In a recent Science Advances paper, researchers from the University of Pittsburgh School of Medicine describe an aerosolized nanobody formulation that was found to effectively block the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian hamsters.
Animals who received inhaled nanobodies have fewer coronavirus particles in their bronchioles (right panel, orange) and are less inflamed (magenta). Image Credit: Nambulli et al., Science Advances
An overview of COVID-19 treatments
As of May 25, 2021, over 168 million people have been infected by the novel SARS-CoV-2, which is the virus responsible for the coronavirus disease 2019 (COVID-19), worldwide. Of these 168 million people, almost 3.5 million people have died as a result of COVID-19.
When SARS-CoV-2 first emerged, many healthcare professionals around the world turned to the use of high-titer convalescent plasma (CP) to reduce the risk of the severe effects of COVID-19 in senior patients. Since every plasma unit that has been obtained from previously infected COVID-19 patients will contain varying amounts of neutralizing antibodies, several institutions began isolating these neutralizing monoclonal antibodies (mAbs) for recombinant productions.
Limitations of mAbs in treating COVID-19
The in vivo evaluations of these mAbs in murine, hamster, and nonhuman primate (NHP) models have provided information on the efficacy of this therapeutic approach, as well as the mechanisms by which mAbs may alter the course of SARS-CoV-2 infection. Despite these findings, mAbs must often be administered in exceedingly high doses through intravenous injections.
There are several possible explanations as to why such high doses of mAbs are required to effectively neutralize SARS-CoV-2. These include the virulence and pathogenesis of SARS-CoV-2, as well as the low efficiency of delivering large biomolecules through the intravenous route to treat pulmonary infections.
To overcome these challenges, a group of researchers from the University of Pittsburgh School of Medicine studied how inhalable nanobodies (Nbs) could be used to treat SARS-CoV-2 in Syrian hamsters.
What is the difference between mAbs and Nbs?
In a previous study, the University of Pittsburgh researchers discuss their development of camelid single-domain antibody fragments or Nbs that primarily target the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) surface protein.
Although both Nbs and mAbs similarly neutralize SARS-CoV-2, Nbs are much smaller than mAbs. Nbs are also much more stable than mAbs and offer a high level of solubility. Both of these characteristics allow for the storage and transportation of these agents to be much easier, which is particularly important during a pandemic. Furthermore, Nbs are substantially cheaper to produce as compared to mAbs.
Targeting inhaled nanobodies against SARS-CoV-2
In their most recent Science Advances study, the researchers evaluated the efficacy of the Pittsburgh inhalable Nanobody 21 (PiN-21) for both the prophylaxis and treatment of SARS-CoV-2-infected Syrian hamsters. Shortly after getting infected with SARS-CoV-2, PiN-21 was delivered intranasally to the hamsters at an average dose of 0.6 milligrams (mg)/kilogram (kg).
The hamsters that received PiN-21 did not experience any significant weight loss as compared to the hamsters that did not receive PiN-21. Moreover, the control hamsters instead experienced a rapid loss of up to 16% of their body weight. In addition to assessing the weight loss in the hamsters, the researchers also found that the intranasal delivery of PiN-21 reduced viral titer levels within the lungs of the hamsters.
When PiN-21 was aerosolized using a nebulizer (PiN-21Alb), the researchers found that about half of the dose of PiN-21 was needed to achieve the same anti-viral effects against SARS-CoV-2 when using PiN-21Alb.
The researchers believe that the aerosolization of the Nbs significantly improved their delivery deep into the lungs. In fact, the researchers confirmed that the Nb treatment successfully penetrated deep into the terminal alveoli, which are lined with alveolar cells that are rich in the angiotensin-converting enzyme 2 (ACE2) receptor.
Since SARS-CoV-2 primarily uses the ACE2 receptor to gain entry into the host cell, the ability of PiN-21 and PiN-21Alb to exert their antiviral effects at this level of the pulmonary system is a remarkable finding. Furthermore, the fact that PiN-21Alb can maintain this efficacy at reduced doses has the potential to minimize any potential adverse effects that this drug might have on the host.
Taken together, the aerosolized Nbs evaluated in this study have the potential to be a convenient and cost-effective solution in reducing the severity and transmission of COVID-19.
- Nambulli, S., Xiang, Y., Tilston-Lunel, N. L., et al. (2021). Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses. Science Advances 7(22). doi:10.1126/sciadv.abh0319.