Delving into the Latest Updates on NTM-1634 with Synapse

Overview

Basic Info

Drug Type

Biological products

Synonyms

BoNT C/D

Target

BTX

Action

inhibitors, modulators

Mechanism

BTX inhibitors(Botulinum toxin inhibitors), Immunomodulators

Therapeutic Areas

Infectious DiseasesNervous System DiseasesRespiratory Diseases+ [1]

Active Indication

BotulismInfluenza, HumanSevere Acute Respiratory Syndrome

Inactive Indication

Influenza A virus infection

Originator Organization

University of California

Active Organization

University of California

Resilience Government Services, Inc.

Dana-Farber Cancer Institute, Inc.

+ [1]

Inactive Organization

National University

License Organization

Agenus, Inc.

XOMA Royalty Corp.

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Clostridium botulinum type C and D strains produce serotype-specific or mosaic botulinum neurotoxin (BoNT). Botulinum C/D and D/C mosaic neurotoxins (BoNT/CD and /DC) are related to avian and bovine botulism, respectively. The two mosaic BoNTs cannot be differentiated from authentic type C and D BoNTs by the conventional serotyping method. In this study, we attempted to establish novel methods for the specific detection of BoNT/CD or/DC. Comparison with nontoxic component genes in type C and D strains revealed that the nucleotide sequence of the ha70 gene is well conserved among either serotype-specific or mosaic BoNT-producing strains. A multiplex PCR method with primers for the light chain of boNT, ntnh, and ha70 gene detection was developed for typing of the boNT gene in type C and D strains. Upon applying this method, twenty-seven type C and D strains, including authentic strains and the isolates from avian and bovine botulism, were successfully divided into type C, C/D mosaic, type D, and D/C mosaic BoNT-producing strains. We then prepared an immunochromatography kit with specific monoclonal antibody showing high binding affinity to each mosaic BoNT. BoNT/CD and /DC in the culture supernatant were detected with limits of detection of 2.5 and 10 LD(50), respectively. Furthermore, we confirmed the applicability of the kit for BoNT/DC using crude culture supernatant from a specimen from a bovine suspected of having botulism. These results indicate that the genetic and immunological detection methods are useful for the diagnosis of avian and bovine botulism.

Toxins

Characterization of Serotype CD Mosaic Botulinum Neurotoxin in Comparison with Serotype C and A

Article

Author: Hata, Tsuyoshi ; Karatsu, Shura ; Miyashita, Shin-Ichiro ; Huang, I Hsun ; Sagane, Yoshimasa ; Fujiishi, Mako ; Hosoya, Keita ; Morobishi, Tamaki ; Dong, Min ; Nagashima, Yuki

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, cleaves proteins involved in neurotransmitter release, thereby triggering flaccid paralyses, which are responsible for botulism. BoNT is classified into seven serotypes (BoNT/A-G); BoNT/A and BoNT/B are used as medical therapeutics and anti-wrinkle reagents. In this study, we investigated the efficacy of BoNT/CD, a mosaic toxin of BoNT/C and BoNT/D, to assess its potential as a therapeutic alternative for BoNT/A. In a cultured neuron assay, BoNT/CD cleaved syntaxin and SNAP-25 with higher efficacy than BoNT/C and BoNT/A. Intramuscularly administrated BoNT/CD induced dose-dependent muscle paralysis, and the paralysis lasted ~21 days in a mouse digit abduction score assay (BoNT/A-induced paralysis lasted ~30 days). BoNT/C failed to induce local paralysis without systemic toxicity. Multiple alignment analyses of the amino acid sequences of the receptor binding domain (HC) of eight BoNT/CDs and two BoNT/Ds showed sequence clustering in five groups. Comparing BoNT/CD strain 003-9 (BoNT/CD003-9) and strain 6813 (BoNT/CD6813) showed that both BoNT/CDs displayed similar efficacies in cultured neurons, but BoNT/CD003-9 displayed higher efficacy in a mouse model than BoNT/CD6813. These findings suggest that BoNT/CD may be a potential alternative for patients who do not respond to existing BoNT-based therapeutics.

ToxinsQ2 · MEDICINE

Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats

Q2 · MEDICINE

ArticleOA

Author: Tomic, Milan T ; Wong, David ; Der, Kenneth ; Ahene, Ago ; Cobb, Ronald R ; Marks, James D ; Martinez, Zachary ; Pham, John ; Espinoza, Yero ; Farr-Jones, Shauna

Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT serotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1 mAbs, each with a distinct human or humanized variable region which bind to distinct epitopes on BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1 (IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three antibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse clinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation demonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure and long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences observed between males and females or among the individual antibodies in each formulation in half-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered to rats. The results presented were used to support the clinical investigation of antibody-based botulism antitoxins.

100 Deals associated with NTM-1634

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Influenza, Human	Phase 1	-	Harvard Medical School	-
Influenza, Human	Phase 1	-	University of California	-
Influenza, Human	Phase 1	-	Resilience Government Services, Inc.	-
Influenza, Human	Phase 1	-	Dana-Farber Cancer Institute, Inc.	-
Severe Acute Respiratory Syndrome	Phase 1	-	Resilience Government Services, Inc.	-
Severe Acute Respiratory Syndrome	Phase 1	-	Harvard Medical School	-
Severe Acute Respiratory Syndrome	Phase 1	-	University of California	-
Severe Acute Respiratory Syndrome	Phase 1	-	Dana-Farber Cancer Institute, Inc.	-
Influenza A virus infection	Preclinical	United States	National University	-
Severe Acute Respiratory Syndrome	Preclinical	United States	National University	-