SARS-CoV-2 is a newly emergent coronavirus, which has adversely impacted human health and has led to the COVID-19 pandemic. There is an unmet need to develop therapies against SARS-CoV-2 due to its severity and lack of treatment options. A promising approach to combat COVID-19 is through the neutralization of SARS-CoV-2 by therapeutic antibodies. Previously, we described a strategy to rapidly identify and generate llama nanobodies (VHH) from naïve and synthetic humanized VHH phage libraries that specifically bind the S1 SARS-CoV-2 spike protein, and block the interaction with the human ACE2 receptor. In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19.
【저자키워드】 SARS-CoV-2, Antibody therapy, 【초록키워드】 COVID-19, Treatment, antibodies, coronavirus, therapy, antibody, neutralization, COVID-19 pandemic, severity, Health, Features, nanobody, SARS-CoV-2 spike protein, therapeutic, SARS-CoV-2 pseudovirus, protein stability, epitope, monoclonal, binding, Combination, Interaction, Analysis, unmet need, domain, naïve, human ACE2 receptor, humanized, approach, human IgG1 Fc, resulting, described, identify, lack, develop, generate, impacted, fused, 【제목키워드】 neutralization, nanobody, development, humanized,