#Safety and Pharmacokinetics of a Four #Monoclonal #Antibody Combination Against #Botulinum C and D #Neurotoxins (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Safety and Pharmacokinetics of a Four Monoclonal Antibody Combination Against Botulinum C and D Neurotoxins

Doris M. Snow, Kathryn Riling, Angie Kimbler, Yero Espinoza, David Wong, Khanh Pham, Zachary Martinez, Carl N. Kraus, Fraser Conrad, Consuelo Garcia-Rodriguez, Ronald R. Cobb, James D. Marks, Milan T. Tomic

DOI: 10.1128/AAC.01270-19

 

ABSTRACT

Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as Tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A-G), which differ between 35% to 68% in amino acid sequence, necessitates the development of serotype specific countermeasures. We present results of a Phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (mAbs), each binding to non-overlapping epitopes on BoNT serotypes C and D resulting in potent toxin neutralization in rodents. This first-in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults (NCT03046550). Three cohorts of eight healthy subjects received a single intravenous dose of NTM-1634 or placebo at 0.33 mg/kg, 0.66 mg/kg or 1 mg/kg. Follow-up examinations and pharmacokinetic evaluations were continued up to 121 days post-infusion. Subjects were monitored using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetic parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well-tolerated with the expected half-lives for human mAbs and with minimal anti-drug antibodies detected over the dose ranges and duration of the study.

Copyright © 2019 Snow et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Botulism; Monoclonal antibodies.

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Reoccurrence of #botulinum #neurotoxin subtype A3 inducing food-borne #botulism, #Slovakia, 2015 (@eurosurveillanc, abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Eurosurveillance, Volume 22, Issue 32, 10 August 2017  / Surveillance and outbreak report

Reoccurrence of botulinum neurotoxin subtype A3 inducing food-borne botulism, Slovakia, 2015

L Mad’arová 1 , BG Dorner 2 3 , L Schaade 3 , V Donáth 4 , M Avdičová 1 , M Fatkulinová 1 , J Strhársky 1 , I Sedliačiková 1 , C Klement 1 5 , MB Dorner 2 3

Author affiliations: 1. Regional Authority of Public Health Banská Bystrica, Banská Bystrica, Slovakia; 2. Robert Koch Institute, Consultant laboratory for neurotoxin-producing clostridia (botulism, tetanus), Berlin, Germany; 3. Robert Koch Institute, Centre for Biological Threats and Special Pathogens, Berlin, Germany; 4. F. D. Roosevelt Teaching Hospital, Department of Neurology, Slovak Medical University, Banská Bystrica, Slovakia; 5. Slovak Medical University, Faculty of Public Health, Bratislava, Slovakia

Correspondence: Martin Bernhard Dorner (dornerm@rki.de)

Citation style for this article: Mad’arová L, Dorner BG, Schaade L, Donáth V, Avdičová M, Fatkulinová M, Strhársky J, Sedliačiková I, Klement C, Dorner MB. Reoccurrence of botulinum neurotoxin subtype A3 inducing food-borne botulism, Slovakia, 2015. Euro Surveill. 2017;22(32):pii=30591. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.32.30591

Received:10 June 2016; Accepted:25 November 2016

 

Abstract

A case of food-borne botulism occurred in Slovakia in 2015. Clostridium botulinum type A was isolated from three nearly empty commercial hummus tubes. The product, which was sold in Slovakia and the Czech Republic, was withdrawn from the market and a warning was issued immediately through the European Commission’s Rapid Alert System for Food and Feed (RASFF). Further investigation revealed the presence of botulinum neurotoxin (BoNT) subtype BoNT/A3, a very rare subtype implicated in only one previous outbreak (Loch Maree in Scotland, 1922). It is the most divergent subtype of BoNT/A with 15.4% difference at the amino acid level compared with the prototype BoNT/A1. This makes it more prone to evading immunological and PCR-based detection. It is recommended that testing laboratories are advised that this subtype has been associated with food-borne botulism for the second time since the first outbreak almost 100 years ago, and to validate their immunological or PCR-based methods against this divergent subtype.

Keywords: Clostridium Botulinum; Botulism; Slovakia.

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Identification and characterization of a novel #botulinum #neurotoxin (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Identification and characterization of a novel botulinum neurotoxin

Sicai Zhang, Geoffrey Masuyer, Jie Zhang, Yi Shen, Daniel Lundin, Linda Henriksson, Shin-Ichiro Miyashita, Markel Martínez-Carranza, Min Dong & Pål Stenmark

Nature Communications 8, Article number: 14130 (2017) / doi:10.1038/ncomms14130

Received: 13 July 2016 – Accepted: 02 December 2016 – Published online: 03 August 2017

 

Abstract

Botulinum neurotoxins are known to have seven serotypes (BoNT/A–G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a novel BoNT with a unique substrate profile. Its discovery posts a challenge to develop effective countermeasures, provides a novel tool for studying intracellular membrane trafficking, and presents a new potential therapeutic toxin for modulating secretions in cells.

Keywords: Botulism.

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#Botulism in #Italy, 1986 to 2015 (@eurosurveillanc, abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Eurosurveillance, Volume 22, Issue 24, 15 June 2017  / Surveillance and outbreak report

Botulism in Italy, 1986 to 2015

F Anniballi 1 2 , B Auricchio 1 2 , A Fiore 1 , D Lonati 3 , CA Locatelli 3 , F Lista 4 , S Fillo 4 , G Mandarino 5 , D De Medici 1

Author affiliations : 1. National Reference Centre for Botulism, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità (ISS), Rome, Italy; 2. These authors contributed equally to this work; 3. Poison Control Centre and National Toxicology Information Centre, IRCCS Maugeri Foundation Hospital, Pavia, Italy; 4. Histology and Molecular Biology Unit, Section Two, Army Medical and Veterinary Research Centre, Rome, Italy; 5. PENTA – The Joint Laboratory on Models and Methodology to Predict and Manage Large Scale Threats to Public Health, International Affairs Unit, Istituto Superiore di Sanità (ISS), Rome, Italy

Correspondence: Fabrizio Anniballi (fabrizio.anniballi@iss.it)

Citation style for this article: Anniballi F, Auricchio B, Fiore A, Lonati D, Locatelli CA, Lista F, Fillo S, Mandarino G, De Medici D. Botulism in Italy, 1986 to 2015. Euro Surveill. 2017;22(24):pii=30550. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.24.30550

Received: 08 August 2016; Accepted:03 February 2017

 

Abstract

Botulism is a rare but severe neuroparalytic disease caused by botulinum toxins. Because of its high potential impact on public health, botulism is a closely monitored communicable disease in Europe. In Italy, which has one of the highest incidence rates in Europe (0.03 cases per 100,000 population), botulism is monitored through a case-based passive surveillance system: the front-line physician who diagnoses a suspected case must notify the Local Health Units immediately, and the Ministry of Health’s office within 12 hours. From 1986 to 2015, 466 confirmed cases of botulism were recorded in Italy (of 1,257 suspected cases). Of these, 421 were food-borne (the most frequently seen form of botulism due to the consumption of improperly home-canned foods), 36 were infant botulism, which accounts for ca 50% of all these types of cases registered in Europe, six were wound-related and three were due to adult intestinal colonisation. This scenario suggests that stronger efforts should be made towards raising public awareness of the risk of food-borne botulism, especially with respect to home-preserved foods, as well as improving the training of front-line medical personnel, to ensure that a quick and accurate diagnosis of botulism can be made.

Keywords: Italy; Botulism; Food Safety.

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