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Target Concepts:
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Query: EC:3.4.24.69 (
botulinum neurotoxin
)
1,901
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Human botulism is most commonly caused by
botulinum neurotoxin
(
BoNT
) serotypes A, B, and E. For this work, we sought to develop a human monoclonal antibody (mAb)-based antitoxin capable of binding and neutralizing multiple subtypes of
BoNT
/E. Libraries of yeast-displayed single chain Fv (scFv) antibodies were created from the heavy and light chain variable region genes of humans immunized with pentavalent-toxoid- and
BoNT
/E-binding scFv isolated by Fluorescence-Activated Cell Sorting (FACS). A total of 10 scFv were isolated that bound one or more
BoNT
/E subtypes with nanomolar-level equilibrium dissociation constants (K
D
). By diversifying the V-regions of the lead mAbs and selecting for cross-reactivity, we generated three scFv that bound all four
BoNT
/E subtypes tested at three non-overlapping epitopes. The scFvs were converted to IgG that had K
D
values for the different
BoNT
/E subtypes ranging from 9.7 nM to 2.28 pM. An equimolar combination of the three mAbs was able to potently neutralize
BoNT
/E1,
BoNT
/E3, and
BoNT
/E4 in a mouse neutralization assay. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing multiple
BoNT
/E subtypes. A derivative of the three-antibody combination (
NTM
-1633) is in pre-clinical development with an investigational new drug (IND) application filing expected in 2018.
...
PMID:A Three Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotype E Subtypes. 2949 81
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.
...
PMID:Safety and Pharmacokinetics of a Four Monoclonal Antibody Combination Against Botulinum C and D Neurotoxins. 3159 Nov 30
