Novel nanobody drug conjugate as a prophylactic or therapeutic against SARS-CoV-2 infection in mice.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, resulted in global health and economic crisis at an exceptional level. The high transmissibility of SARS-CoV-2, a lack of population immunity, and the prevalence of severe clinical outcomes created a need for the rapid development of effective therapeutic countermeasures. Sybodies, or synthetic nanobodies, are a novel and unique class of synthetic antigen-binding fragments ideal for large-scale production. We created a neutralizing sybody directed against the receptor-binding domain (RBD) epitope of the Spike protein of SARS-CoV-2 and conjugated it to remdesivir to create nanobody-drug-conjugate (NDC). We used a mouse model of infection to determine the capacity of the NDC to reduce disease severity and mortality. K18-hACE2 mice treated with NDC prior to, simultaneously with, and/or post-SARS-CoV-2 infection had reduced weight loss, mortality, lung pathology, and viral RNA in their lungs. This protection was found to be dependent on the protein structure of the sybody. Delivery of these novel therapeutic NDCs through nasal inhalation using a nebulizer could offer a convenient method for patients to self-administer treatments or as a prophylaxis. This platform therapy could apply to new variants of the ongoing SARS-CoV-2 epidemics, or to other pathogens of future pandemic potential.