The Novel Clostridial Neurotoxin Produced by Strain IBCA10-7060 Is Immunologically Equivalent to BoNT/HA

Fan, Yuding; Barash, Jason R.; Conrad, Fraser; Lou, Jianlong; Tam, Christina; Cheng, Luisa W.; Arnon, Stephen S.; Marks, James D.

doi:10.3390/toxins12010009

Cited by 16 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Botulinum toxin (BoNT), the most potent toxin known to humans, (1,2) is produced by the obligate anaerobic organism Clostridium botulinum with 7 neurotoxin serotypes identified to date (A-G). (3,4) Mechanisms of BoNT intoxication include ingestion of food contaminated by preformed toxin, infection of wounds, (5) toxicoinfection in infants and adults, iatrogenic chemodenervation. (6) An additional theoretical mechanism is dispersal of a weaponized toxin (7,8) After toxicoinfection in infants, foodborne intoxication is most common; there is also a rising incidence of wound botulism among intravenous drug users.…”

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

Guptill

Raja

Juel

et al. 2021

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Objective Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given post-exposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. Methods This double-blind, single-center, placebo-controlled dose escalation study, randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at pre-specified time points for PK and immunogenicity analyses. Results Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life >20 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent anti-drug antibody responses in the low and middle dosing groups and none at the highest dose. Interpretation NTM-1632 is well-tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and post-exposure prophylaxis.

show abstract

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

Guptill

Raja

Juel

et al. 2021

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Botulinum neurotoxin (BoNT) is one of the most toxic substances known in nature and classified as a Tier 1 select agent by the Centers for Disease Control and Prevention (CDC) in the United States [ 1 , 2 , 3 ]. There are at least seven immunologically distinct serotypes of BoNT (A–G) that include more than 40 subtypes [ 4 , 5 , 6 , 7 , 8 ]. BoNT/E is one of the four BoNT serotypes (with BoNT/A, BoNT/B, and rarely BoNT/F) known to cause human botulism.…”

Section: Introductionmentioning

confidence: 99%

Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells

Lam

Perry

Shoemaker

et al. 2020

Toxins

View full text Add to dashboard Cite

Botulinum neurotoxin serotype E (BoNT/E) is one of the major causes of human botulism, which is a life-threatening disease caused by flaccid paralysis of muscles. After receptor-mediated toxin internalization into motor neurons, the translocation domain (HN) of BoNT/E transforms into a protein channel upon vesicle acidification in endosomes and delivers its protease domain (LC) across membrane to enter the neuronal cytosol. It is believed that the rapid onset of BoNT/E intoxication compared to other BoNT serotypes is related to its swift internalization and translocation. We recently identified two neutralizing single-domain camelid antibodies (VHHs) against BoNT/E1 termed JLE-E5 and JLE-E9. Here, we report the crystal structures of these two VHHs bound to the LCHN domain of BoNT/E1. The structures reveal that these VHHs recognize two distinct epitopes that are partially overlapping with the putative transmembrane regions on HN, and therefore could physically block membrane association of BoNT/E1. This is confirmed by our in vitro studies, which show that these VHHs inhibit the structural change of BoNT/E1 at acidic pH and interfere with BoNT/E1 association with lipid vesicles. Therefore, these two VHHs neutralize BoNT/E1 by preventing the transmembrane delivery of LC. Furthermore, structure-based sequence analyses show that the 3-dimensional epitopes of these two VHHs are largely conserved across many BoNT/E subtypes, suggesting a broad-spectrum protection against the BoNT/E family. In summary, this work improves our understanding of the membrane translocation mechanism of BoNT/E and paves the way for developing VHHs as diagnostics or therapeutics for the treatment of BoNT/E intoxication.

show abstract

“…One of the initial variants of BoNT identified through in silico data mining of gene sequences was BoNT/H. This was identified from a toxin reported to cause infant botulism in 2014 by the C. botulinum strain IBCA10-7060 [ 53 ]. Initially, the authors presumed that it was a novel variant, a bivalent strain of B2 toxin, which was denoted as serotype H. In early experiments, it was found that the toxin could be weakly neutralised by antibodies against currently known serotypes.…”

Section: Recombinant Botulinum Toxin and Application Of In Silico mentioning

confidence: 99%

Botulinum Toxin: An Update on Pharmacology and Newer Products in Development

Choudhury

Baker

Chatterjee

et al. 2021

Toxins

View full text Add to dashboard Cite

Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic.

show abstract

The Novel Clostridial Neurotoxin Produced by Strain IBCA10-7060 Is Immunologically Equivalent to BoNT/HA

Abstract: Background: Botulinum neurotoxins (BoNTs) comprise seven agreed-on serotypes,

Cited by 16 publications

References 33 publications

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells

Botulinum Toxin: An Update on Pharmacology and Newer Products in Development

Contact Info

Product

Resources

About