1. Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.
- Author
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Duty JA, Kraus T, Zhou H, Zhang Y, Shaabani N, Yildiz S, Du N, Singh A, Miorin L, Li D, Stegman K, Ophir S, Cao X, Atanasoff K, Lim R, Mena I, Bouvier NM, Kowdle S, Carreño JM, Rivero-Nava L, Raskin A, Moreno E, Johnson S, Rathnasinghe R, Pai CI, Kehrer T, Cabral EP, Jangra S, Healy L, Singh G, Warang P, Simon V, Sordillo EM, van Bakel H, Liu Y, Sun W, Kerwin L, Teijaro J, Schotsaert M, Krammer F, Bresson D, García-Sastre A, Fu Y, Lee B, Powers C, Moran T, Ji H, Tortorella D, and Allen R
- Subjects
- Administration, Intranasal, Animals, Antibodies, Viral therapeutic use, Humans, Immunoglobulin G, Membrane Glycoproteins, Mice, Neutralization Tests, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics, Viral Envelope Proteins, Antibodies, Neutralizing therapeutic use, COVID-19 Drug Treatment
- Abstract
Background: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern., Methods: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167., Findings: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice., Conclusions: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials., Funding: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560)., Competing Interests: Declaration of interests The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, and Pfizer, outside of the reported work. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines, which list F.K. as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. F.K. has consulted for Merck and Pfizer (before 2020) and is currently consulting for Pfizer, Third Rock Ventures, Seqirus, and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. Sorrento and Mount Sinai scientists are inventors on patent applications on the use of neutralizing antibodies described in these studies for the treatment and prevention of SARS-CoV-2 infections., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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