Summary: Scientists have developed the most broadly protective antivenom yet, using antibodies from a donor who built immunity through years of self-injection with lethal snake venoms. By combining two antibodies from the donor with a small molecule inhibitor, the antivenom protected mice from deadly snakes like black mambas and king cobras.
The three-part cocktail neutralized toxins from 13 of 19 tested species and partially protected against the others. Researchers now aim to test the formulation in dogs and ultimately develop universal antivenoms for both elapids and vipers to help vulnerable communities worldwide.
Key Facts:
- Unique Source: Antibodies from a hyper-immune donor formed the basis for the new antivenom.
- Broad Protection: A 3-part cocktail protected against 13 deadly snake species and partially against others.
- Global Potential: The antivenom could lead to universal treatments, especially for underserved regions.
Source: Cell Press
By using antibodies from a human donor with a self-induced hyper-immunity to snake venom, scientists have developed the most broadly effective antivenom to date, which is protective against the likes of the black mamba, king cobra, and tiger snakes in mouse trials.
Described May 2 in the Cell Press journal Cell, the antivenom combines protective antibodies and a small molecule inhibitor and opens a path toward a universal antiserum.
How we make antivenom has not changed much over the past century. Typically, it involves immunizing horses or sheep with venom from single snake species and collecting the antibodies produced.
While effective, this process could result in adverse reactions to the non-human antibodies, and treatments tend to be species and region-specific.
While exploring ways to improve this process, scientists stumbled upon someone hyper-immune to the effects of snake neurotoxins.
“The donor, for a period of nearly 18 years, had undertaken hundreds of bites and self-immunizations with escalating doses from 16 species of very lethal snakes that would normally a kill a horse,” says first author Jacob Glanville, CEO of Centivax, Inc.
After the donor, Tim Friede, agreed to participate in the study, researchers found that by exposing himself to the venom of various snakes over several years, he had generated antibodies that were effective against several snake neurotoxins at once.
“What was exciting about the donor was his once-in-a-lifetime unique immune history,” says Glanville.
“Not only did he potentially create these broadly neutralizing antibodies, in this case, it could give rise to a broad-spectrum or universal antivenom.”
To build the antivenom, the team first created a testing panel with 19 of the World Health Organization’s category 1 and 2 deadliest snakes across the elapid family, a group which contains roughly half of all venomous species, including coral snakes, mambas, cobras, taipans, and kraits.
Next, researchers isolated target antibodies from the donor’s blood that reacted with neurotoxins found within the snake species tested.
One by one, the antibodies were tested in mice envenomated from each species included in the panel. In this way, scientists could systematically build a cocktail comprising a minimum but sufficient number of components to render all the venoms ineffective.
The team formulated a mixture comprising three major components: two antibodies isolated from the donor and a small molecule. The first donor antibody, called LNX-D09, protected mice from a lethal dose of whole venom from six of the snake species present in the panel.
To strengthen the antiserum further, the team added the small molecule varespladib, a known toxin inhibitor, which granted protection against an additional three species. Finally, they added a second antibody isolated from the donor, called SNX-B03, which extended protection across the full panel.
“By the time we reached 3 components, we had a dramatically unparalleled breadth of full protection for 13 of the 19 species and then partial protection for the remaining that we looked at,” says Glanville.
“We were looking down at our list and thought, ‘what’s that fourth agent’? And if we could neutralize that, do we get further protection?”
Even without a fourth agent, their results suggest that the three-part cocktail could be effective against many other, if not most, elapid snakes not tested in this study.
With the antivenom cocktail proving effective in mouse models, the team now looks to test its efficacy out in the field, beginning by providing the antivenom to dogs brought into veterinary clinics for snake bites in Australia. Further, they wish to develop an antivenom targeting the other major snake family, the vipers.
“We’re turning the crank now, setting up reagents to go through this iterative process of saying what’s the minimum sufficient cocktail to provide broad protection against venom from the viperids,” says lead author Peter Kwong, Richard J. Stock professor of medical sciences at Columbia University Vagelos College of Physicians and Surgeons and formerly of the National Institutes of Health.
“The final contemplated product would be a single, pan-antivenom cocktail or we potentially would make two: one that is for the elapids and another that is for the viperids because some areas of the world only have one or the other.”
The other major goal is to approach philanthropic foundations, governments, and pharmaceutical companies to support the manufacturing and clinical development of the broad-spectrum antivenom.
“This is critical, because although there are millions of snake envenomations per year, the majority of those are in the developing world, disproportionately affecting rural communities,” Glanville says.
Funding:
This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the National Institutes of Health Small Business Innovation Research program, and the US Department of Energy.
About this neuroscience and neurotoxin research news
Author: Jordan Greer
Source: Cell Press
Contact: Jordan Greer – Cell Press
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Snake-venom protection by a cocktail of varespladib and broadly neutralizing human antibodies” by Jacob Glanville et al. Cell
Abstract
Snake-venom protection by a cocktail of varespladib and broadly neutralizing human antibodies
Snake envenomation is a neglected tropical disease, with 600 species causing over 100,000 deaths and 300,000 permanent disabilities in humans annually.
Broadly neutralizing antibodies and broad chemical inhibitors have been proposed as solutions, but how to develop a therapeutically effective cocktail and the number of required components have been unclear.
To address this gap, we iteratively recovered two broadly neutralizing antivenom antibodies from the memory B cells of a hyperimmune human donor with extensive snake venom exposure.
The antibodies recognized conserved neutralizing epitopes on prevalent long and short snake neurotoxins, with crystal structures revealing antibody mimicry of the interfaces between these neurotoxins and their host target, the nicotinic acetylcholine receptor.
We combined and tested these antibodies and the phospholipase inhibitor varespladib.
A 3-component cocktail rescued animals from whole-venom challenge of all species in a 19-member WHO Category 1 and Category 2 elapid diversity set, with complete protection against most snakes observed.
