Nebulized delivery of a broadly neutralizing SARS-CoV-2 RBD-specific nanobody prevents clinical, virological, and pathological disease in a Syrian hamster model of COVID-19

Thomas J. Esparza, Yaozong Chen, Negin P. Martin, Helle Bielefeldt-Ohmann, Richard A. Bowen, William D. Tolbert, Marzena Pazgier*, David L. Brody*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

There remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and in vitro characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor-binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad in vitro neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an in vivo pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection. Abbreviations: ACE2–angiotensin converting enzyme 2BSA–buried surface areaCDR–complementary determining regionRBD–receptor binding domainRBM–receptor-binding motifSARS-CoV-2 - severe acute respiratory syndrome coronavirus 2.

Original languageEnglish
Article number2047144
JournalmAbs
Volume14
Issue number1
DOIs
StatePublished - 2022
Externally publishedYes

Keywords

  • COVID-19
  • SARS-CoV-2
  • nebulized delivery
  • neutralizing nanobody
  • single-domain antibody

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