ArticleJournal of molecular biology2017
Epitopes and Mechanism of Action of the Clostridium difficile Toxin A-Neutralizing Antibody Actoxumab.
Article in Journal of molecular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 42 citations in OpenAlex.
- Development of Peptide Glucosyltransferase Inhibitors With Comprehensive Coverage Across Clostridioides difficile Toxin B Sub-Types.Biotechnology and bioengineering · 2026Article
- Review
- Mouse monoclonal antibodies againstInfection and immunity · 2025Article
- Large Clostridial Toxins: A Brief Review and Insights into Antigen Design for Veterinary Vaccine Development.Molecular biotechnology · 2025Review
- Study on immunogenicity of recombinant ferritin hemagglutinin of canine distemper virus.Virology journal · 2025Article
- Mechanisms ofFrontiers in cellular and infection microbiology · 2025Review
- Development and characterization of phage display-derived anti-toxin antibodies neutralizing TcdA and TcdB ofMicrobiology spectrum · 2023Article
- Structure and conformational dynamics ofLife science alliance · 2022Article
- Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics.Nature reviews. Microbiology · 2022Review
- Human α-Defensin-6 NeutralizesInternational journal of molecular sciences · 2022Article
- Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives.ACS infectious diseases · 2022Review
- Immunoinformatics Approach Toward the Introduction of a Novel Multi-Epitope Vaccine AgainstFrontiers in immunology · 2022Article
- Neutralizing epitopes onFrontiers in immunology · 2022Article
- Novel structural insights for a pair of monoclonal antibodies recognizing non-overlapping epitopes of the glucosyltransferase domain ofCurrent research in structural biology · 2022Article
- Large Clostridial Toxins: Mechanisms and Roles in Disease.Microbiology and molecular biology reviews : MMBR · 2021Review
- A novel single-domain antibody multimer that potently neutralizes tetanus neurotoxin.Vaccine: X · 2021Article
- Targeted Therapeutic Strategies in the Battle Against Pathogenic Bacteria.Frontiers in pharmacology · 2021Review
- Generation and Characterization of Typhoid Toxin-Neutralizing Human Monoclonal Antibodies.Infection and immunity · 2020Article
- Recent advances in the treatment ofInfection and drug resistance · 2019Article
- Article
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
The exotoxins toxin A (TcdA) and toxin B (TcdB) are produced by the bacterial pathogen Clostridium difficile and are responsible for the pathology associated with C. difficile infection (CDI). The antitoxin antibodies actoxumab and bezlotoxumab bind to and neutralize TcdA and TcdB, respectively. Bezlotoxumab was recently approved by the FDA for reducing the recurrence of CDI. We have previously shown that a single molecule of bezlotoxumab binds to two distinct epitopes within the TcdB combined repetitive oligopeptide (CROP) domain, preventing toxin binding to host cells. In this study, we characterize the binding of actoxumab to TcdA and examine its mechanism of toxin neutralization. Using a combination of approaches including a number of biophysical techniques, we show that there are two distinct actoxumab binding sites within the CROP domain of TcdA centered on identical amino acid sequences at residues 2162-2189 and 2410-2437. Actoxumab binding caused the aggregation of TcdA especially at higher antibody:toxin concentration ratios. Actoxumab prevented the association of TcdA with target cells demonstrating that actoxumab neutralizes toxin activity by inhibiting the first step of the intoxication cascade. This mechanism of neutralization is similar to that observed with bezlotoxumab and TcdB. Comparisons of the putative TcdA epitope sequences across several C. difficile ribotypes and homologous repeat sequences within TcdA suggest a structural basis for observed differences in actoxumab binding and/or neutralization potency. These data provide a mechanistic basis for the protective effects of the antibody in vitro and in vivo, including in various preclinical models of CDI.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.