| 1 | Hetero-bivalent nanobodies provide broad-spectrum protection against SARS-CoV-2 variants of concern including Omicron显示文摘SARS-CoV-2 variants with adaptive mutations have continued to emerge,causing fresh waves of infection even amongst vaccinated population.The development of broad-spectrum antivirals is thus urgently needed.We previously developed two hetero-bivalent nanobodies(Nbs),aRBD-2-5 and aRBD-2-7,with potent neutralization activity against the wild-type(WT)Wuhan isolated SARS-CoV-2,by fusing aRBD-2 with aRBD-5 and aRBD-7,respectively.Here,we resolved the crystal structures of these Nbs in complex with the receptor-binding domain(RBD)of the spike protein,and found that aRBD-2 contacts with highly conserved RBD residues and retains binding to the RBD of the Alpha,Beta,Gamma,Delta,Delta plus,Kappa,Lambda,Omicron BA.1,and BA.2 variants.In contrast,aRBD-5 and aRBD-7 bind to less conserved RBD epitopes non overlapping with the epitope of aRBD 2,and do not show apparent binding to the RBD of some variants.However,when fused with aRBD-2,they effectively enhance the overal binding affinity.Consistently,aRBD-2-5-Fc and aRBD-2-7 Fc potently neutralized all of the tested authentic or pseudotyped viruses,incuding WT,Alpha,Beta,Gamma,Delta,and Omicron BA.1,BA.1.1 and BA.2.Furthermore,aRBD-2-5-FC provided prophylactic protection against the WT and mouse-adapted SARS CoV-2 in mice,and conferred protection against the Omicron BA.1 variant in hamsters prophylatically and therapeutically,indicating that aRBD-2-5-Fc could potentially beneft the prevention and treatment of COVID-19 caused by the emerging variants of concern.Our strategy provides new solutions in the development of broad-spectrum therapeutic antibodies for COVID-19. | Huan Ma Xinghai Zhang Peiyi Zheng Peter H.Dube Weihong Zeng Shaohong Chen Qingyu Cheng Yunru Yang Yan Wu Junhui Zhou Xiaowen Hu Yan Xiang Huajun Zhang Sandra Chiu Tengchuan Jin | 2022 | Cell Research2022，32，9： | 1 |
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