|Researchers have shown that small antibodies can prevent the Rift Valley fever virus (above) from entering cells. - LAGUNA DESIGN / Science Source|
For more than 20 years, researchers have tried with limited success to develop antibodies in new treatments against bacterial and viral infections.
Now a team of scientists has developed a new approach: fixing tiny llama blood antibodies with a type of super bacterial glue. The interconnected antibodies protect mice from two dangerous viruses, and they could control other pathogens.
The new work may have “overcome a lot of obstacles” that thwarted previous attempts, said Jennifer Maynard, protein engineer at the University of Texas at Austin. “I think it will be a very general technology that will be useful for infectious diseases and for cancer. “
Antibodies treat a range of diseases, including cancer and autoimmune diseases. A handful of modified antibodies have been approved as infection therapies, but producing functional antibodies is difficult for several reasons. Genetic modification of cells to make antibodies can be tricky, and the modified molecules may not bend into the right shape to perform their task. A potential alternative is the miniature antibodies pumped by the immune cells of llamas, camels and sharks, which are about half the size of standard antibodies. These diminutive proteins are faster and cheaper to make than their larger counterparts, and they do not fold badly.
Molecular biologist Paul Wichgers Schreur of Wageningen Bioveterinary Research and his colleagues wanted to know if miniature antibodies could provide protection against bunyaviruses, a group of viruses that the World Health Organization says could cause future epidemics. Researchers tested antibodies against two of these viruses. The Rift Valley fever virus mainly attacks cattle in Africa and the Middle East, but it can also make people sick. The Schmallenberg virus, discovered in Germany in 2011, does not cause disease in humans, but in goats and sheep it causes miscarriages and horrible birth defects.
After injecting llamas into either virus, scientists have isolated immune cells that make antibodies from animals’ blood. They showed that llamas began to make more than 70 varieties of small antibodies that recognized and clung to the proteins of the two viruses.
To determine the potency of these miniature antibodies, the researchers then measured whether the molecules could prevent viruses from invading monkey kidney cells in a dish. Individual varieties of antibodies had little effect, so the researchers tried to mix them up. That’s when they turned to their super bacterial glue, which consists of two types of protein fragments. Streptococcus pyogenes bacteria. When fragments of different types meet, they lock. If the fragments are connected to other molecules, these molecules are also linked. Using superglue, the researchers were able to attach two or three llama antibodies together, allowing them to bind to the virus. Wichgers Schreur and colleagues found that bound antibodies were much better than individual antibodies in preventing the two viruses from entering cells.
The scientists then tested the super-bonded antibodies in mice that had received lethal doses of either virus. All untreated mice infected with the Rift Valley fever virus died within 3 days, but more than 20% of the rodents that received a trio of bound antibodies were still alive after 10 days. The approach also worked against the Schmallenberg virus: a combination of antibodies spared all the mice, while the control animals perished in 5 days, the scientists report in the journal. eLife.
The study shows that the small antibody approach “is possible and offers new opportunities to optimize it,” says Wichgers Schreur. Researchers still need to answer several questions before they can consider testing the strategy in humans, he says, for example if they can produce sufficient amounts of the bound antibodies. He adds that the approach could work against other types of viruses, but that it will probably not be ready in time to fight the coronavirus that is causing the current pandemic.