Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies

Abstract

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A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential

“…Importantly, Nb11-59 herein demonstrates neutralizing abilities more than 4 fold higher than other reported Nbs, including n3130 and n3088 with IC50 of 4.0 μg/mL and 2.6 μg/mL, respectively, against authentic SARS-CoV-2 30 . The published neutralizing Nbs towards SARS-CoV-2 were evaluated mainly in the pseudoviruse system, with IC50 ranging from 0.003 μg/mL to 12.32 μg/mL 19,[31][32][33][34] . Of note, IC50 of molecules tested in the pseudoviruse system might be 2-100 fold lower than that in the authentic SARS-CoV-2 29,32 .…”

“…Here, we report Nb phage display libraries derived from four camels immunized with the SARS-CoV-2 spike RBD, from which 381 Nbs were identified to recognize the RBD including the variants of SARS-CoV-2. Unlike the reported Nbs that require fusion with Fc domain to become bivalent or multiple antibodies and thereby neutralize SARS-CoV-2 19,20 , we have successfully identified 7 monovalent Nbs with potent neutralizing activities. Nb11-59, at a concentration lower than 1 μg/mL, significantly inhibited the replication of authentic SARS-CoV-2 in vitro, and our monovalent Nb11-59 could be easily delivered by nebulization considering its small size and high stability.…”

“…Patients with confirmed SARS-CoV-2 infection had mild to severe respiratory illness with symptoms of fever, cough, headache, dyspnea and pneumonia 4 . To date, no vaccine or therapeutic has been approved to prevent or treat COVID- 19. As of August 1 st , there are more than 17 million confirmed cases of COVID-19, resulting in more than 680,000 related deaths globally.…”

“…Due to their structure nature, Nbs can be easily constructed into multivalent or multi-specific formats and produced with convenient steps of purification at low manufacturing cost 16,17 . Given these biophysical advantages, Nbs can be easily nebulized and delivered directly to lungs via an inhaler, which make Nbs a particularly promising format for developing neutralizing antibodies targeting respiratory pathogens including SARS-CoV-2 18,19 . The inhaled formulation could potentially allow for easier administration outside the hospital, at earlier stages of disease, which is very important in helping to stem the tide of the pandemic caused by COVID-19.…”

An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction

“…It should be noted that the nanobody Ty1 can be readily produced in bacteria at very high yield (in excess of mg/L culture), making it an excellent candidate for a low-cost, scalable antiviral agent against SARS-CoV-2, and we provide the amino acid sequence, encouraging direct exploitation as such. While nanobodies capable of binding SARS-CoV-2 spike have recently been isolated, these were generated after SARS-CoV-1 spike immunization 19 , or PCR maturation 20 . Also, in both cases a fusion to human Fc domain is required for neutralization of SARS-CoV-2, precluding expression in bacterial culture.…”