Inhalable Nanobodies treat SARS-CoV-2 infections in hamsters

Scientists have engineered a nanobody PiN-21 which was found to exhibit anti-SARS-CoV-2 viral effects in Syrian hamsters. 

Monoclonal antibodies obtained from convalescent plasma are a potent and strong treatment against COVID-19 infections. These antibodies have to be injected in large doses and quite frequently due to their lower potency as they are monovalent. Monoclonal antibodies are less effective in COVID-19 treatment and possess a more prophylactic effect. The high cost of bulk manufacturing augments the limited clinical use of monoclonal antibodies.  

Scientists from the University of Pittsburgh isolated smaller “nanobodies” from llama serum, as an alternative to monoclonal antibodies. Nanobodies or single-domain antibodies are antibodies without the Fc (fragment of crystallisation) region. These nanobodies were able to combat a SARS CoV-2 infection more effectively and at a lower dosage than monoclonal antibodies. Nanobodies can remain stable at room temperature for up to six weeks and are highly soluble thus enabling cheaper production, easy storage and delivery of these nanobodies. 

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The nanobodies predominantly target the Receptor Binding Domain of the Spike glycoprotein receptor of the SARS-CoV-2 virus to neutralise it. The small size allows for easy delivery of the nanobodies into the lungs. The nanobodies can also be fabricated into an inhalable aerosol mist to deliver antiviral therapy which can improve patient compliance (inhalation is preferred to injection) Since only a low dose of the nanobody is required, adverse effects are minimal.

Prof Yi Shi and his colleagues at the University of Pittsburgh School of Medicine constructed a new type of nanobody called the Pittsburgh Inhalable Nanobody-21 (PiN-21). They took an ultrapotent Nanobody-21 and made it into a trimeric form to enhance its antiviral activity. PiN-21 effectively blocked SARS-CoV-2 activity at a concentration as low as 0.1ng/ml and is the most potent nanobody identified to date. The scientists then tested the antiviral efficacy of Pin-21 via aerosols in Syrian Hamsters. The results of this study were published in Science Advances.

The concerns regarding nanobodies included their smaller size lowering their pharmacokinetic ability and exhibiting a lower immune functioning due to the absent Fc region. Hence it is necessary to test out the in-vivo effects of nanobodies as scientists cannot rely solely on the in-vitro results. 

The scientists first administered PiN-21 (0.6mg/kg) to the hamsters intranasally at the time of infection. These hamsters did not lose any bodyweight as weight loss is usually observed with a SARS-CoV-2 infection. The placebo-treated hamster lost up to 16% of its initial body weight within a week of the infection. The viral load in the upper respiratory tract and the lungs of the PiN-21 treated hamsters had decreased considerably and the infection cleared out within 10 days of treatment. These experiments demonstrate the high in vitro neutralization potential of PiN-21 which can be replicated in in-vivo studies, independent of Fc-mediated immune responses. 

The antiviral effect was even more prominent when the infected hamsters inhaled the PiN-21 nanobody aerosols (<0.2mg/kg). The small size of the nanobodies alleviates the issue of forming clumps in the lungs. There was a significant reversal of weight loss caused by the SARS-CoV-2 virus. The treatment also reduced the SARS-CoV-2 genomic RNA levels in the pulmonary tissues. PiN-21 decreased the viral load by a million fold and reversed the virus-associated inflammatory lung tissue damage as compared to the placebo control. 

Researchers state that both nanobodies and vaccines are vital in combating the virus. Vaccines remain the strongest tool to stop the spread of the virus but nanobodies can treat people who have the SARS-CoV-2 infection and can be given to those who can’t get vaccinated for various medical reasons. Further clinical trials need to be done in Non-Human Primate models and then humans in order to confirm its antiviral activity and as a possible COVID-19 treatment. The emerging SARS-CoV-2 variants have managed to escape clinical antibodies and vaccine therapies. Hence, using stable nanobodies like PiN-21 as an aerosol can help to block immune evasion by the virus. 

“We envision that PiN-21 aerosolization treatment could provide both a convenient and cost-effective solution to alleviate disease onset and reduce virus transmission, especially for mild COVID-19 patients as well as in high-risk groups, such as seniors, immunocompromised individuals, and infants, in both inpatient and outpatient settings,” postulate the scientists.

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