Importance of Intravenous Injection of Diphtheria Antiserum

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

doi:10.1016/s0140-6736(58)92061-0

Cited by 12 publications

(1 citation statement)

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“…Although guinea pigs do not exhibit respiratory symptoms when subcutaneously challenged with diphtheria toxin, they do express the cell surface receptor for the toxin and are susceptible to the end organ effects of systemic toxin (peripheral neuropathy, cardiomyopathy). 22 A modified version of the National Institutes of Health (NIH) Minimum Requirements assay designed for determination of potency of polyclonal DAT was utilized to estimate the concentration of S315 mAb that provides equivalent protection to DAT in guinea pigs subcutaneously injected with diphtheria toxin. 23 We used this model to evaluate the relative potency of a novel human mAb to equine polyclonal DAT utilizing 2 different endpoints: overall survival at 30 d post-toxin exposure and survival without hind limb paralysis.…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%