Scientists at the National Institutes of Health have identified new antibody-based weapons in the fight against COVID-19 from an unlikely source—a llama named Cormac. Promisingly, these novel antibodies have the potential to be developed into inhalable therapeutic aerosols for treating COVID.
Camelids, an umbrella term for alpacas, camels, and llamas, produce two distinct forms of antibodies in response to invading pathogens such as viruses. While one resembles the Y-shaped protein structures of human antibodies, the other form is much smaller and unique to camelids—tiny antibodies known as “nanobodies”. These single-domain antibodies are of particular interest to drug developers for their ability to be converted into a fine mist for administration by inhalation. For respiratory infections like COVID-19, this means delivering these virus-neutralizing proteins as aerosols directly to the site of the infection.
Nanobodies are also more stable and cost-effective for producing in large quantities.
Thomas J. "T.J." Esparza, B.S., and David L. Brody, M.D., Ph.D., from the NIH's National Institute of Neurological Disorders and Stroke (NINDS) led the discovery of NIH-CoVnb-112, the nanobody targeting SARS-CoV-2’s spike protein.
"For years TJ and I had been testing out how to use nanobodies to improve brain imaging. When the pandemic broke, we thought this was a once in a lifetime, all-hands-on-deck situation and joined the fight," said Brody
"We hope that these anti-COVID-19 nanobodies may be highly effective and versatile in combating the coronavirus pandemic."
In the hunt for COVID-19 therapeutics, several drug development groups have leveraged nanobody-based therapies' power and potential. However, Esparza and the team took a slightly different approach to find the needles in the haystack—nanobodies with particularly high affinities for the spike protein.
"The SARS-CoV-2 spike protein acts like a key. It does this by opening the door to infections when it binds to a protein called the angiotensin converting enzyme 2 (ACE2) receptor, found on the surface of some cells," said Esparza
"We developed a method that would isolate nanobodies that block infections by covering the teeth of the spike protein that bind to and unlock the ACE2 receptor."
Cormac the llama received five immunizations with the spike protein over the course of a month to trigger an immune response. Analysis of hundreds of nanobodies produced by Cormac’s immune system revealed around 13 lead candidates. NIH-CoVnb-112, in particular, stood out with its ability to bind to the ACE2 receptor up to 10 times tighter than other nanobody frontrunners, blocking the virus from entering host cells.
Importantly, NIH-CoVnb-112 was able to be converted into an aerosol for administration to patients via an inhaler, similar to that used to dispense treatments for asthmatics. "One of the exciting things about nanobodies is that, unlike most regular antibodies, they can be aerosolized and inhaled to coat the lungs and airways," commented Brody.
According to Esparza, the data presented in the study represent a promising first step towards the commercialization of this therapeutic. "With support from the NIH, we are quickly moving forward to test whether these nanobodies could be safe and effective preventative treatments for COVID-19. Collaborators are also working to find out whether they could be used for inexpensive and accurate testing."