A next generation cross-serotype binding antitoxin for treatment of post-exposure botulinum poisoning - PROJECT SUMMARY Botulinum poisoning is a rare neurotoxin-mediated syndrome that results in progressive respiratory and muscular paralysis and leads to death if untreated. Aerosolized botulinum neurotoxins (BoNT) are particularly lethal and of major concern as potential biological weapons. Given this concern, the U.S. has stockpiled the only approved antidote for BoNT poisoning, BAT®, to be used in case of intentional or unintentional release of infectious BoNT. BAT® consists of a polyclonal mixture of antibodies against botulinum toxin types A-G that is derived from equine serum following a complicated and time-consuming manufacturing process. While effective in abstracting BoNT in circulation, BAT® is associated with a number of primary safety concerns that limit its use to patients with a confirmed botulism diagnosis. As the earliest symptoms of botulism poisoning are non-specific, BAT® treatment is often administered well into the disease course when many patients require additional aggressive supportive care measures such as mechanical ventilation for survival. As such, a next generation BoNT antitoxin that is human-compatible, confers protection against multiple serotypes, demonstrates rapid clearance of circulating toxin, and can be safely administered as an early intervention upon suspicion of BoNT exposure is critically needed to replace BAT®. To address this need, NightHawk Biosciences, Inc. (NHB) is developing a multivalent botulinum antitoxin product based on their novel Terminator technology, which sequesters target pathogens by binding them to circulating red blood cells (RBCs) via receptor type I (CR1) and delivers them to fixed-tissue macrophages for engulfment. To date, experimental results indicate that the Terminator system can be used to induce RBC immune adherence to effectively remove a variety of pathogens from circulation, drastically reducing the blood concentration of pathogenic particles within minutes of treatment. Critically, Terminator has demonstrated good safety and tolerability in humans, positioning it potentially as a drug of low regret that can be safely administered prior to clinical confirmation of diagnosis. In this Phase I SBIR, NHB will advance a Terminator BoNT antitoxin candidate consisting of a unique antibody complex in which a human CR1 antibody is fused to an antibody targeting the BoNT serotypes associated with human disease (A, B, E, and F). To adequately de-risk this candidate for IND-enabling studies, this proposal will 1) demonstrate selective and high- affinity cross-serotype binding and specific uptake into macrophages; 2) define the kinetics of Terminator- mediated clearance of BoNTs in vivo; and 3) demonstrate efficacy to protect against BoNT poisoning in a postexposure mouse model. Phase II studies will expand efficacy evaluations into aerosol challenge models and initiate IND-enabling toxicology and dose-refining studies.
