On the pathogenesis of diphtheria

Tasman, Abel; Minkenhof, J. E.; Vink, Hans; Brandwijk, A. C.; Smith, Larry

doi:10.1007/bf02548444

Cited by 1 publication

(1 citation statement)

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“…Some of the surviving animals in the DAT or S315 dosed cohorts developed transient limb weakness, described historically in this model and attributed to toxin-mediated peripheral neuropathy. 24 Therefore, we sought to determine the doses of DAT and mAb required to prevent a systemic sign of toxicity, using hind limb paralysis (clinical score = 4) as a marker of end-organ damage.…”

Section: Resultsmentioning

confidence: 99%

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model

et al. 2016

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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 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg 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 µg/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.

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Section: Resultsmentioning

confidence: 99%