Science & Technology, India (Commonwealth Union) – Researchers from the Scripps Research Institute and the Evolutionary Venomics Lab (EVL) at the Centre for Ecological Sciences (CES), Indian Institute of Science (IISc) have engineered a synthetic human antibody capable of neutralizing a potent neurotoxin produced by the Elapidae family of highly venomous snakes, including the cobra, king cobra, krait, and black mamba.
Utilizing a methodology utilized on prior occasions for the screening of antibodies against HIV and COVID-19, the team successfully synthesized this novel venom-neutralizing antibody. Senji Laxme RR, a PhD student at EVL, CES, and co-first author of the study published in Science Translational Medicine, pointedout that it marks the inaugural application of this particular strategy in developing antibodies for snakebite treatment.
The scientists believe that this breakthrough brings us closer to a universal antibody solution capable of providing broad protection against various snake venoms.
Researchers of the study pointed out that snakebites claim numerous lives annually, particularly in regions like India and sub-Saharan Africa. The current approach to developing antivenoms entails injecting snake venom into equines such as horses, ponies, and mules, and subsequently harvesting antibodies from their blood. However, this method faces several challenges.
“These animals get exposed to various bacteria and viruses during their lifetime,” said Kartik Sunagar, who is Associate Professor at the CES and joint corresponding author of the study. “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.”
The team’s developed antibody targets a conserved region situated within the core of a major toxin known as the three-finger toxin (3FTx) found in elapid venom. Despite variations among different elapid species in their production of 3FTxs, certain regions within the protein exhibit similarity. Focusing on one such conserved region—a disulfide core—the team created an extensive library of synthetic antibodies derived from humans, which were showcased on yeast cell surfaces. Subsequently, they assessed the antibodies’ capability to bind to 3FTxs from diverse elapid snakes worldwide. Following extensive screening, they identified a single antibody with strong binding affinity to various 3FTxs. Remarkably, among the 149 variants of 3FTxs documented in public repositories, this antibody demonstrated binding to 99 of them.
The researchers proceeded to evaluate the efficacy of their antibody using animal models. In one series of experiments, they mixed the synthetic antibody with a toxic 3FTx derived from the Taiwanese banded krait before administering it to mice. Mice injected solely with the toxin did not see positive results, whereas those administered with the toxin-antibody mixture survived beyond the 24-hour observation period and exhibited complete health.
Furthermore, the team tested their antibody against the entire venom of the monocled cobra from Eastern India and the black mamba from sub-Saharan Africa, yielding similar promising outcomes. Notably, the antibody’s efficacy was found to be nearly 15 times greater than that of conventional products. Critically, even when administered after a delay—0 minutes, 10 minutes, and 20 minutes post-venom injection—the antibody successfully rescued mice. In contrast, the conventional antivenom demonstrated optimal efficacy only when administered alongside the venom, with even a 10-minute delay significantly diminishing its potency.
Moreover, the team utilized cryo-electron microscopy (cryo-EM) to elucidate the crystal structure of the toxin-antibody complex. They discovered striking similarities between their binding and the binding observed between the toxin and receptors present in muscles and nerve cells. Sunagar indicated that their antibody appears to emulate the toxin-binding site of the receptor within our bodies. Consequently, venom toxins bind to their antibody rather than the receptor. Given that the antibody effectively neutralizes venom even with delayed administration, it suggests its capability to displace toxins bound to receptors.”
To produce the antibody, the researchers employed human-derived cell lines, eliminating the necessity of injecting venom into animals such as horses. Laxme indicated that due to the fact that the antibody is entirely human-derived, they anticipate minimal off-target effects or allergic reactions.
“This solves two problems at the same time,” explained Sunagar. “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.”
