Prototype treatment shows great potential in neutralizing snake toxins from multiple species

Prototype treatment for snake bite envenoming proves effective against the venom of African and Asian elapid snakes, such as some cobra, mamba, and krait species, new research shows.

Snakes bite 5.4 million people each year—and roughly half are injected with venom, according to the WHO. Between 81,000 and 138,000 people die, while around three times as many suffer amputations and other permanent disabilities. Due to their size, children often suffer the most severe effects.

For 128 years, our primary treatment against snakebite has been using mixtures of polyclonal antibodies derived from immunized animal blood. Although they are proven effective, these medicines may cause adverse reactions that can sometimes be severe. So, the search for novel ways to treat severe snakebite envenoming is ongoing.

Recently, an international team of scientists led by DTU reached remarkable results and developed a new modernized prototype treatment that proves effective against the venom of African and Asian elapid snakes, such as some cobra, mamba, and krait species—many of which are among the world's deadliest.

We have previously developed antibodies against the venom toxins from single snake species; however, our new results demonstrate that our technology has great potential in neutralizing toxins from multiple species, even from different continents. This broadened cross-neutralization capacity is very promising. It could provide the basis for more effective treatments for snakebite victims in the future."

Andreas Hougaard Laustsen-Kiel, Professor at DTU Bioengineering

He conducted the research with colleagues at DTU, ETH Zurich, Universidad de Costa Rica, and industrial partners Sophion Bioscience and IONTAS. Their work is published in Nature Communications.

New antibody works against several neurotoxins

In essence, their approach is to develop antibodies of fully human origin, which offer fewer adverse reactions, competitive costs, and, when fine-tuned, superior efficacy. They use phage display technology, a popular in vitro methodology within drug discovery, to select antibodies that bind well to the toxins in the venom, enabling broad neutralization.

"There has been a revolution in recombinant antibody technology over the last three decades. I am delighted to be involved in these efforts to direct phage display technology to the blight of snakebite envenomation," says John McCafferty, the inventor of antibody phage display. He founded IONTAS and has recently established a new anti-venom group at the University of Cambridge.

Deliberately selecting hundreds of antibody candidates and testing the most promising against toxins in different snake venoms, the researchers found that one in particular (2554_01_D11) was especially potent and broadly neutralizing. It bound to various neurotoxins present in the venoms of the monocled cobra, the forest cobra, the spectacled cobra, the king cobra, the black mamba, and the many-banded krait.

Subsequent in vivo studies showed that the antibody prevented or delayed death from venom. For the monocled cobra specifically, the antibody completely prevented lethality in envenomed mice.

"In light of the positive results regarding the neutralization of venom from the monocled cobra, we mimicked a true rescue situation, injecting mice with cobra venom and then administering the antibody. And sure enough, we were able to prevent death when the antibody was injected rapidly after envenoming", says José María Gutiérrez, emeritus professor of Instituto Clodomiro Picado, University of Costa Rica.

While the antibody could not prevent death from black mamba venom, survival was prolonged by several hours, suggesting that the antibody provided a partial neutralization of the venom.

"These are remarkable results," says Andreas Hougaard Laustsen-Kiel:

"The antibody we used worked against different neurotoxins derived from different snake species from different parts of the world. These toxins are far from identical but share some crucial similarities in their structure. And apparently, these are just enough for our antibody to display extensive cross-reactivity. We have yet to establish the boundaries of what this antibody can neutralize. Still, we would like to see if it shows the same promise concerning neurotoxins from, for example, the blue krait, the banded krait, and the Egyptian cobra."

The researchers expect antibodies, such as 2554_01_D11, will be helpful when designing future envenoming therapies. At the same time, however, they stress that their pipeline for discovery could be useful in developing other broadly neutralizing antibodies against toxins from other animals, bacteria, viruses, and parasites or even in developing cancer therapies.

Source:
Journal reference:

Ledsgaard, L., et al. (2023) Discovery and optimization of a broadly-neutralizing human monoclonal antibody against long-chain α-neurotoxins from snakes. Nature Communications. doi.org/10.1038/s41467-023-36393-4.

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