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nanobodies with cross-neutralizing activity provide prominent therapeutic efficacy in mild and severe COVID-19 rodent models

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Virologica Sinica 2023年第5期38卷 787-800页

作者： Qiuxue Han Shen wang Zhenshan wang Cheng Zhang Xinyue wang na fengtiecheng wang Yongkun Zhao Hang Chi Feihu Yan Xianzhu Xia Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100021China Changchun Veterinary Research Institute Chinese Academy of Agricultural SciencesChangchun132122China Jiangsu Co-innovation Centre for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou225009China

The weakened protective efficacy of COVID-19 vaccines and antibodies caused by SARS-CoV-2 variants presents a global health emergency,which underscores the urgent need for universal therapeutic antibody intervention for clinical ***,we screened three alpacas-derived nanobodies(Nbs)with neutralizing activity from twenty RBD-specific *** three Nbs were fused with the Fc domain of human IgG,namely aVHH-11-Fc,aVHH-13-Fc and aVHH-14-Fc,which could specifically bind RBD protein and competitively inhibit the binding of ACE2 receptor to *** effectively neutralized SARS-CoV-2 pseudoviruses D614G,Alpha,Beta,Gamma,Delta,and Omicron sub-lineages BA.1,BA.2,BA.4,and BA.5 and authentic SARS-CoV-2 prototype,Delta,and Omicron BA.1,BA.2 *** mice-adapted COVID-19 severe model,intranasal administration of aVHH-11-Fc,aVHH-13-Fc and aVHH-14-Fc effectively protected mice from lethal challenges and reduced viral loads in both the upper and lower respiratory *** the COVID-19 mild model,aVHH-13-Fc,which represents the optimal neutralizing activity among the above three Nbs,effectively protected hamsters from the challenge of SARS-CoV-2 prototype,Delta,Omicron BA.1 and BA.2 by significantly reducing viral replication and pathological alterations in the *** structural modeling of aVHH-13 and RBD,aVHH-13 binds to the receptor-binding motif region of RBD and interacts with some highly conserved *** together,our study illustrated that alpaca-derived Nbs offered a therapeutic countermeasure against SARS-CoV-2,including those Delta and Omicron variants which have evolved into global pandemic strains.

关键词： COVID-19 SARS-CoV-2 nanobody Broad-spectrum Therapeutic Rodent models

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