Antivenom, the only effective treatment for venomous snakebites, saves thousands of lives each year. But the process used to produce antivenom is laborious and antiquated. It involves milking venom from snakes, injecting that venom into horses or sheep and then bleeding the animals to extract the antibodies they produce. “It’s a very, very old-school type of medicine,” says Andreas Hougaard Laustsen-Kiel, an antibody researcher at the Technical University of Denmark, who is working to develop better antivenoms.
What’s more, because each species of venomous snake carries a unique concoction of toxins in its venom, antivenom produced from the venom of one species typically doesn’t work against another. Antivenom manufacturers can inject animals with venoms from multiple snake species, but even the products currently on the market that work against venom from multiple species don’t cover all snakes in a given region. So physicians have to make an educated guess about which snake caused the bite and select a product accordingly.
Researchers, both in academia and at private companies, have long dreamed of developing better antivenoms that are less cumbersome to produce and that work against wide swaths of the world’s 200 or so species of snake that pose the greatest threat to humans.
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Last week a team of researchers reported in Science Translational Medicine that it has made a bit of headway. The team developed a synthetic antibody that neutralizes one of the most potent classes of neurotoxins found in the venom of elapids, a family of snakes that includes mambas, cobras and Australian copperheads, to name a few. Unlike current antivenoms, this therapy could be produced in cells rather than in animals. And it addresses another major downside of current antivenoms. Because these therapies are derived from human antibodies rather than horse antibodies, they may not be as likely to elicit an allergic reaction.
It’s just a first step, to be sure. “Snake venoms are very complex,” says Kartik Sunagar, a venom expert at the Indian Institute of Science and co-author of the study. This antibody against one type of neurotoxin would likely need to be combined with other antibodies targeting other toxins to produce a workable replacement for conventional antivenoms. The team is one of several around the world that are researching the problem. These investigators are hunting for antibodies in the blood of alpacas and in that of a snake enthusiast who has been bitten (voluntarily) hundreds of times. They’re also taking a separate approach of testing pills developed to treat sepsis and lead poisoning to combat the most lethal components of snake venom. And they’re tweaking the conventional antivenom production process to make antivenoms that work on even more species of snakes.
The latest work began with a library of human antibodies that researchers at the Scripps Research Institute collected as part of an effort to find therapies for HIV. The idea was to comb through this collection to look for antibodies that would bind to the most important toxins in snake venom that affect humans. “The snakes develop these venoms to target their natural prey,” not to harm us, Sunagar says. That’s good news because it means that many of the components in snake venom won’t harm humans. “There are only a handful of toxins in the venomous snakes around the world that one needs to neutralize,” he says.
Venom toxins fall into different families and subfamilies. But even within a single subfamily there can be hundreds of variants. Invariably some portions of the toxins, however, are conserved. “So if you can hit that sort of Achilles heel, you can neutralize almost the entire subfamily,” says Laustsen-Kiel. The new paper shows that an antibody named 95Mat5 can neutralize one particular type of toxin known as a long-chain alpha-neurotoxin. It’s a deadly toxin that can paralyze muscles, including those that help us breathe. When the researchers injected their synthetic antibody targeted against this subfamily into mice, they found that it could rescue the animals from neurotoxicity even when they injected it 20 minutes after the animals received the venom—unlike the conventional antivenom, which was much less effective after just a 10-minute delay. “The conventional antivenom is only effective if you inject it alongside the toxin,” Sunagar says.
The next step is to find more of these antibodies that target other toxins and eventually develop a cocktail that can neutralize the venom of many different snakes. The goal isn’t necessarily to find something that will treat every snakebite. “I don’t believe in the idea of making a ‘universal’ antivenom for the whole world,” Laustsen-Kiel says. It makes more sense to develop antivenoms that can cover all snakes in a particular region.
Laustsen-Kiel and his colleagues have been combing through human antibody libraries looking for promising candidates. Now they’re testing some of them in animals but have yet to publish their research. “We might actually have a cocktail that could work against all North American coral snakes,” he says.
One South San Francisco–based company, Centivax, is taking a different tack. They are hoping to fish out promising antibodies from the blood of one man. Tim Friede, director of herpetology at Centivax, is a snake enthusiast and former truck mechanic who has been bitten a couple of hundred times and injected with a variety of toxins in an attempt to render himself immune to snake venom. In a preprint first posted in 2022, researchers from Centivax and the National Institutes of Health reported that Friede’s blood yielded an antibody that shows some promise in neutralizing long-chain alpha neurotoxin. The antibody, named Centi-LNX-D9, provided complete protection against whole venom from the monocled cobra, black mamba, yellow-lipped sea krait, Egyptian cobra, cape cobra, Indian cobra and king cobra.
