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TitleA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 8042, Year 2023
Publish dateDec 5, 2023
AuthorsWanbo Tai / Kai Yang / Yubin Liu / Ruofan Li / Shengyong Feng / Benjie Chai / Xinyu Zhuang / Shaolong Qi / Huicheng Shi / Zhida Liu / Jiaqi Lei / Enhao Ma / Weixiao Wang / Chongyu Tian / Ting Le / Jinyong Wang / Yunfeng Chen / Mingyao Tian / Ye Xiang / Guocan Yu / Gong Cheng /
PubMed AbstractThe respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by ...The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by intravenous administration and the short half-life period of antibodies in the lungs by intranasal or aerosolized immunization, mRNA encoding broadly neutralizing antibodies with lung-targeting capability can perfectly provide high-titer antibodies in lungs to prevent the SARS-CoV-2 infection. Here, we firstly identify a human monoclonal antibody, 8-9D, with broad neutralizing potency against SARS-CoV-2 variants. The neutralization mechanism of this antibody is explained by the structural characteristics of 8-9D Fabs in complex with the Omicron BA.5 spike. In addition, we evaluate the efficacy of 8-9D using a safe and robust mRNA delivery platform and compare the performance of 8-9D when its mRNA is and is not selectively delivered to the lungs. The lung-selective delivery of the 8-9D mRNA enables the expression of neutralizing antibodies in the lungs which blocks the invasion of the virus, thus effectively protecting female K18-hACE2 transgenic mice from challenge with the Beta or Omicron BA.1 variant. Our work underscores the potential application of lung-selective mRNA antibodies in the prevention and treatment of infections caused by circulating SARS-CoV-2 variants.
External linksNat Commun / PubMed:38052844 / PubMed Central
MethodsEM (single particle)
Resolution3.01 - 3.3 Å
Structure data

35932

8j1t

EMDB-35932: Local refined cryo-EM reconstruction of Omicron BA.5 RBD in complex with 8-9D Fab
PDB-8j1t: Local refined cryo-EM structure of Omicron BA.5 RBD in complex with 8-9D Fab
Method: EM (single particle) / Resolution: 3.3 Å

35934

8j1v

EMDB-35934: Cryo-EM reconstruction of SARS-CoV2 Omicron BA.5 spike in complex with 8-9D Fabs
PDB-8j1v: Cryo-EM structure of SARS-CoV2 Omicron BA.5 spike in complex with 8-9D Fabs
Method: EM (single particle) / Resolution: 3.01 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM complex

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