Tests can reveal if an antibody can turn into a killer

What makes a soldier change sides? That’s a very good question, especially when the soldier is an antibody that is supposed to defend the body against one of the most dangerous snake venoms in the world, but ends up helping the venom kill the body.

The question became timely after a group of DTU researchers slightly changed the way they tested an antibody that had previously shown promise as an antidote to snake venom. In the first experiment on mice, the harmful effect on muscle tissue of the venom of Bothrops asper, a lancehead snake from Costa Rica, was neutralized as expected. But in the second experiment, the antibody increased the potency of the snake venom, so that it no longer just affected muscle tissue, but ended up killing the mice.

The research is published in the journal Natural communications.

When and how the antibody was administered made the difference between life and death. In the first experiment, snake venom and the antibody were mixed for 30 minutes before being injected into the mouse’s muscle tissue. This method is only slightly similar to treating a real snake bite. In the second experiment, the researchers simulated the usual real-world scenario, in which antivenom is administered after a snake bite: first, they injected the poison into the muscle tissue of the mouse. Three minutes later, they injected the antibody into the mice’s veins.

“The fact that the antibody amplifies the toxin when the venom and antidote are administered in different ways is an incredibly interesting finding from a research point of view,” says postdoc Christoffer Vinther Sørensen from DTU, who was testing the antibody when the observation was made.

“This is an important discovery that we have arrived at,” says Professor Bruno Lomonte of the University of Costa Rica. Alongside his colleague Professor Julián Fernández, he has collaborated with Sørensen and his project supervisor at DTU, Professor Andreas Hougaard Laustsen-Kiel, for the past four years. They hope this discovery will help speed up the development of the next generation of antivenoms, ensuring that many people in need can benefit from them sooner.

The phenomenon observed by researchers is known as antibody-dependent enhancement of toxicity (ADET). It has never before been observed in relation to toxins from the animal world and remains a mystery in most areas. For example, scientists don’t know how an antibody designed to fight venom can switch sides and intensify the toxins’ attacks on the body.

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

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

“Antibodies can fail in several ways. By mapping these methods, we and other antidote researchers can in the future ensure that promising antibodies are tested as soon as possible in the most essential experiments. We hope this will allow us to rule out suboptimal antibodies and quickly arrive at a final antivenom capable of neutralizing the most dangerous snake venoms in the world,” explains Sørensen, and adds: “Even if we don’t know why a ‘soldier’ ​​changes camp, we now know that it’s something to watch out for, even with our close friends, antibodies.”