccine-design strategy has been developed using the nontoxic recombinant domains of BoNTs as antigens, but not the full toxin. 11 , 12 Previous animal studies have demonstrated that the HC domains are nontoxic, and sufficient to generate a protective immune response against natural BoNTs. Besides, the recombinant Hc fragments can be synthesized in large quantities, and are less hazardous than traditional toxin-inactivated vaccines.…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of a tetravalent botulinum vaccine

Shi¹,

Liu

et al. 2022

Human Vaccines & Immunotherapeutics

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Botulinum neurotoxins (BoNTs) are the most toxic known proteins. Naturally occurring botulism in humans is caused by botulinum serotypes A, B, E, and F. Vaccination is an effective strategy to prevent botulism. In this study, a tetravalent botulinum vaccine (TBV) that can prevent serotypes A, B, E, and F was developed using the C-terminal receptor-binding domain of BoNT (Hc) as an antigen. To develop a suitable vaccine formulation, in vitro binding experiments of antigens and aluminum adjuvant in different buffers, and in vivo experiments of TBV at different antigen concentrations, were conducted. Our results showed that the optimal vaccine formulation buffer was a pH 6.0 phosphate buffer, and the suitable antigen concentration was 40 or 80 µg/ml of each antigen. A pilot-scale TBV was then prepared and evaluated for immunogenicity and stability. The results showed that TBV could elicit strong protective efficacy against each BoNT in mice, and remain effective after two years of storage at 4ºC, indicating that the preparation was stable and highly effective. Adsorption experiments also showed that the antigens could be well adsorbed by the aluminum adjuvant after 2 years of storage. Our results provide valuable experimental data supporting the development of a tetravalent botulinum vaccine, which is a promising candidate for the prevention of botulinum serotypes A, B, E, and F.

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Botulinum Neurotoxins (BoNTs)—Antibody and Vaccine

Abstract: Botulism, caused by exposure to one or more of the eight serotypes of botulinum neurotoxins (BoNTs) (BoNT/A through H), is often fatal without rapid treatment. [...]

Cited by 7 publications

References 15 publications

Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A

Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A

Pharmacology of Botulinum Toxins: From Poison to Remedy

Development and evaluation of a tetravalent botulinum vaccine

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