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
Affiliations
Thomas J. Esparza
The National Institute of Neurological Disorders and Stroke Intramural Research Program, Laboratory of Functional and Molecular Imaging, Bethesda, MD, USA
Yaozong Chen
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Negin P. Martin
Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, NC, USA
Helle Bielefeldt-Ohmann
School of Chemistry & Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, Qld, Australia
Richard A. Bowen
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
William D. Tolbert
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Marzena Pazgier
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
David L. Brody
The National Institute of Neurological Disorders and Stroke Intramural Research Program, Laboratory of Functional and Molecular Imaging, Bethesda, MD, USA
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
