Development of a bispecific nanobody conjugate broadly neutralizes diverse SARS-CoV-2 variants and structural basis for its broad neutralization
-
Published:2023-11-30
Issue:11
Volume:19
Page:e1011804
-
ISSN:1553-7374
-
Container-title:PLOS Pathogens
-
language:en
-
Short-container-title:PLoS Pathog
Author:
Yang Jing,
Lin Sheng,
Chen Zimin,
Yang Fanli,
Guo Liyan,
Wang Lingling,
Duan Yanping,
Zhang Xindan,
Dai Yushan,
Yin Keqing,
Yu Chongzhang,
Yuan Xin,
Sun Honglu,
He Bin,
Cao Yu,
Ye Haoyu,
Dong Haohao,
Liu Xianbo,
Chen Bo,
Li Jian,
Zhao Qi,
Lu GuangwenORCID
Abstract
The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility and profound immune-escape capacity makes it an urgent need to develop broad-spectrum therapeutics. Nanobodies have recently attracted extensive attentions due to their excellent biochemical and binding properties. Here, we report two high-affinity nanobodies (Nb-015 and Nb-021) that target non-overlapping epitopes in SARS-CoV-2 S-RBD. Both nanobodies could efficiently neutralize diverse viruses of SARS-CoV-2. The neutralizing mechanisms for the two nanobodies are further delineated by high-resolution nanobody/S-RBD complex structures. In addition, an Fc-based tetravalent nanobody format is constructed by combining Nb-015 and Nb-021. The resultant nanobody conjugate, designated as Nb-X2-Fc, exhibits significantly enhanced breadth and potency against all-tested SARS-CoV-2 variants, including Omicron sub-lineages. These data demonstrate that Nb-X2-Fc could serve as an effective drug candidate for the treatment of SARS-CoV-2 infection, deserving further in-vivo evaluations in the future.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
National Postdoctoral Program for Innovative Talents of China
China Postdoctoral Science Foundation
Publisher
Public Library of Science (PLoS)
Subject
Virology,Genetics,Molecular Biology,Immunology,Microbiology,Parasitology