Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants

J. Andrew Duty, Thomas Kraus, Heyue Zhou, Yanliang Zhang, Namir Shaabani, Soner Yildiz, Na Du, Alok Singh, Lisa Miorin, Donghui Li, Karen Stegman, Sabrina Ophir, Xia Cao, Kristina Atanasoff, Reyna Lim, Ignacio Mena, Nicole M. Bouvier, Shreyas Kowdle, Juan Manuel Carreño, Laura Rivero-NavaAriel Raskin, Elena Moreno, Sachi Johnson, Raveen Rathnasinghe, Chin I. Pai, Thomas Kehrer, Elizabeth Paz Cabral, Sonia Jangra, Laura Healy, Gagandeep Singh, Prajakta Warang, Viviana Simon, Emilia Mia Sordillo, Harm van Bakel, Yonghong Liu, Weina Sun, Lisa Kerwin, John Teijaro, Michael Schotsaert, Florian Krammer, Damien Bresson, Adolfo García-Sastre, Yanwen Fu, Benhur Lee, Colin Powers, Thomas Moran, Henry Ji, Domenico Tortorella, Robert Allen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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).

Original languageEnglish
Pages (from-to)705-721.e11
JournalMed
Volume3
Issue number10
DOIs
StatePublished - 14 Oct 2022

Keywords

  • COVID-19
  • Omicron BA.1
  • Omicron BA.1.1
  • Omicron BA.2
  • Pre-clinical research
  • intranasal
  • intravenous
  • neutralizing antibody
  • variants of concern

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