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

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

doi:10.1016/j.celrep.2022.110348

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

Journal Article · 19 January 2022 · Cell Reports

DOI: https://doi.org/10.1016/j.celrep.2022.110348 · OSTI ID:1981563

Tanaka, Shiho ^[1]; Olson, C. Anders ^[1];

^[2]; Higashide, Wendy ^[1]; Gonzalez, Marcos ^[1]; Taft, Justin ^[3]; Richardson, Ashley ^[3]; Martin-Fernandez, Marta ^[3]; Bogunovic, Dusan ^[3]; Gnanapragasam, Priyanthi N.P. ^[2];

^[2];

^[1]; Niazi, Kayvan ^[1]; Rabizadeh, Shahrooz ^[1];

^[1]

ImmunityBio, Inc., Culver City, CA (United States)
California Institute of Technology (CalTech), Pasadena, CA (United States)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)

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.

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Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); ImmunityBio, Inc., Culver City, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Caltech Merkin Institute; George Mason University; Howard Hughes Medical Institute; Burroughs Wellcome Fund; ImmunityBio, Inc

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1981563

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 6 Vol. 38; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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

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