Fu Y, da Fonseca Rezende E Mello J, Fleming BD, Renn A, Chen CZ, Hu X, Xu M, Gorshkov K, Hanson Q, Zheng W, Lee EM, Perera L, Petrovich R, Pradhan M, Eastman RT, Itkin Z, Stanley TB, Hsu A, Dandey V, Sharma K, Gillette W, Taylor T, Ramakrishnan N, Perkins S, Esposito D, Oh E, Susumu K, Wolak M, Ferrer M, Hall MD, Borgnia MJ, Simeonov A

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two ...

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distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.

Date: Aug. 11, 2022

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