Rapid identification of neutralizing antibodies against SARS-CoV-2 variants by mRNA display

Shiho Tanaka; C Anders Olson; Christopher O Barnes; Wendy Higashide; Marcos Gonzalez; Justin Taft; Ashley Richardson; Marta Martin-Fernandez; Dusan Bogunovic; Priyanthi N P Gnanapragasam; Pamela J Bjorkman; Patricia Spilman; Kayvan Niazi; Shahrooz Rabizadeh; Patrick Soon-Shiong

doi:10.1016/j.celrep.2022.110348

Rapid identification of neutralizing antibodies against SARS-CoV-2 variants by mRNA display

Cell Rep. 2022 Feb 8;38(6):110348. doi: 10.1016/j.celrep.2022.110348. Epub 2022 Jan 20.

Authors

Affiliations

¹ ImmunityBio, Inc., 9920 Jefferson Boulevard, Culver City, CA 90232, USA.
² ImmunityBio, Inc., 9920 Jefferson Boulevard, Culver City, CA 90232, USA. Electronic address: anders.olson@immunitybio.com.
³ Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
⁴ Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA.
⁵ Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Plaza, New York, NY 10029-5674, USA.
⁶ ImmunityBio, Inc., 9920 Jefferson Boulevard, Culver City, CA 90232, USA. Electronic address: patrick@nantworks.com.

Abstract

The increasing prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly reactive neutralizing antibodies (nAbs). Utilizing mRNA display, we identify a set of antibodies against SARS-CoV-2 spike (S) proteins and characterize the structures of nAbs that recognize epitopes in the S1 subunit of the S glycoprotein. These structural studies reveal distinct binding modes for several antibodies, including the targeting of rare cryptic epitopes in the receptor-binding domain (RBD) of S that interact with angiotensin-converting enzyme 2 (ACE2) to initiate infection, as well as the S1 subdomain 1. Further, we engineer a potent ACE2-blocking nAb to sustain binding to S RBD with the E484K and L452R substitutions found in multiple SARS-CoV-2 variants. We demonstrate that mRNA display is an approach for the rapid identification of nAbs that can be used in combination to combat emerging SARS-CoV-2 variants.

Keywords: SARS-CoV-2; SARS-CoV-2 variants; anti-spike antibody; antibody; antibody design; mRNA display; neutralizing antibody.

Abstract

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