For more than 20 years, researchers have tried with limited success to engineer antibodies into new treatments for bacterial and viral infections. Now, a team of scientists has come up with a new approach: fastening together tiny antibodies from llama blood with a type of bacterial superglue. The interconnected antibodies protect mice from two dangerous viruses, and they could subdue other pathogens.
The new work has been able to “bypass a lot of the hurdles” that stymied 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 for cancer.”
Antibodies treat a range of illnesses, including cancer and autoimmune diseases. A handful of engineered antibodies have been approved as therapies for infections, but producing functioning antibodies is hard for several reasons. Genetically altering cells to make the antibodies can be tricky, and the engineered molecules may not fold into the right shape to perform their task. A potential alternative is the miniature antibodies pumped out 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 don’t misfold.
Molecular biologist Paul Wichgers Schreur of Wageningen Bioveterinary Research and colleagues wanted to know whether the miniature antibodies could provide protection from bunyaviruses, a group of viruses the World Health Organization has warned could cause future epidemics. The researchers tested the antibodies against two such viruses. Rift Valley fever virus mainly attacks livestock in Africa and the Middle East, but also occasionally sickens people. Schmallenberg virus, discovered in Germany in 2011, doesn’t cause illness in humans, but in goats and sheep it induces miscarriages and gruesome birth defects.
After injecting llamas with either virus, the scientists isolated immune cells that produce antibodies from the animals’ blood. They showed that llamas began to manufacture more than 70 varieties of small antibodies that recognized and latched onto proteins from the two viruses.
To determine how potent these miniature antibodies were, the researchers then measured whether the molecules could stop the viruses from invading monkey kidney cells in a dish. Individual varieties of antibodies had little effect, so the researchers tried mixing them. That’s when they turned to their bacterial superglue, which consists of two types of protein fragments from Streptococcus pyogenes bacteria. When fragments of different types meet, they lock together. If the fragments are connected to other molecules, those molecules are then linked as well. Using the superglue, the researchers could tether together two or three llama antibodies, allowing them to gang up on the virus. Wichgers Schreur and colleagues found that linked antibodies were much better than individual antibodies at preventing both viruses from entering cells.
The scientists then tested the superglued antibodies in mice that had received lethal doses of either virus. All untreated mice infected with Rift Valley fever virus died within 3 days, but more than 20% of the rodents that received a trio of linked antibodies were still alive after 10 days. The approach also worked against Schmallenberg virus: One antibody combination spared all of the mice, whereas control animals perished within 5 days, the scientists report in the journal eLife.
The study shows the small antibody approach “is possible and gives new opportunities to optimize it,” Wichgers Schreur says. Researchers still need to answer several questions before they can think about testing the strategy in people, he says, such as whether 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 fight the coronavirus causing the current pandemic.