The following is based on Wilcox C. 2024. Powerful new antivenom raises hopes for a universal solution to lethal snakebites. Science News 21 Feb 2024.
A significant step toward developing an antivenom that could be applied to any of the 200 or so dangerous venomous snake species in the world, researchers have found a strong antibody that can neutralize a critical type of neurotoxin produced by four distinct deadly snake species from South Asia, Southeast Asia, and Africa.
“We are wiping out a major subclass of neurotoxins here,” says Nicholas Casewell, a toxinologist at the Liverpool School of Tropical Medicine and co-author on a paper describing the antibody published today in Science Translational Medicine. “I think this is a really huge step in terms of what can be achieved by a single antibody.”
Snake venom is a mixture of dozens or perhaps hundreds of chemicals that attack tissues, blood clotting, or nerve cells. They are responsible for the estimated 81,000 to 138,000 deaths and hundreds of thousands of disabled deaths worldwide each year. Antenoms, a mixture of antibodies extracted from sheep or horses and injected with non-lethal amounts of venom, is the usual course of treatment. Lead scientist Kartik Sunagar of the Indian Institute of Science’s evolutionary venomics group notes that while these medications save lives, “antivenoms suffer from numerous problems.”
For starters, different snake species have different venoms. Therefore, the course of treatment relies on the type that bit you, which isn’t always known. Even among the same species, venoms can differ; Sunagar’s team found that in certain parts of India, antivenom applied in response to a bite from the Monocellate Cobra (Naja kaouthia) is nearly useless.
For starters, different snake species have different venoms, therefore the course of treatment relies on the type that bit you, which isn’t always known. Even among the same species, venoms can differ; Sunagar’s team found that in certain parts of India, antivenom applied in response to a bite from the monocellate cobra (Naja kaouthia) is nearly useless.For starters, different snake species have different venoms, therefore the course of treatment relies on the type that bit you, which isn’t always known. Even among the same species, venoms can differ; Sunagar’s team found that in certain parts of India, antivenom applied in response to a bite from the monocellate cobra (Naja kaouthia) is nearly useless.For starters, different snake species have different venoms, therefore the course of treatment relies on the type that bit you, which isn’t always known. Even among the same species, venoms can differ; Sunagar’s team found that in certain parts of India, antivenom applied in response to a bite from the monocellate cobra (Naja kaouthia) is nearly useless.
Since many antivenoms are designed to be effective against multiple snakes from the same area, they are not as effective against one another. For example, about one in seven people bitten by the Black Mamba (Dendroaspis polylepis) are not saved by one such cocktail that is commonly employed in Africa. Despite getting dozens of vials of the medicine, some people have died.
Additionally, these medications may result in significant immunological reactions, including the potentially fatal anaphylaxis, as they are derived from animal proteins. According to Andreas Laustsen-Kiel, a toxinologist at the Technical University of Denmark who was not involved in the work, “any snake bite is a race against time: The quicker you get antivenom, the better the clinical outcome.” For this reason, doctors frequently wait until a patient has symptoms before giving antivenom.
As part of a consortium supported by the Wellcome Trust, Sunagar collaborated with Casewell and Joseph Jardine, a protein engineering specialist at Scripps Research, to address these problems. Jardine’s group generated synthetic copies of long-chain three-finger alpha-neurotoxins, a vital component of the venom of many snakes, using lab-grown cells (3FTx-L). These poisons stop nerve cells from reacting to a vital neurotransmitter, which results in paralysis. Then, to determine which artificial human antibody best bonded to the toxins, the team evaluated about 100 billion of them in the lab’s enormous antibody library, which is far larger than the immune systems of any animal exposed to venom could produce. According to Jardine, “it’s really a needle in a very big haystack.” Ultimately, the investigators identified several dozen auspicious contenders.
These were forwarded to Casewell, whose group examined the extent to which they shielded human cells from the poison. The most effective antibody was 95Mat5, and the researchers discovered why it was so effective: The major 3FTx-L in the venom of the Southeast Asian Many-banded Krait (Bungarus multicinctus), alpha-bungarotoxin, coupled to the antibody precisely at the same location as it binds to ion channels on human nerve and muscle cells.
In order to test antivenoms, Sunagar’s team injected groups of five mice with a normally deadly dosage of alpha-bungarotoxin mixed with the antibody in order to determine whether 95Mat5 protects animals. Every mouse made it through. Even 20 minutes after the venom injection, mice injected with the whole krait species’ venom—which is thought to comprise at least forty distinct toxins—were also protected by 95Mat5. Black Mamba and Monocellate Cobra venoms worked similarly. “You would be insane to think that you can neutralize a snake’s venom by focusing on just one toxin, if you had asked me six years ago,” Sunagar replies.
In order to investigate the potential animal protective effects of 95Mat5, Sunagar and colleagues injected groups of five mice with a conventional antivenom test dose of alpha-bungarotoxin combined with the antibody. Not a single mouse perished. Even after being administered 20 minutes after the venom, 95Mat5 was able to preserve mice injected with the entire venom of the same krait species, which is thought to include at least forty distinct toxins. Similarly, this applied to Black Mamba and Monocellate Cobra venoms. “You would be insane to think that you can neutralize a snake’s venom by focusing on just one toxin, for example,” Sunagar would have told you six years ago, if you had asked.
As for the neutralization of snake venom, Laustsen-Kiel finds it “surprising” that it has neutralized the infamous huge mamba poison. “That clearly indicates that it’s a high-quality antibody.”
According to Casewell and Jardine, 95Mat5 could be used in addition to current antivenoms, which are ineffective against 3FTx-Ls. Additionally, the antibody is less likely to have unfavorable side effects because it is human. However, snakebite is a neglected health issue that largely affects low- and middle-income countries, and it’s unclear who would pay for the antibody’s further development and manufacturing. According to Laustsen-Kiel, “the next steps are probably more driven by the economy, strategic decisions, and the priorities of health care systems than they are by science and technology.”
According to Jardine, the group intends to use the same method of discovery to find other types of highly strong snake toxins. Their far-off dream is to produce an antibody cocktail that will neutralize the venoms of all harmful snakes on the earth. According to Jardine, “you wouldn’t have to stock hundreds of antivenoms.” “You could keep one universal one in stock.”
