Snakebites claim over 100,000 lives annually, with hundreds of thousands more suffering permanent disabilities like amputations. These devastating incidents primarily occur in Africa, Asia, and Latin America. Different regions face threats from various venomous snakes, with black mambas, cobras, and vipers posing dangers in Africa, and Indian cobras, kraits, and vipers plaguing Asia. In Central and northern South America, the Bothrops asper, a pit viper, is responsible for a significant portion of serious bites.
A team of venom and antivenom specialists dedicated four years to developing a therapeutic antibody to combat the Bothrops asper's venom. The antibody appeared to meet all safety and efficacy standards in initial testing. However, during the final stages, a critical discovery emerged – the antibody, designed to neutralize the venom's toxins, actually enhanced their effects.
This discovery, although initially disheartening, turned out to be a valuable learning experience. By sharing this novel failure mode for antivenoms, the researchers exposed a previously unrecognized gap in current antivenom testing protocols.
The researchers believe this discovery will have a more significant impact than a successful antibody would have. This newfound knowledge allows antivenom researchers to focus their efforts on avoiding similar last-minute failures.
A significant portion of the Bothrops asper's venom comprises phospholipases A₂ (PLA₂s) and PLA₂-like toxins, which cause severe and often irreversible muscle damage. One particularly potent toxin is Myotoxin II, whose mechanism of action remains partially unclear. It directly targets muscle fibers, causing localized damage that poses a challenge for traditional antivenom treatments.
The research team focused on developing human monoclonal antibodies to neutralize Myotoxin II. Throughout the initial four years, these antibodies consistently demonstrated impressive neutralizing effects in lab tests, including the current gold standard test using live mice.
However, the researchers opted for an additional experiment that more realistically mimicked a human envenoming scenario, where the antibody is administered after the venom injection. The results were both surprising and disappointing. The most promising antibody actually enhanced the toxin's effects instead of neutralizing them, as documented in their published research paper.
The unexpected phenomenon, termed "antibody-dependent enhancement of toxicity," is a novel finding in the field of toxin immunology. Similar observations have been made with other toxins, such as those from poisonous mushrooms and bacteria, but never before with toxins from animals. Further research is needed to fully understand the underlying mechanisms.
Despite the setback, this discovery presents a valuable opportunity for the antivenom research community globally. Researchers working on antivenoms for various snake species can use this knowledge to re-evaluate their preclinical testing models, including the current gold standard.
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