Laustsen-Kiel has been increasingly interested in nonhuman antibodies produced by camelids such as alpacas and camels. These smaller proteins, called nanobodies, bind equally well, Laustsen-Kiel says. They’re also cheaper to produce and “super stable.” He and his team have inoculated alpacas with snake venom to create libraries of nanobodies that they can use to fish out the most promising candidates.
Synthetic antibodies would probably still be given in hospitals and clinics, as is the case for traditional antivenom. But some people are working to develop pills that target specific toxic components of snake venom—to be dispensed in rural communities where people most often get bitten.
That approach has been adopted by the company Ophirex, which has been working for nearly a decade on the drug varespladib. The drug, originally developed by Eli Lilly and Shionogi to treat sepsis, shuts down a toxic enzyme known as sPLA2, which can induce muscle weakness, paralysis and a wide range of other symptoms. The company has already completed a clinical trial of the drug and has another in the works.
Nicholas Casewell, a venom biologist at the Liverpool School of Tropical Medicine in England, is working to develop drugs to target a class of venom enzymes called metalloproteinases. “These are toxins that cause bleeding and clotting problems,” he says. They’re what make the bite of vipers such as the fer-de-lance in Central America or the saw-scaled viper in West Africa so deadly. One of the most promising molecules they’ve tested is a drug called 2,3-dimercapto-1-propanesulfonic acid (DMPS), which is used to remove metals from the blood in the case of lead or other metal poisonings. For snake venoms with a high concentration of metalloproteinases, these drugs might be a cure for people with snakebites. Even if they don’t work as a standalone treatment, they might be able to stave off tissue damage and bleeding and buy people time to get to a health care facility where they can get antivenom.
Testing drugs to treat snakebites is tricky. Researchers can’t withhold antivenom, the standard of care for snakebites. So in the trials run by Ophirex, participants receive traditional antivenom, either alone or with the new treatment being tested. The combination can make it difficult to tease out whether the drug actually really has an impact on someone who has been bit.
Casewell is still doing animal research, but he hopes that when he and his colleagues move their therapy into clinical trials, they can reduce some of these uncertainties by recruiting participants in communities where antivenom isn’t immediately available. Participants in the study would receive the drug soon after they have been bitten. But they would still receive antivenom once they reach the hospital. “That should buy us a window to measure the effect of the drug before antivenom is given,” Casewell says.
Combining these pills with antibodies might produce even more effective therapies. "For me the really appealing experiment is what happens when you combine the two," says Matt Lewin, chief scientific officer at Ophirex. Centivax trialed that in mice and found that the combination of varespladib and the company’s antibody derived from the snake enthusiast did work better than the antibody alone.*
Revolutionizing the way antivenom is produced won’t happen overnight. But in the meantime, the existing antivenom production can be improved without a complete overhaul.
That’s what Kavi Ratanabanangkoon, an immunochemist at Mahidol University in Thailand, has been working on for more than a decade. Current antivenom production systems rely on horses’ ability to generate antibodies against snake venom. But there’s a limit to how many toxins the horses can handle at once and still produce a robust immune response, he says. So instead of giving the horses snake venom in its entirety, Ratanabanangkoon had the idea to filter it to retain only the most toxic components. He hoped that would allow him to administer toxins from a variety of species while still limiting the total number of venom proteins.
Nobody was interested in his idea at first. But when Ratanabanangkoon approached the Royal Thai Army, they agreed to let him test the concept on three retired army horses. He and his colleagues selected venom samples from six elapid species from 12 different geographic locations. They filtered the venom to separate out the neurotoxins (which are, conveniently, the smallest proteins in the venom, making it easy to remove the bigger, nontoxic ones) and then gave this cocktail to the horses. The strategy worked. In 2016 the team reported that the antibodies the horses produced neutralized venoms from all six species plus 16 other elapid snake species found in Africa and Asia. And in 2020 the researchers reported that it works on nine other elapids—a total of 36 snake venoms belonging to 10 genera from four continents.
José María Gutiérrez of the University of Costa Rica says it’s crucial to work on improving existing antivenom production strategies even as other teams work to develop new ones. “I think the animal-derived antivenom will continue to be the mainstay in therapy,” he says.
But Gutiérrez also thinks that developing broader-acting cocktails that can counteract venom from many snakes might be feasible. After all, he says, the world doesn’t need a universal antivenom that can treat any snakebite. “We need wide-spectrum antivenoms for different regions.” That’s a much more realistic goal.
*Editor’s Note (3/4/24): This paragraph was edited after posting to correct the descriptions of varespladib and Matt Lewin’s position at Ophirex.