MassBiologics; Department of Pediatrics, Division of Immunology/Infectious Disease; Department of Quantitative Health Sciences
Bacterial Infections and Mycoses | Immunology of Infectious Disease | Immunoprophylaxis and Therapy
Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving > /= 27.5 microg of S315 or > /= 1.75 IU of DAT survived whereas animals receiving < /= 22.5 microg of S315 or < /= 1.25 IU of DAT died, yielding a potency estimate of 17 microg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 microg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.
anti-toxin, diphtheria, monoclonal antibody, potency
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Copyright © 2016 The Author(s).
DOI of Published Version
Virulence. 2016 Aug 17;7(6):660-8. doi: 10.1080/21505594.2016.1171436. Epub 2016 Apr 12. Link to article on publisher's site
Smith, Heidi L.; Cheslock, Peter S.; Leney, Mark; Barton, Bruce A.; and Molrine, Deborah C., "Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model" (2016). Pediatric Publications and Presentations. 175.
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