Once a black mamba sinks its fangs into a victim’s flesh—injecting venom that can paralyze body parts, including, fatally, muscles that pull air into our lungs—survival depends on respiratory support, or, more effectively, antivenom therapies.
Yet for some people, current antivenoms, though they may be life-saving, can also cause adverse reactions such as itching and swelling, fever, and anaphylaxis. These side effects arise because antivenoms are molecular foreigners: They are animal-based, containing antibodies produced mostly by horses in response to receiving small, non-lethal doses of snake venom. Some treatments contain as little as 5% therapeutic antibodies which increases the risk of bad reactions.
Now, a team of researchers from Costa Rica, Denmark, and the U.K. reports an antivenom cocktail made of human recombinant antibodies capable of neutralizing black mamba venom in mice (Nat. Comm. 2018, DOI: 10.1038/s41467-018-06086-4). The antibodies were discovered using phage display, the technology awarded with half of the 2018 Nobel Prize in Chemistry announced earlier today.
“Phage display creates a physical link between an antibody and the gene which encodes it” engineered into a phage virus, says study coauthor John McCafferty. McCafferty is chief executive officer of U.K. biotechnology company IONTAS, which develops novel antibody therapeutics, and one of the inventors of the phage display technique.
The technique lets scientists screen antibodies that bind to therapeutic targets and then identify those antibodies using their attached phages. Scientists have used the strategy to find pharmaceuticals, striking gold with Humira, AbbVie’s monoclonal antibody drug to treat inflammatory and autoimmune diseases that has topped global sales lists for the past several years.
In this work, the team screened IONTAS’s library of about 40 billion human antibodies against a partially-purified venom containing dendrotoxin proteins, which along with so-called short and long neurotoxins give the black mamba its lethal bite. The venom binding screen flagged 90 antibodies and the researchers sequenced the DNA of each. Then, from about a quarter of those antibodies, they devised cocktails for injecting straight into mice’s brains, along with the poisonous venom.
A cocktail containing three human immunoglobulin G antibodies spared the mice from venom-induced death. The authors note, however, that the result is specific to their brain-injection model, where dendrotoxins are the main toxic component, as opposed to an intravenous injection model, in which other neurotoxins would dominate.
Cecilie Knudsen, study coauthor and biomedical researcher in Andreas Laustsen’s laboratory at the Technical University of Denmark, says the team plans to test the cocktails in mouse experiments which would better mimic real-world situations.
Claire Komives, a snake antivenom expert at San Jose State University, says the human antibody cocktails “would be the Mercedes Benz of antivenom treatments.”
However, Komives notes, black mamba bite victims usually die quickly, before they can get to a hospital. She wonders how the treatment will be made readily available at a reasonable price. Current antivenoms cost between $20 and $120 per dose depending on quality, according to a price list on the World Health Organization (WHO) website.
“The truth is that the horse-based antivenoms do work and work well when they are made with the proper snake venoms for the place where people get bitten,” Komives says, adding that doctors have strategies for managing allergic reactions to current treatments. “Making them in horses is much, much cheaper than making recombinant antibodies, at least for now,” she says.
Affordability is a key challenge for new antibody treatments since the typical snakebite victim is impoverished, says Liverpool School of Tropical Medicine’s Robert Harrison, whose research focuses on improving the treatment of snakebites. Snakebites claim up to 140,000 lives each year, predominantly in parts of sub-Saharan Africa, as well as south and southeast Asia, according to WHO. The team may also face new hurdles to development, Harrison says, since these monoclonal antibodies will require different regulatory protocols from those that exist for current antivenoms.
Regarding the hypothetical cost of their antivenom, Knudsen cites a recent Nature Correspondence from Laustsen and colleagues which estimates that a common African snakebite could be treated with a pan-African recombinant-antibody antivenom for between $30 and $150.
“We see this publication as a ‘proof of concept’ study which illustrates the potential of modern antibody engineering approaches to the generation of human or human-like antivenoms for all snakes,” McCafferty says. “We do not, however, underestimate the challenge of the task ahead,” he says.