Despite the great progress made in vaccination against the Sars-CoV-2 coronavirus, there is still no effective means of treating Covid-19. The first tests of an inhalable agent are now giving cause for hope. In tests with golden hamsters, even a small dose of the nanoantibodies reduced the viral load in the animals’ airways and lungs and prevented severe inflammation. If this effect is also confirmed in humans, such “nanobodies” could enable treatment of Covid-19 that is easy to use and inexpensive to produce, as the researchers explain. They could also help slow down the transmission.
So far, there are hardly any drugs that can slow down the Sars-CoV-2 infection or prevent a severe course of Covid-19. Hopes for antiviral agents such as Remdesivir turned out to be premature because this often only temporarily inhibits the multiplication of the coronavirus and usually only works in the early stages of the infection. Another approach is monoclonal antibodies – immunoglobulins that bind precisely to certain structures of the spike protein of Sars-CoV-2, which ideally block the virus from binding to our cells and thus neutralize it. So far, however, none of these antibody agents has been able to achieve a powerful effect. In addition, the monoclonal antibodies are complex to produce, usually have to be administered in high doses and are therefore relatively expensive.
Antibody fragments in the test
In search of alternatives, Sham Nambulli of the University of Pittsburgh and his colleagues examined a number of nanoantibodies in more detail. These are tiny peptides – fragments of antibodies that, like these, specifically dock onto certain structures of the Sars-CoV-2 spike protein. The finished nanobodies, however, are four times smaller than antibodies and much cheaper to manufacture. In the first cell culture experiments, some of these nanoantibodies had already shown a very good effect against the coronavirus. They neutralized the pathogen in far lower doses than the classic monoclonal antibodies.
Nambulli and his team have now tested with golden hamsters whether this effect is similarly potent in living animals. For their study, they infected golden hamsters with Sars-CoV-2 and administered the so-called PiN-21 nanoantibodies in the form of a nasal spray or inhalation six hours later. The idea behind it: The lung tissue that is heavily infected by the virus is only accessible to a limited extent for normal-sized antibodies. “One of the reasons for this is the notoriously low efficiency with which such intravenously administered large biomolecules pass through the plasma-lung barrier,” explain the researchers. If, on the other hand, a drug is administered as a nasal spray or by inhalation, it reaches the lungs directly via the airways – and thus to the place where it is supposed to work.
Lower viral load, less inflammation
In the tests with the hamsters, the nanoantibodies administered via the respiratory tract actually showed an effect: the control animals treated only with a placebo lost up to 16 percent weight in the next few days and the pneumonia typical of Covid-19 developed. The hamsters who inhaled the nanobodies, on the other hand, did not lose weight and the viral load in the airways and lungs fell by between 10,000 and million times by the fifth day. “On the second day after infection, the virus was no longer detectable in the upper respiratory tract, either through nasal or throat swabs,” reports the team. The otherwise typical severe inflammation of the bronchi and lungs did not occur in the golden hamsters treated with the nanoantibody spray. In addition, the PiN-21 group had significantly fewer inflammatory changes in the tissue and did not develop any edema, bleeding or scarring, as the researchers report. A dose of around 0.2 micrograms per kilogram of body weight has proven to be effective. For comparison: According to the researchers, monoclonal antibodies administered by infusion typically require ten to 50 milligrams per kilogram of body weight.
These nanobodies are significantly more effective than most of the monoclonal antibodies currently being tested: “The ability to prevent virus replication and lung pathology in both the hamsters’ upper and lower respiratory tract contrasts sharply with the clinical antibodies, which struggle even with high doses to control the infection in these animals, ”said Nambulli and his team. According to the scientists, such nanobodies therefore open up new, promising opportunities to effectively prevent severe courses of Covid-19. “We are enthusiastic and encouraged by our data, because they suggest that PiN-21 can provide high levels of protection against severe disease – and that it may also prevent human-to-human transmission of the coronavirus,” says Nambulli’s colleague Yi Shi . Because of the comparatively low production costs, such nanoantibody sprays could also be produced and used in poorer countries such as India. However, further tests still have to be carried out in order to investigate the dosage and possible side effects more precisely, as the scientists emphasize. Only then could clinical studies with humans follow.
Source: Sham Nambulli (University of Pittsburgh) et al., Science Advances, doi: 10.1126 / sciadv.abh0319