Fc-modified SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models. (preprint)

The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from COVID-19-convalescent patients, and identified antibodies that exhibited comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced, and showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.

Identification of Anti-COVID-19 Agents, Cepharanthine and Nelfinavir, and Their Potential Usage for Combination Treatment (preprint)

Antiviral treatments targeting the coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine: the anti-inflammatory drug Cepharanthine and HIV protease inhibitor Nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry into cells, whilst Nelfinavir inhibited the catalytic activity of viral main protease to suppress viral replication. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will shorten the period until viral clearance by 5.5-days and the combining Cepharanthine/Nelfinavir enhanced their predicted efficacy to control viral proliferation. In summary, this study identifies a new multidrug combination treatment for COVID-19.Funding: This work was supported by The Agency for Medical Research and Development (AMED) emerging/re-emerging infectious diseases project (JP19fk0108111, JP19fk0108110, JP20fk0108104); the AMED Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS, JP19am0101114, JP19am0101069, JP19am0101111) program; The Japan Society for the Promotion of Science 260 KAKENHI (JP17H04085, JP20H03499, JP15H05707, 19H04839); The JST MIRAI program; and Wellcome Trust funded Investigator award (200838/Z/16/Z). Conflict of Interest: None.