For more than 20 years, scientists have worked to isolate or engineer antibodies for diagnostic tools or treatments. This work is challenging and expensive.
Antibodies are tiny Y-shaped structures made of four proteins. The tips of the Y recognize and bind to antigens like viruses, and the stem end directs what’s done after binding. Scientists have found simpler antibodies in llamas, and engineered these to help treat two dangerous viruses.
Llamas and nurse sharks were discovered to produce antibodies that are about half the size of human antibodies in the 1980s, but their use began to take off in 2012. These smaller antibodies are much easier to produce and engineer than human antibodies, and they can get inside cells easily and access deep tissues.
Scientists use them to track proteins in the body, neutralize viruses and label cancer cells. It’s also possible to make them even smaller, using just the section from the tip of the Y. These “nanobodies” are inherently soluble and can bind to antigens that are difficult to access.
Because nanobodies are so small, they can also be made in large amounts using genetically engineered bacteria like E. coli.
Now scientists have added a new twist, linking different antibodies together to make them more effective in treating infections by two dangerous pathogens.
Bunyaviruses are a group of viruses that could cause future epidemics. These viruses are spread by arthropods like mosquitoes and are a threat to animals and humans.
Rift Valley fever virus causes recurrent outbreaks in Africa and the Arabian Peninsula. Rift Valley fever virus mainly infects livestock, causing pregnancy loss. Rift Valley fever virus also can infect humans by contact with infected animal tissue or through a mosquito bite.
Schmallenberg virus infects cows and leads to fever, reduced milk production and birth defects, but it doesn’t infect humans. Rift Valley fever virus and Schmallenberg virus do not have effective therapies.
The scientists infected llamas with Rift Valley fever virus or Schmallenberg virus and then isolated antibody-producing cells from the animals’ blood. They discovered that the llamas made 70 different varieties of antibodies that bound to Rift Valley fever virus or Schmallenberg virus proteins. They tested each of the antibodies, but no individual antibody helped much to prevent infection.
The scientists found a way to permanently link multiple antibodies together using two bacterial proteins, called SpyTag and SpyCatcher. When two or three antibodies were linked, they were much more effective in preventing Rift Valley fever virus and Schmallenberg virus infections.
The scientists tested different combinations of antibodies and compared them with control groups of untreated mice. For the Rift Valley fever virus tests, all the untreated mice died, but 20 percent of the ones treated with antibodies survived. For the Schmallenberg virus tests, all the untreated mice died, but one combination of antibodies protected all the treated mice.
This approach could be used to make antibodies to treat a variety of viral infections. Converting llama antibodies into nanobodies makes them easy to produce in large amounts.
We hope that this will be another option should another viral pandemic occur.