A Breath of Fresh Air: Botulism Antidote in Development

Courtesy Photo | A single dose of Cyto-111 provides protection in mice at times refractory to antitoxin treatment. Mice lethally intoxicated with 2x LD50 BoNT/A become symptomatic between 6-8 hours after intoxication. Treatment was initiated with a single dose of Cyto-111 or antitoxin (sufficient to neutralize 10,000x LD50) administered at different times post-intoxication. Whereas a single treatment of Cyto-111 significantly protected mice from death at all time points, antitoxin was only partially effective at 6 hours after intoxication, and became less effective at longer treatment latencies. This data indicates that intraneuronal activity of Cyto-111 reverses symptoms of botulism at time when current standard-of-care fails. * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001. (Image courtesy of Konstantin Ichtchenko, Ph.D.)  

FORT BELVOIR, VA, UNITED STATES

05.23.2018

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

Odorless, tasteless and difficult to detect, botulinum neurotoxins (BoNTs) are some of the most toxic poisons on earth. A teaspoon of pure BoNT powder has the potential to kill up to 10 million people, posing a serious threat to warfighters and civilians if weaponized. Perhaps even more worrying, the toxin can be produced from common sources using widely-published methods. The Defense Threat Reduction Agency’s Chemical and Biological Technologies Department is addressing this threat by funding the development of a ground-breaking therapeutic to treat respiratory symptoms that will increase survivability.

BoNTs cause neuromuscular paralysis by severing proteins necessary for neurotransmitter release, resulting in clinical botulism and death by asphyxiation at lethal doses. The emergence of neuromuscular weakness is typically the first sign of exposure. Currently, there is no countermeasure to reverse intoxication. The currently approved mass-market treatment for exposure to BoNTs is only effective while the toxin remains in circulation – it is ineffective against toxin that has been internalized into neurons. Once internalized, the toxin can persist for months causing prolonged respiratory disease. An urgent need exists for a botulism antidote capable of disrupting toxin activity within neurons.

Konstantin Ichtchenko, Ph.D., has bioengineered a novel mechanism to specifically deliver functional, single domain antibodies to the presynaptic compartment of neurons where the toxic BoNT protease resides. Using this technology platform, Ichtchenko and his team have developed a revolutionary post-symptomatic, intra-neuronal botulism antidote, named Cyto-111. It is the first botulism therapeutic found to reverse respiratory symptoms and increase chances of survival following symptomatic botulism.

Cyto-111 is an antibody fusion protein, consisting of a single domain antibody against the intra-neuronal toxin protease fused to a proprietary recombinant molecular vehicle. Acting as a 'Trojan horse,’ the molecular vehicle delivers the antibody to the presynaptic compartment of intoxicated neurons. The countermeasure has been demonstrated to be effective in multiple in vitro systems, and in three species (mice, rats and guinea pigs).

Cyto-111 is also effective as a prophylactic against BoNT intoxication. This prophylactic indication would be especially important for warfighters entering hostile territory.
The U.S. Medical Research Institute of Chemical Defense established a comprehensive infrastructure to evaluate the safety and efficacy of botulinum countermeasures using physiologically relevant in vitro and in vivo models. This infrastructure supports the studies required to file an investigational new drug application to the U.S. Food and Drug Administration. Currently, Cyto-111 is undergoing preclinical testing in non-human primates.

The overall objective of these collaborative studies is to establish a countermeasure that effectively minimizes the threat from weaponized BoNT to both warfighters and civilians, enabling survival of BoNT exposure and, ultimately, mission success.

POC: Mike Johnson; [e-mail]

• Date Taken: 05.23.2018
• Date Posted: 05.23.2018 09:11
• Story ID: 278058
• Location: FORT BELVOIR, VA, US