Sci Rep . Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2

[tetano]

Sci Rep


. 2020 Oct 20;10(1):17806.
doi: 10.1038/s41598-020-74761-y.
Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2


Jianbo Dong ¹ , Betty Huang ² , Bo Wang ² , Allison Titong ² , Sachith Gallolu Kankanamalage ² , Zhejun Jia ² , Meredith Wright ² , Pannaga Parthasarathy ² , Yue Liu ^{2 3}



Affiliations

• PMID: 33082473
• DOI: 10.1038/s41598-020-74761-y

Abstract

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 na?ve 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.