Safety and pharmacodynamics of a novel recombinant botulinum toxin E (rBoNT-E): Results of a phase 1 study in healthy male subjects compared with abobotulinumtoxinA (Dysport®)

Article

Author: Volteau, Magali ; Pons, Laurent ; Picaut, Philippe ; Vilain, Claire

Naturally occurring botulinum toxin (BoNT) serotypes have different pharmacological features of therapeutic and aesthetic interest. This phase 1, double-blind, placebo-controlled study (EudraCT: 2016-002609-20) assessed safety, tolerability and pharmacodynamics (PD) of the first recombinant BoNT serotype E (rBoNT-E) versus abobotulinumtoxinA (Dysport®), administered to extensor digitorum brevis (EDB) of healthy males. Subjects were randomised 3:1 (n = 28) to single ascending rBoNT-E (0.04-3.6 ng) doses or placebo. A further 24 subjects received abobotulinumtoxinA (20, 40, or 70 U) or placebo. PD were assessed using compound muscle action potential (CMAP) amplitude. Demographics were similar between groups. All rBoNT-E doses were well tolerated (no severe treatment-emergent adverse events [TEAEs], serious adverse events, or treatment-related toxicities). Most TEAEs were mild/moderate and treatment-unrelated. rBoNT-E had a faster onset of action (days 1-2 post-injection), greater peak effect (>90% CMAP inhibition), and shorter duration of effect at highest tested doses versus abobotulinumtoxinA (onset of action ≤7 days post-injection; 70% maximal CMAP inhibition). rBoNT-E duration of effect was 2-7 weeks versus >26 weeks for abobotulinumtoxinA. Dose-dependent effects were observed for magnitude and duration of EDB CMAP inhibition, plateauing at 0.9 and 3.6 ng. rBoNT-E demonstrated a good safety profile and a PD profile that may address unmet therapeutic and aesthetic patient needs.

01 Jan 2018·Indian Journal of Medical ResearchQ4 · MEDICINE

Development of immunodetection system for botulinum neurotoxin serotype E

Q4 · MEDICINE

ArticleOA

Author: Ponmariappan, Sarkaraisamy ; Sarita, R ; Kamboj, Dev Vrat ; Sharma, Arti ; Jain, A K

Background & objectivesBotulism, a potentially fatal paralytic illness, is caused by the botulinum neurotoxins (BoNTs) secreted by Clostridium botulinum. It is an obligate anaerobic, Gram-positive, spore-forming bacterium. BoNTs are classified into seven serotypes based on the serological properties. Among these seven serotypes, A, B, E and, rarely, F are responsible for human botulism. The present study was undertaken to develop an enzyme-linked immunosorbent assay (ELISA)-based detection system for the detection of BoNT/E.MethodsThe synthetic gene coding the light chain of BoNT serotype E (BoNT/E LC) was constructed using the polymerase chain reaction primer overlapping method, cloned into pQE30UA vector and then transformed into Escherichia coli M15 host cells. Recombinant protein expression was optimized using different concentrations of isopropyl-β-D-1-thiogalactopyranoside (IPTG), different temperature and the rBoNT/E LC protein was purified in native conditions using affinity column chromatography. The purified recombinant protein was checked by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and further confirmed by western blot and matrix-assisted laser desorption ionization-tandem time-of-flight (MALDI-TOF). Polyclonal antibodies were generated against rBoNT/E LC using Freund's adjuvant in BALB/c mice and rabbit. Sandwich ELISA was optimized for the detection of rBoNT/E LC and native crude BoNT/E, and food matrix interference was tested. The developed antibodies were further evaluated for their specificity/cross-reactivity with BoNT serotypes and other bacterial toxins.ResultsBoNT/E LC was successfully cloned, and the maximum expression was achieved in 16 h of post-induction using 0.5 mM IPTG concentration at 25°C. Polyclonal antibodies were generated in BALB/c mice and rabbit and the antibody titre was raised up to 128,000 after the 2^nd booster dose. The developed polyclonal antibodies were highly specific and sensitive with a detection limit about 50 ng/ml for rBoNT/E LC and 2.5×10^[3] MLD₅₀ of native crude BoNT/E at a dilution of 1:3000 of mouse (capturing) and rabbit (revealing) antibodies. Further, different liquid, semisolid and solid food matrices were tested, and rBoNT/E LC was detected in almost all food samples, but different levels of interference were detected in different food matrices.Interpretation & conclusionsThere is no immune detection system available commercially in India to detect botulism. The developed system might be useful for the detection of botulinum toxin in food and clinical samples. Further work is in progress.

09 Aug 2017·Protein & Peptide LettersQ4 · BIOLOGY

In-Vivo Neutralization of Botulinum Neurotoxin Serotype E Using Rabbit Polyclonal Antibody Developed against BoNT/E Light Chain

Q4 · BIOLOGY

Article

Author: Ponmariappan, S. ; Jain, A. K. ; Rani, Sarita ; Sharma, Arti ; Kamboj, D. V.

BACKGROUNDClostridium botulinum is an obligate anaerobic, Gram positive bacterium that secretes extremely toxic substances known as botulinum neurotoxins (BoNTs) that cause serious paralytic illness called botulism. Based upon the serological properties, these neurotoxin have been classified into seven serotypes designated from A to G. Due to extreme toxicity of BoNTs, these neurotoxins have been designated as category A biowarfare agents. There is no commercial neutralizing antibody available for the treatment of botulism. Hence there is an urgent need to develop therapeutic intervention for prevention and cure of botulism within short period. BoNT antiserum injection is still the effective treatment.METHODIn the present study, the recombinant light chain of BoNT/E was successfully purified in soluble form. The purified rBoNT/E LC was used for the generation of polyclonal antibody in rabbit. In order to find out the neutralizing capacity of generated antisera, rabbit antiserum was incubated with 20 LD50 of botulinum neurotoxin type E for 1 hour at 37°C and then injected intraperitoneally (IP) into mice. Further in another set of experiments antiserum was administered in different ways that included administration of - antiserum and BoNT/E toxin simultaneously without preincubation, one after another at the same and different time points for its therapeutic ability. To find out cross neutralization capacity, rBoNT/E LC antiserum was pre-incubated with 5 LD50 of BoNT/A, BoNT/B, BoNT/F and then injected (IP) into mice. In all the cases mice were observed continuously for 96 hours.RESULTThe results clearly indicate that developed polyclonal rabbit antiserum showed serotype specific neutralization of BoNT/E toxin only but not of BoNT/A, BoNT/B and BoNT/F.CONCLUSIONThe developed antibodies will be used for preventive and therapeutic intervention of type 'E' botulism.

100 Deals associated with Botulinum toxin E(Ipsen SA)

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Indication	Highest Phase	Country/Location	Organization	Date
Muscle Spasticity	Phase 1	-	Ipsen SA	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


MDS2019	Phase 1	-	28	rBoNT-E	(wjrcnyfprg) = Most treatment-emergent adverse events were considered unrelated to treatment, and no unexpected treatment-related toxicities were identified with rBoNT-E or aboBoNT-A uiyxxntegq (mnajfqjfng )	Positive	22 Sep 2019
				aboBoNT-A

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