The immune systems of camelids such as llamas and alpacas make tiny “nanobodies” many scientists believe could inspire treatments that offer advantages over traditional antibodies. Now, researchers from the University of Bonn, the Karolinska Institutet and Scripps Research Institute have designed a nanobody-based drug for COVID-19.
By fusing two nanobodies selected from a llama and an alpaca that were immunized with SARS-CoV-2—the novel coronavirus behind COVID-19—the researchers were able to synthesize nanobodies that can simultaneously attack multiple sites of the virus’s spike protein, according to a new study published in Science. The tiny antibodies also fought mutated variants of the virus, the team showed in lab dishes.
A company called Dioscure Therapeutics has spun off from the University of Bonn with plans to bring its lead COVID-19 candidates, DIOS-202 and DIOS-203, into clinical trials this year.
Nanobodies are composed of heavy chains and use a single variable domain to recognize their targets, whereas conventional antibodies have both heavy and light chains, as well as variable heavy and light domains. Therefore, nanobodies may hold an advantage in that their small size allows them to penetrate deeper into tissue. Nanobodies are also more stable and are easier to produce, potentially making them less costly.
For the new study, the researchers injected a piece of SARS-CoV-2 spike protein, along with the inactivated virus, into one alpaca and one llama to elicit the production of antibodies against the virus. Among the millions of antibodies generated by the animals, the team eventually picked four nanobodies—one from the llama and three from the alpaca—that showed the best ability to bind and neutralize the virus in lab dishes.
The spike protein is crucial for the coronavirus to infect healthy cells, so it is the main target of multiple COVID-19 vaccines and antibody drugs.
The researchers showed that nanobodies appear to trigger a key structural change when they bind to the virus. “The change is likely to be irreversible—the virus is therefore no longer able to bind to host cells and infect them,” Paul-Albert König, Ph.D., the study’s lead author, explained in a statement.
The simple structure of nanobodies allows for combinations to form new molecules, so the scientists linked two nanobodies that target different parts of the spike protein. They found that the engineered nanobodies were more than 100-fold more effective at neutralizing the virus than single-armed ones in cell culture were.
What’s more, the combined nanobodies worked against a virus variant that mutates very quickly, the team showed. This means the treatment could significantly reduce the risk of the virus becoming resistant, König said.
Several other research groups are developing nanobody-based COVID-19 candidates. Scientists from the University of Texas at Austin, the National Institutes of Health and Ghent University in Belgium linked two nanobodies to create a therapy that prevented SARS-CoV-2 from invading cells.
Twist Bioscience recently reported that two of its nanobodies protected hamsters from weight loss—an indicator of COVID-19 disease severity—at a similar level to that of plasma from COVID-19 survivors. A team at the University of California, San Francisco posted encouraging preclinical results for its aerosol formulation of nanobodies.
Dioscure is now accelerating development of its two lead candidates. The company hopes the drugs could be used to treat infected COVID-19 patients or as an alternative to vaccines for prevention.