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For more than a century the mainstay of snakebite treatment has been antivenom produced by injecting horses with snake poison and harvesting the resulting antibodies.
But horse-derived antibodies come with the risk of severe side effects. So, when Andreas Hougaard Laustsen and his colleagues developed a lab-grown antivenom, it promised safer treatment for toxic snakebites, a neglected disease which kills some 138,000 people annually.
Laustsen, an advisor to the WHO on snakebites and head of the Tropical Pharmacology Lab at the Technical University of Denmark, tells SciDev.Net about how modern biotechnology can help tackle an ancient foe — the poisonous serpent.
How does your experimental antivenom differ from existing ones?
It’s important to highlight that existing antivenoms, when they’re produced properly, are life-saving and effectively neutralise snake venom. They’re based on antibodies — there are a few different, specific formats — but you could say that they are essentially based on horse-derived antibodies. The problem is when you take something from a horse and inject it into a human being, the human immune system will recognise it as foreign. It will either cause serum sickness […] or you can end up getting anaphylaxis, which is an immediate hyper- allergic reaction, a similar effect to people who are allergic to wasps and get stung.
We thought: why not substitute the horse antibodies with human antibodies? And while we’re at it, instead of using humans to produce antibodies — which, of course, would be unethical — why not introduce some of the technologies that are being used for producing monoclonal antibodies or therapeutic antibodies?
Eight out of the 10 best-selling drugs are human antibodies, and because of the huge interest in this field, a lot of production technologies have been developed for using these molecules at a low cost. Essentially, we want to remove the risk of adverse reactions to antivenoms and be able to manufacture them at a lower cost.
What are the other pitfalls of using antibodies extracted from animals?
When you take antibodies from a horse, you don’t differentiate between antibodies that recognise venom toxins and antibodies that were developed by the horse against all sorts of other things, for example bacteria and viruses. For 99 per cent of antivenoms, you get the entire lot (of antibodies) and probably around 70 to 90 per cent of the antibodies are not directed against medically relevant snake toxins, so those antibodies don’t do any good.
What we’re trying to do is limit the number of antibodies we want to produce to only those that target medically relevant snake toxins. It is estimated that there are around 25,000 different components in snake venom, if you count all snake venoms. We want to focus on the most relevant venom components, which means lower development costs as well.
What are the next steps for your research?
We have developed antibodies against some of the important neurotoxins from the black mamba. If we’re just looking at targeting the black mamba, we probably need two more antibodies that we’re working on so we can have the full subset of antibodies that can be used to do a so-called rescue experiment. A rescue experiment is where you inject a mouse with venom in a way that simulates a snakebite. That would typically be an intramuscular injection. Then you wait a bit and inject antivenom directly into the veins and see if it saves the mouse’s life. That’s the next stage, which, depending on a few things, could potentially be reached within a year.
It’s important to question whether a product like that could be brought into clinical trials and further development. However, I don’t think it’s commercially feasible or relevant to just produce a black mamba antivenom. I think there’s simply just too little species coverage. Looking at Africa, where the black mamba lives, what might be relevant is an antivenom that works against all five mamba species as well as neurotoxic cobra bites.This is relevant because when you think about how the final product would work, the treating physician should not be in too much doubt about whether the antivenom would be effective in a given bite.
Why are physicians sometimes hesitant to use antivenom?
In many cases, snakebite victims don’t necessarily get a severe envenoming. There are many snakes that deliver dry bites [where no poison is injected]. Seen from the snake’s perspective, its mission is not to kill you and eat you — there are no venomous snakes big enough to swallow a human being. Its goal is basically to deter us. Some snakes deliver a lot of dry bites to chase us away, other snake species tend to inject venom. Since there are issues with antivenom, both in terms of costs and adverse reactions, physicians are hesitant to use it until it’s indicated, which basically means you let the patient develop symptoms, at which stage you could say you’re already behind in the race against the toxins.
How optimistic are you about the development of new antivenoms?
No one who understands antivenoms questions whether antibodies are therapeutically right. What they are questioning is: is it too expensive to develop and manufacture?
People who understand venom generally do not have the facilities or infrastructure to develop antibodies. Many of the labs that have the facilities to develop antibodies don’t know that snakebites are a problem, nor do they have any interest in it because snakebite envenoming is not commercially attractive.
We’re in extremely early days of what you could call next-generation antivenom work. Most attempts have been sporadic; people finding something that works a little bit. There are few antivenom research labs that have proper antibody discovery facilities. I hope it will drastically change in the next two years.
This piece was produced by SciDev.Net’s Global desk.