Researchers at the Evolutionary Venomics Lab (EVL) at the Centre for Ecological Sciences (CES), the Indian Institute of Science (IISc), and the Scripps Research Institute have created a synthetic human antibody that is capable of neutralizing a strong neurotoxin that is produced by the highly toxic Elapidae family of snakes, which includes the black mamba, king cobra, krait, and cobra.
The scientists synthesized the novel venom-neutralizing antibody by modifying an existing method for screening for antibodies against COVID-19 and HIV.
This is the first time that this particular strategy is being applied to develop antibodies for snakebite treatment.
Senji Laxme RR, PhD student at EVL
The findings were published in the journal Science Translational Medicine.
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 several problems.
These animals get exposed to various bacteria and viruses during their lifetime.
As a result, antivenoms also include antibodies against microorganisms, which are therapeutically redundant. Research has shown that less than 10% of a vial of antivenom actually contains antibodies that are targeted towards snake venom toxins.
Kartik Sunagar, Associate Professor at CES
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, the 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.
Our antibody seems to mimic the toxin-binding site of the receptor in our body.
Venom toxins, therefore, are binding to our antibody instead of the receptor. Since our antibody neutralises venom even with delayed administration, it may suggest that it can displace toxins that are bound to receptors.
Kartik Sunagar
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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.
Because the antibody is fully human, we don’t expect any off-target or allergic responses.
Senji Laxme RR
This solves two problems at the same time.
First, it is an entirely human antibody and, hence, side-effects, including fatal anaphylaxis, occasionally observed in patients being treated with conventional antivenom, can be prevented. Secondly, this would mean that animals need not be harmed in future to produce this life-saving antidote.
Kartik Sunagar
Antibodies against different snake venoms may also be produced using the same method, and they can then be included in a single antivenom treatment.
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At this stage, a clinician cannot rely on this single antibody for treatment as this is only effective against certain elapid snakes. We are in the process of discovering additional antibodies against other snake venom toxin targets. A universal antivenom in future would consist of a couple of such synthetic antibodies that would hopefully neutralise venoms of most snakes in various parts of the world. A universal product, or at least a cocktail of antibodies that work pan-India, could then be taken to human clinical trials.
Kartik Sunagar
Source: Indian Institute of Science (IISc) News
Journal Reference: Khalek, Irene S., et al. “Synthetic Development of a Broadly Neutralizing Antibody against Snake Venom Long-chain α-neurotoxins.” Science Translational Medicine, 2024, https://doi.org/10.1126/scitranslmed.adk1867.
