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Researchers have shown that small antibodies can block Rift Valley fever virus (above) from entering cells.
LAGUNA DESIGN / Science Source
By Mitch Leslie
For more than 20 years, researchers have tried with limited success to design antibodies in new treatments for bacterial and viral infections. Now, a team of scientists has devised a new approach: to bind small antibodies in the blood of the flame with a type of bacterial superglue. Interconnected antibodies protect mice from two dangerous viruses and can subject other pathogens.
The new work has been able to “get around many obstacles” that hampered previous attempts, says protein engineer Jennifer Maynard of the University of Texas, Austin. “I think this will be a very general technology that will be useful for infectious diseases and cancer.”
Antibodies treat a variety of diseases, including cancer and autoimmune diseases. A handful of engineered antibodies have been approved as therapies for infections, but the production of functional antibodies is difficult for several reasons. Genetically altering cells to make antibodies can be tricky, and engineered molecules may not fold in the right way to do their job. A potential alternative is miniature antibodies pumped by llama, camel and shark immune cells, which are about half the size of standard antibodies. These tiny proteins are faster and cheaper to make than their larger counterparts, and they don’t fold incorrectly.
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 warned might cause future epidemics. The researchers tested the antibodies against two of those viruses. The Rift Valley fever virus mainly attacks livestock in Africa and the Middle East, but also occasionally makes people sick. The Schmallenberg virus, discovered in Germany in 2011, does not cause disease in humans, but in goats and sheep it induces miscarriages and horrible birth defects.
After injecting llamas with any of the viruses, the scientists isolated immune cells that produce antibodies from the animals’ blood. They showed that the flames began to make more than 70 varieties of small antibodies that recognized and bound to the proteins of the two viruses.
To determine how powerful these miniature antibodies were, the researchers measured whether the molecules could prevent viruses from invading the monkeys’ kidney cells on a plate. The individual varieties of antibodies had little effect, so the researchers attempted to mix them. It was then that they turned to their bacterial superglue, which consists of two types of protein fragments from Streptococcus pyogenes bacteria When fragments of different types are found, they unite. If the fragments are connected to other molecules, those molecules also bind. Using the super glue, the researchers were able to bind two or three flame antibodies together, allowing them to bind to the virus. Wichgers Schreur and colleagues found that bound antibodies were much better than single antibodies at preventing both viruses from entering cells.
The scientists then tested the super-stuck 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 Schmallenberg virus: a combination of antibodies saved all mice, while control animals perished within 5 days, scientists report in the journal. elife.
The study shows that the small antibody approach “is possible and provides new opportunities to optimize it,” says Wichgers Schreur. The researchers still need to answer several questions before they can think of trying the strategy on people, he says, as if they can produce sufficient amounts of the linked antibodies. He adds that the approach could work against other types of viruses, but it probably won’t be ready in time to combat the coronavirus causing the current pandemic.
