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Infection and immunity2013; 81(11); 3992-4000; doi: 10.1128/IAI.00462-13

Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication.

Abstract: Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.
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Publication Date: 2013-08-12 PubMed ID: 23940209PubMed Central: PMC3811848DOI: 10.1128/IAI.00462-13Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article focuses on the development of a human monoclonal antibody as an alternative treatment for diphtheria instead of using equine diphtheria antitoxin which is in short supply and not commercially available in certain countries including the US.

Objective and Background of the Study

  • The study aims to establish an alternative to diphtheria antitoxin (DAT) for the treatment of Corynebacterium diphtheriae or diphtheria.
  • DAT, the typical treatment for over 100 years, is derived from equine (horse) antibodies and is not readily available globally.
  • The exploration of human monoclonal antibodies (hMAbs) as an alternative is considered a more reliable and safer option.

Methods

  • The researchers obtained hMAbs from antibody-secreting cells in the blood of human volunteers who were immunized.
  • A diverse range of hMAbs were isolated that had the ability to recognize not just diphtheria toxoid, but also several recombinant protein fragments of the diphtheria toxin.

Results

  • In the study, 45 unique hMAbs were tested for neutralization capability against diphtheria toxin using in vitro cytotoxicity assays. The most effective, identified as 315C4, achieved a 50% neutralization at a concentration of 0.65 ng/ml.
  • Further tests on guinea pigs using an in vivo lethality model showed that a 25µg dosage of 315C4 fully protected them from toxin-induced illness and death. This represents a relative potency of 64 International Units (IU) per milligram. In comparison, 1.6 IU of DAT was required to achieve the same level of protection.
  • It was also established that 315C4 binds to the receptor-binding domain of the diphtheria toxin, blocking its ability to bind to its target receptor, known as the heparin-binding epidermal growth factor-like growth factor.

Conclusions and Future Implications

  • The discovery and subsequent study of a potent and specific human neutralizing antibody against diphtheria toxin opens possibilities for a potentially effective therapeutic alternative to equine DAT.
  • This could provide a more readily available and safer option to treat diphtheria, a disease that remains endemic in many parts of the world.

Cite This Article

APA
Sevigny LM, Booth BJ, Rowley KJ, Leav BA, Cheslock PS, Garrity KA, Sloan SE, Thomas W, Babcock GJ, Wang Y. (2013). Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication. Infect Immun, 81(11), 3992-4000. https://doi.org/10.1128/IAI.00462-13

Publication

Infection and immunity
ISSN: 1098-5522
NlmUniqueID: 0246127
Country: United States
Language: English
Volume: 81
Issue: 11
Pages: 3992-4000

Researcher Affiliations

Sevigny, Leila M
  • MassBiologics of the University of Massachusetts Medical School, Boston, Massachusetts, USA.
Booth, Brian J
    Rowley, Kirk J
      Leav, Brett A
        Cheslock, Peter S
          Garrity, Kerry A
            Sloan, Susan E
              Thomas, William
                Babcock, Gregory J
                  Wang, Yang

                    MeSH Terms

                    • Animals
                    • Antibodies, Monoclonal / isolation & purification
                    • Antibodies, Monoclonal / therapeutic use
                    • Cell Line
                    • Corynebacterium diphtheriae / immunology
                    • Diphtheria / prevention & control
                    • Diphtheria Antitoxin / isolation & purification
                    • Diphtheria Antitoxin / therapeutic use
                    • Diphtheria Toxin / antagonists & inhibitors
                    • Disease Models, Animal
                    • Epitope Mapping
                    • Guinea Pigs
                    • Healthy Volunteers
                    • Humans
                    • Immunotherapy / methods
                    • Neutralization Tests
                    • Protein Binding
                    • Survival Analysis

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