Universal antivenom against deadly snake toxins developed by researchers

Scientists at Scripps Research have developed an antibody that can block the effects of deadly toxins found in the venoms of a wide variety of snakes found in Africa, Asia and Australia.

The antibody, which protected mice from the normally deadly venom of snakes, including black mambas and king cobras, is described in Scientific translational medicine. The new research used laboratory-produced forms of toxins to screen billions of different human antibodies and identify one capable of blocking the toxins’ activity. This represents a big step towards a universal antivenom that would be effective against the venom of all snakes.

“This antibody acts against one of the major toxins found in many species of snakes that contribute to tens of thousands of deaths each year,” says lead author Joseph Jardine, Ph.D., assistant professor of immunology and in microbiology at Scripps Research. “This could be incredibly valuable for people in low- and middle-income countries who experience the highest number of deaths and injuries from snakebites.”

More than 100,000 people each year, mostly in Asia and Africa, die from snakebite envenomation, making it deadlier than most neglected tropical diseases. Current antivenoms are produced by immunizing animals with snake venom, and each generally only works against a single species of snake. This means that many different antivenoms must be made to treat snakebites in different regions.

Jardine and his colleagues have previously studied how neutralizing antibodies against the human immunodeficiency virus (HIV) may work by targeting areas of the virus that cannot mutate. They realized that the challenge of finding a universal antivenom was similar to their quest for an HIV vaccine; just as the rapidly evolving HIV proteins have small differences among themselves, different snake venoms have enough variation that an antibody binding to one will generally not bind to the others.

But like HIV, snake toxins also have retained regions that cannot mutate, and an antibody targeting these could potentially act against all variants of that toxin.

In the new work, the researchers isolated and compared venom proteins from a variety of elapids, a major group of venomous snakes including mambas, cobras and kraits. They found that a type of protein called three-fingered toxins (3FTx), found in all elapid snakes, contained small sections that appeared similar across species. Additionally, 3FTx proteins are considered highly toxic and responsible for whole-body paralysis, making them an ideal therapeutic target.

With the goal of discovering an antibody to block 3FTx, researchers created an innovative platform that introduced the genes for 16 different 3FTxs into mammalian cells, which then produced the toxins in the laboratory. The team then turned to a library of more than 50 billion different human antibodies and tested which ones bound to the 3FTx protein of the multi-banded krait (also known as Chinese krait or Taiwanese krait) , which had the most similarities to other 3FTx. proteins.

This narrowed their search to around 3,800 antibodies. Then they tested these antibodies to see which ones also recognized four other 3FTx variants. Of the 30 antibodies identified in this review, one stood out as having the strongest interactions among all toxin variants: an antibody called 95Mat5.

“We were able to zoom in on the very small percentage of antibodies that were cross-reacting with all of these different toxins,” says Irene Khalek, a Scripps Research scientist and first author of the new paper. “This was only possible thanks to the platform we developed to screen our antibody library against multiple toxins in parallel.”

Jardine, Khalek and their colleagues tested the effect of 95Mat5 on mice injected with toxins from the many-banded krait, Indian spitting cobra, black mamba and king cobra. In all cases, mice simultaneously injected with 95Mat5 were not only protected from death, but also from paralysis.

When researchers studied exactly how 95Mat5 was so effective at blocking 3FTx variants, they found that the antibody mimicked the structure of the human protein that 3FTx usually binds to. Interestingly, the broad-acting HIV antibodies that Jardine has already studied also work by mimicking a human protein.

“It’s amazing that for two completely different problems, the human immune system converged on a very similar solution,” Jardine says. “It was also exciting to see that we could make an effective antibody entirely synthetically: we didn’t immunize any animals or use snakes.”

Although 95Mat5 is effective against the venom of all elapids, it does not block the venom of vipers, the second largest group of venomous snakes. Jardine’s group is currently searching for broadly neutralizing antibodies against another elapid toxin, as well as two pit viper toxins. They suspect that combining 95Mat5 with these other antibodies could provide broad coverage against many, if not all, snake venoms.

“We believe that a cocktail of these four antibodies could potentially function as a universal antivenom against any medically relevant snake in the world,” says Khalek.