Abstract
Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT serotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1 mAbs, each with a distinct human or humanized variable region which bind to distinct epitopes on BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1 (IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three antibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse clinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation demonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure and long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences observed between males and females or among the individual antibodies in each formulation in half-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered to rats. The results presented were used to support the clinical investigation of antibody-based botulism antitoxins.
Highlights
Botulinum toxin (BoNT) is the most potent toxin known, with a long duration of action
Human botulism is caused by botulinum neurotoxin (BoNT) serotypes A, B, E, F [5,6,7,8,9], C, D, [10,11,12]
The clinical observations that were observed included chromodacryorrhea, exophthalmia, microphthalmia, red discharges in the noses or genitalia, alopecia, and soft stool. These effects were determined to be independent of dose by the attending veterinarian and most likely the result of the stress due to the dose administration procedures
Summary
Botulinum toxin (BoNT) is the most potent toxin known, with a long duration of action. Human botulism is caused by botulinum neurotoxin (BoNT) serotypes A, B, E, F [5,6,7,8,9], C, D, [10,11,12] and G [13] Due to their lethality and ease of distribution, BoNTs are classified as Category A agents by the US Centers for Disease Control and Prevention (CDC) [14]. They are Tier 1 agents as defined by the Federal Select Agent Program and are among the six agents with the highest risk for potential use as bioweapons. As a result of these threats, there is an urgent need for safe and effective therapies that could be stockpiled, as well as sensitive and rapid diagnostic tests
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