Monoclonal Antibody Combinations Prevent Serotype A and Serotype B Inhalational Botulism in a Guinea Pig Model.

Milan Tomic,Yero Espinoza,James Marks,Ronald Cobb,Doris Snow,Shauna Farr-Jones,Zachary Martinez,Nancy Niemuth,Christopher Earnhart,Emily Syar,Traci Pals,Khanh Pham,Dean Kobs

doi:10.3390/toxins11040208

Abstract

Botulinum neurotoxins (BoNT) are some of the most toxic proteins known, with a human LD50 of ~1 ng/kg. Equine antitoxin has a half-life in circulation of less than 1 day and is limited to a treatment rather than a prevention indication. The development of monoclonal antibodies (mAbs) may represent an alternative therapeutic option that can be produced at high quantities and of high quality and with half-lives of >10 days. Two different three mAb combinations are being developed that specifically neutralize BoNT serotypes A (BoNT/A) and B (BoNT/B). We investigated the pharmacokinetics of the anti-BoNT/A and anti-BoNT/B antibodies in guinea pigs (Cavia porcellus) and their ability to protect guinea pigs against an aerosol challenge of BoNT/A1 or BoNT/B1. Each antibody exhibited dose-dependent exposure and reached maximum circulating concentrations within 48 h post intraperitoneal or intramuscular injection. A single intramuscular dose of the three mAb combination protected guinea pigs against an aerosol challenge dose of 93 LD50 of BoNT/A1 and 116 LD50 of BoNT/B1 at 48 h post antibody administration. These mAbs are effective in preventing botulism after an aerosol challenge of BoNT/A1 and BoNT/B1 and may represent an alternative to vaccination to prevent type A or B botulism in those at risk of BoNT exposure.

Highlights

The botulinum neurotoxins (BoNTs) produced by bacteria of the genus Clostridium are the most toxic proteins known [1,2]
To determine the ability of these recombinant antitoxins to be used as an alternative to vaccination with rBV for the prevention of inhalational botulism, we evaluated the ability of NTM-1631 and NTM-1632 to prevent BoNT serotypes A (BoNT/A) and BoNT/B inhalational botulism in an aerosol challenge model in guinea pigs
To validate route of administration and determine timing of BoNT exposure, the concentration of each component monoclonal antibodies (mAbs) and the neutralizing antibody concentration (NAC) of NTM-1631 and NTM-1632 was evaluated in guinea pigs

Summary

Introduction

The botulinum neurotoxins (BoNTs) produced by bacteria of the genus Clostridium are the most toxic proteins known [1,2]. The HC binds receptors on the presynaptic membrane [5,6] leading to BoNT endocytosis. Botulism can occur by the inhalation route [19,20] but there is only a single case report of naturally occurring inhalational botulism in laboratory workers [21]. Each of these etiologies result in similar clinical symptoms including symmetrical cranial nerve palsies followed by descending, symmetric, flaccid muscle paralysis of voluntary muscles which may progress to respiratory compromise and death [16,22]

Methods

Results

Conclusion