A new method for developing antibodies from RNA can be used to neutralise not only SARS-CoV-2 but also other viruses, including in future pandemics.
The COVID-19 pandemic shows the important role of antibodies in health and disease. Drug manufacturers have developed an extensive array of antibodies that can inhibit SARS-CoV-2 from multiplying or penetrating human cells. These are very important methods of fighting serious illness and death from COVID-19.
Traditional antibodies are made from proteins, but new research shows a potentially smarter way to make antibodies towards viruses by using RNA instead of proteins.
The RNA antibodies are called aptamers and have many advantages over traditional antibodies. The researchers showed that they can develop affordable and easy-to-produce RNA aptamers that can neutralise infection by SARS-CoV-2 and other viruses relatively quickly and simply.
“One advantage of RNA aptamers is that they can be produced chemically in a laboratory, which is much easier than producing protein-based antibodies. In this study, we showed that they are just as effective in inhibiting SARS-CoV-2 from entering cells,” explains a researcher behind the study, Jørgen Kjems, Professor, Interdisciplinary Nanoscience Center and Department of Molecular Biology and Genetics, Aarhus University.
The research has been published in the Proceedings of the National Academy of Sciences of the United States of America.
Animals or humans required to make traditional antibodies
Traditional protein-based antibodies are relatively difficult to produce and all are derived from animals (or people) exposed to a specific viral protein or whole virus, such as SARS-CoV-2, with the immune system gradually developing antibodies. Then blood can be drawn and purified and the antibodies extracted.
Researchers can also clone selected antibodies from people with COVID-19, produce them in human cells in culture and use them to treat other people with COVID-19.
“The greatest advantage of our method is not requiring animals or people to make antibodies but instead designing and producing them chemically in the laboratory. By added extra chemical groups to them we can make the more stable than traditional antibodies,” says Jørgen Kjems.
Selecting antibodies from countless RNA fragments
To make the RNA aptamers, researchers exposed a virus, in this case SARS-CoV-2, to quadrillions (1015) of RNA library fragments in a test tube, some of which can bind to SARS-CoV-2.
Screening for RNA-based antibodies requires attaching miniscule magnetic beads to the SARS-CoV-2 spike protein and then applying to the cocktail of RNA fragments. Spike-binding RNA fragments can then be harvested with a magnet.
The researchers then exponentially enrich the relevant RNA strands by PCR and repeat the process until they obtain a handful of RNA fragments that all bind exceptionally well to the spike protein.
“A spike protein with RNA bound to the tip cannot interact with the ACE2 receptor on the surface of human cells, and then SARS-CoV-2 cannot enter the cells. We have now started to test the RNA aptamers in mice,” explains Jørgen Kjems.
Testing in mice
The researchers are currently investigating whether injecting the aptamers into mice lungs can prevent serious illness and death.
“Our leading candidate very effectively inhibits the uptake of viruses into human cells, and we hope it can lead to a new treatment. We are also investigating using the aptamers in rapid tests for SARS-CoV-2 because they bind to the spike protein they can determine whether the virus is present. Our preliminary experiments with a rapid test indicate that the aptamers are more sensitive than traditional antibodies. They are also are more stable and therefore do not degrade over time. Further, rapid tests can probably be created that can differentiate between different variants,” says Jørgen Kjems.
Culminating a decade of research
The RNA aptamers are extremely easy to replicate once the genetic code is sequenced in the aptamer. Researchers can do this chemically in the laboratory without using animals or other steps that could delay the process.
This also makes RNA aptamers cheaper, and their chemical structure is more stable than proteins. This makes them suitable for both treatment and rapid tests in regions where keeping medicine cold or frozen before use is more difficult. The aptamers can be stored at room temperatures for years.
“The aptamers culminate a decade of research, and we have become really proficient at making them stable, overcoming our previous difficulty. The new chemical modifications to the building blocks of RNA prevent them from being recognised by the enzymes that normally degrade RNA, keeping them very stable even in human saliva and in the blood,” explains Jørgen Kjems.
Targeting other viruses
Although SARS-CoV-2 is the hot topic right now, the aptamers have potential beyond this pandemic.
Jørgen Kjems’ group is also making aptamers against influenza and sees potential in quickly using the same method to develop aptamers against any other future viral disease.
“We will probably be battling SARS-CoV-2 and influenza for many years to come. But we cannot keep vaccinating constantly, so treatments will be required for people, especially those who become severely ill. In addition, we need technologies to quickly develop treatments to combat the next pandemic,” concludes Jørgen Kjems.