New hope for treating lethal snakebites

Current antivenoms used to treat human snakebite victims aren’t always effective. However, a recent study by Kartik Sunagar at the Indian Institute of Science and his colleagues identified an antibody that could protect mice against a potent toxin produced by snakes such as cobras, kraits, and mambas (Sci. Transl. Med. 2024, DOI: 10.1126/scitranslmed.adk1867). The research team relied on a library containing billions of artificially-designed human antibodies to ultimately find a good candidate called 95Mat5.

To treat snakebites, clinicians typically use a cocktail of antibodies made by animals such as horses when injected with low doses of snake venom. But only a small percentage of those antibodies are therapeutically relevant and work best on venom from snake species used to elicit the horses’ response. That makes treating bites challenging when its other snake species involved or populations whose venom protein composition is highly variable, Sunagar says, stressing the need for better options.

“The study to me is state of the art on how to make a good antibody,” says Andreas Hougaard Laustsen-Kiel at the Technical University of Denmark who specializes in antibody development against snake venom and was not involved in this research. “They managed to find an antibody that seems to be better than what has been reported before.”

Sunagar and his colleagues first looked for antibodies that bound to five variants of a neurotoxin known as 3FTx-L derived from medically-relevant Asian and African snakes. The team identified 16 antibody candidates, of which one antibody bound effectively to the toxin and neutralized it.

The team found that this antibody 95Mat5 mimics the structural features of the receptor that the toxin attaches to enter human cells. “It acts like a sponge and soaks those toxins away from the receptors,” Sunagar says. “That’s what prevents neurotoxicity.”

In experiments in mice, the researchers found that 95Mat5 saved the animals and rescued them from neurotoxicity even when the antibody was given 20 min after venom injection. “20 min may not seem a lot,” Sunagar says, “but you have to consider that it’s for small-bodied mice, not humans.” Also, conventional antivenom fails “even if you give it [to the mice] 5-10 min later,” he says.

The team was particularly surprised by 95Mat5’s ability to protect mice against black mamba venom. That’s because “only about 17% of its venom is composed of the toxin that we were targeting,” says Irene Khalek, a biomedical scientist at the Scripps Research Institute in California and the study’s first author, and the rest is made of other toxin classes. However, the antibody couldn’t protect the rodents from king cobra’s venom, probably because it has a unique collection of toxins, Khalek says. 95Mat5 did however delay deaths in mice injected with that snake’s lethal venom.

The researchers suspect that a good broad-spectrum antivenom will need at least four to five antibodies, that target major toxins. 95Mat5 may be a good candidate. Laustsen-Kiel argues that it could be well more than four to five antibodies. But “it really comes down to clinical judgement of what snakes you really want to have covered,” he says.

For now, Khalek and her colleagues are working toward finding antibodies against venom from species such as rattlesnakes and vipers that can attack the body’s cardiovascular system and lead to fatal hemorrhage and tissue damage. Once they identify the right cocktail of antibodies, the final test would be in human clinical trials.