The Elapidae family of very deadly snakes, which includes the cobra, king cobra, krait, and black mamba, produces a strong neurotoxin that can be neutralised by a synthetic human antibody created by the Indian Institute of Science (IISc).
The scientists synthesised the novel venom-neutralizing antibody by modifying an existing method for screening for antibodies against COVID-19 and HIV. The co-first author of the study published in Science Translational Medicine, Senji Laxme RR, a PhD student at EVL, CES, states that this is the first time that this specific technique is being used to generate antibodies for the treatment of snakebite.
This breakthrough, according to the researchers, moves us one step closer to developing a universal antibody that can provide wide protection against a range of snake venoms.
Each year, snakebites claim thousands of lives, primarily in sub-Saharan Africa and India. Currently, injecting snake venom into horses, ponies, and mules and harvesting antibodies from their blood is the method used to create antivenoms. However, there are a number of issues.
The study’s co-corresponding author and associate professor at CES, Kartik Sunagar, says, “These animals get exposed to various bacteria and viruses during their lifetime.” Consequently, antibodies against microbes are also included in antivenoms, which is therapeutically redundant. Less than 10% of antivenom vials really contain antibodies that are specific to the poisons found in snake venom, according to research.
The team’s antibody targets a conserved area in the centre of the elapid venom’s main toxin, known as the three-finger toxin (3FTx). While distinct elapid species generate distinct 3FTxs, a few areas within the protein exhibit similarities. The group focused on a disulphide core, one such preserved area. They created a sizable collection of synthetic human antibodies that were seen on the surfaces of yeast cells. Next, they examined how well the antibodies bound to 3FTxs from different species of elapid snakes found worldwide. They reduced their options to one antibody that could bind firmly to a variety of 3FTxs after doing repeated screenings. 99 out of the 149 3FTx variations that are available in public sources could be bound by this antibody.
After that, the researchers used animal models to test their antibodies. In one series of tests, they injected mice with the synthetic antibody after pre-mixing it with a poisonous 3FTx made by the Taiwanese firm krait. After receiving only the poison, mice perished in four hours. However, individuals who received the toxin-antibody combination appeared perfectly healthy and lived past the 24-hour monitoring period.
Similar findings were obtained when the scientists tested its antibody against the whole venom of the black mamba from sub-Saharan Africa and the monocled cobra from Eastern India. The antibody’s effectiveness was discovered to be over fifteen times greater than that of the traditional product. Importantly, the antibody continued to be able to save animals when it was initially injected with venom and then administered after a time delay of 0, 10, and 20 minutes. However, the conventional product was only effective when administered in conjunction with the venom. The efficacy of the conventional antivenom was dramatically lowered even after a 10-minute delay.
Furthermore, the researchers employed cryo-EM to decipher the toxin-antibody complex’s crystal structure and discovered that their binding was very comparable to the toxin’s binding to receptors in muscles and nerve cells. According to Sunagar, “our antibody appears to mimic the toxin-binding site of the receptor in our body.” As a result, rather of attaching to the receptor, venom toxins are binding to our antibody. Our antibody’s ability to neutralise venom even after delayed injection raises the possibility that it may be able to displace poisons attached to receptors.
The venom did not need to be injected into horses or other animals beforehand since the researchers were able to manufacture the antibodies using human-derived cell lines. “We do not anticipate any allergic reactions or off-target reactions because the antibody is fully human,” Laxme adds.
Sunagar claims that “this solves two problems at the same time.” First off, since it is a wholly human antibody, adverse reactions that can occasionally be fatal—such as anaphylaxis—can be avoided in patients receiving traditional antivenom treatment. Second, this would imply that future production of this life-saving cure wouldn’t need harming animals.
Antibodies against different snake venoms may also be produced using the same method, and they can then be included into a single antivenom treatment. “At this stage, a clinician cannot rely on this single antibody for treatment as this is only effective against certain elapid snakes,” explains Sunagar on the next steps in the clinical trial process. We are now searching for other antibodies directed against targets of snake venom. In the future, a global antivenom may comprise a few of these man-made antibodies, which should be able to counteract the venoms of most snakes found around the world. Clinical studies on humans might potentially be conducted for a universal product, or at the very least, a combination of antibodies that function across India.
-Rashmi Kumari
