“So we began pulling out antibodies from Tim’s blood,” he told the Telegraph. “The results were thrilling.”
Researchers identified two broadly neutralising antibodies – a special class of antibodies able to neutralise a wide variety of snake toxins – in Friede’s blood. They then combined these with a small molecule known to disarm some venom to create a single snakebite treatment.
According to preclinical trial results published in the journal Cell on Friday, the antivenom cocktail protected mice from 13 venomous snakes and partially protected against a further six.
The results could pave the way for a universal snakebite treatment, which has long been considered the “Holy Grail” of snakebite research.
“There is no doubt that this work moves the field forwards in an exciting direction,” said Professor Nicholas Casewell, director of the Centre for Snakebite Research and Interventions at the Liverpool School of Tropical Medicine, who was not involved in the study.
‘He immunised himself’
The need for updated antivenoms is acute. Each year, between 81,000 and 138,000 people die from snakebites, the vast majority in rural parts of Africa, Asia and Latin America, while a further 400,000 suffer life-changing injuries including amputations, sight loss and open ulcers that never heal.
Yet the process of developing antivenoms has barely changed in a century – it is still based on milking snakes, injecting their venom into horses, and harvesting their antibodies. The resulting drugs are difficult to administer, can trigger severe side effects, and each protects against just one of the world’s 650 venomous snake species.
A near-universal alternative would not only simplify treatment, but make antivenom a more commercially viable product for manufacturers, by boosting the size of a potential market. Yet this has proven an elusive goal – some have warned it may not even be feasible.
This is because snake venom has evolved over centuries into some of the most complex toxins on earth – even among the same species, toxins vary by geographical region. A universal treatment would mean developing an antivenom to neutralise all of the most dangerous toxins found in dozens of snake species at once.
The latest research suggests scientists are looking for solutions in the right places – including Friede’s blood.
“I stumbled across these news articles about him, and it kind of blew my mind, that over the course of 18 years he had immunised himself 600-plus times with escalating doses of venom from 16 species from every continent, and eventually had 202 bites,” said Glanville.
“So I got in touch and said, ‘this may be an awkward question, but I’d love to get my hands on some of your blood’. And his answer was, ‘I’ve been waiting for this call for a long time’.”
Using these samples initially posed an ethical dilemma, given the risks Friede took by allowing snakes to bite him and injecting himself with their venom.
“It may be obvious, but no one should try what Tim Friede did – it’s not good for you,” said Glanville. “Tim did something remarkable and it could help medical science – but also because he’s run this experiment, there’s no need for anyone else to. Please, nobody try this.”
But it was because of a concept from his work on HIV and flu that Glanville and his collaborator, Peter Kwong of Columbia University, were excited by Friede’s blood: they were looking for broadly neutralising antibodies.
They hoped that proteins might exist that could target structurally similar toxins found across multiple snakes. When they ran tests in the lab, they knew they were on to something.
“When I tested [Friede’s] serum versus my own serum, his was off the chart, reacting to all the snakes,” said Glanville. “I had specifically picked some venoms that he said he’d never been exposed to, yet his serum hit that too. That was really exciting, because it was my first signal that he probably had these universal antibodies.”
Through a process of elimination, the team then identified two of the most important broadly neutralising antibodies from “Tim’s library” (his blood). They were keen to base a treatment on human antibodies because of the high safety profile.
Later, the researchers combined these two proteins with a small molecule called varespladib, which is known to inhibit certain venom enzymes. Then they tested the cocktail in mice.
“We had to sojourn with the mice overnight and monitor them, to make sure they didn’t die,” said Granville. “We were a little punch drunk in the morning but when all the mice were seeing the light of day, it was pretty profound.”
Others have also identified the promise of monoclonal antibodies to target antivenom – teams led by professor Andreas Lausten in the Netherlands, and Dr Joe Jardine in the United States, have also identified specific antibodies that appear to disarm certain toxins.
But Casewell said “the breadth of the protective benefit is certainly novel” in the Cell paper.
“[This] provides a strong piece of evidence that combining relatively few antibodies and/or drugs together is feasible as a therapeutic strategy,” he said. “It could lead to a future therapy that could be beneficial to snakebite patients in many different parts of the world.”
Still, there are limitations to the latest study. Lausten told the Telegraph that another component would likely need to be added to the mix to ensure full protection against all 19 snakes.
He also said further preclinical trials needed to look beyond fatality, because “there are many other morbidities involved in snakebite that a good antivenom would need to deal with, including dermonecrosis, local tissue damage, coagulopathies, and simply pain”.
The current antivenom cocktail only targets toxins found in elapid snakes, the family of animals characterised by their fixed fangs which includes cobras, mambas and taipans.
The treatment will not work against vipers, a separate family of venomous snakes with folding fangs that includes rattlesnakes and adders. Glanville said his team are now developing a separate antivenom to use against bites from these species.
“The intention is basically to have two syringes – one that hits the elapids, and one that hits the vipers. And if you’re in a situation where you don’t know what you were bitten in, you take both,” Glanville said.
He said the ultimate goal would be for these to be administered “like an epipen for antivenom”, which would make it available in even the most remote regions – including rural Guatemala, where Glanville grew up. As a child, he was all too aware of the challenges in accessing antivenom.
But for now, the main priority is refining and testing the elapid snake antivenom cocktail. Before entering safety trials in humans, the team wants to incorporate a fourth component into the cocktail, to tackle the partial protection achieved against six snakes. They are also looking to run experiments in pet dogs bitten by snakes.
It is likely that any product faces at least five years of trials before reaching snakebite victims, which could prove an expensive endeavour. There are also some concerns that a final antibody product could be prohibitively pricey for the markets where most people are bitten: lower income countries.
“As of yet, no snakebite monoclonal antibodies have entered evaluation in clinical trials,” said Caswell. “This endeavour is highly challenging, largely due to the costs associated with the development of biologic therapeutics, and the challenging financial market associated with neglected tropical diseases for commercial entities.
“There is a strong need for safer and more effective treatments for snakebite though, so those of us in the field hope that these barriers can be overcome in the coming years.”
