Surprising Twist in Snake Venom Research: Antibodies Switch Roles from Cure to Killer

DTU researchers have carried out tests indicating that a therapeutic antibody may actually increase the toxicity of snake venom. This was discovered after making a slight alteration in the testing of an antibody previously thought to be a viable antidote for the venom of Bothrops Asper snakes. Image source: Andrew DuBois.

An antibody that presented potential promise did not pass the testing stage. Interestingly, this failure brings us closer to developing a wide-ranging antidote for some of the most deadly snake venoms in the world.

The case is particularly intriguing when the 'soldier' in question is an antibody. Ordinarily, its job would be to protect the body against the venom of some of the most poisonous snakes in the world. However, in this case, the antibody seemed to aid the venom in killing the body instead of defending against it.

The topic has come under scrutiny after DTU researchers altered the testing approach for an antibody that had previously shown potential as an antidote to snake toxins. In the first experiment involving mice, it successfully neutralized the destructive impact on muscle tissue caused by the venom of Bothrops asper, a snake found in Costa Rica. However, in a subsequent experiment, the snake venom's potency was amplified by the antibody, resulting in the death of the mice instead of merely affecting muscle tissue.

Every year, snakebites cause over 100,000 deaths.

In 2017, snakebites were added to the World Health Organization's list of neglected tropical diseases. Each year, about 5.4 million individuals are bitten by snakes, predominantly in poor regions where pharmaceutical companies can't penetrate the market. Every year, around 100,000 individuals die from snakebites, and three times that number suffer permanent disabilities.

An international team of researchers, led by Professor Andreas Hougaard Laustsen-Kiel from DTU, is working on a new generation of broad-spectrum antivenoms. The goal is to create antidotes based on antibodies that are compatible with the human immune system and can be grown in cell tanks.

The manner and timing of the antibody's administration were critical in the distinction between life and death. Initially, the venom and antibody were mixed and left for 30 minutes before being injected into the mice's muscle tissue, a method slightly resembling the treatment for an actual snakebite.

In the second experiment, the researchers recreated the usual scenario where an antivenom is administered post-snakebite. The venom was initially injected into the mice's muscle tissue, and after three minutes, the antibody was injected into their bloodstream.

Christoffer Vinther Sørensen was present alongside the longest venomous snake in the world — the king cobra in Indonesia. Image source: Christoffer Vinther Sørensen.

Christoffer Vinther Sørensen from DTU, who was responsible for testing the antibody, described the finding that the antibody increases the potency of the toxin when the venom and antidote are given in different ways as "an incredibly fascinating discovery from a research point of view."

"We have arrived at a significant discovery," said Professor Bruno Lomonte from the University of Costa Rica. Over the past four years, Professor Lomonte, along with his colleague Professor Julián Fernández, has collaborated with Christoffer Vinther Sørensen and his project supervisor at DTU, Professor Andreas Hougaard Laustsen. They express hopes that this breakthrough will speed up the development of the next generation of antivenom, ultimately offering help to many people sooner.

The finding has been recently published in the esteemed scientific journal, Nature Communications.

ADET – A Complex Occurrence

Antibody-Dependent Enhancement of Toxicity (ADET) is an immunological phenomenon similar to Antibody-Dependent Enhancement (ADE), both subjects of ongoing research. ADE is associated with viral infections whereby antibodies from a prior infection bind with a new strain of the same virus or a related one but fail to neutralize it. In certain scenarios, this non-neutralizing binding may amplify the virus's damaging effect.

Antibodies, dynamically functioning as part of the body's defense mechanism against pathogens, bind to bacteria, viruses, or toxins, preventing their development or toxic effects.

The researchers have found evidence of a phenomenon known as antibody-dependent enhancement of toxicity (ADET), which hasn't been previously observed in relation to animal-derived toxins. Uncertainty still shrouds most aspects of it, particularly the mechanism by which an antibody made to counteract venom unknowingly facilitates the toxins' attack on the body.

“We haven’t figured out how this happens, but it helps to identify another important aspect that should be tested when working with antibodies,” says Christoffer Vinther Sørensen.

The venom from Bothrops Asper, a Costa Rican lancehead snake, can cause debilitating damage to muscle tissue. Credit: Vanesa Zarzosa

His research project is part of international research work aimed at finding a broad-spectrum antivenom based on human antibodies that can be used as treatment against the world’s most dangerous snake venoms.

“Antibodies can fail in many ways. By mapping these ways, we and other antidote researchers in the future can ensure that promising antibodies are tested as soon as possible in the most essential experiments. We hope that this allows us to discard antibodies that are not optimal and quickly arrive at a final antivenom that can neutralize the world’s most dangerous snake venoms,” says Christoffer Vinther Sørensen and adds:

“While we don’t know why a ‘soldier’ switches sides, we now know that it’s something to keep an eye on, even with our close friends, the antibodies.”