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

• Published in: Cell reports (Cambridge) Vol. 38; no. 6; p. 110348
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.02.2022; Elsevier; The Authors
• Subjects: anti-spike antibody; antibody; antibody design; display; mRNA; mRNA display; neutralizing antibody; SARS-CoV-2; SARS-CoV-2 variants; antibody design; SARS-CoV-2; antibody; SARS-CoV-2 variants; neutralizing antibody; mRNA display; anti-spike antibody
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110348

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. [Display omitted] •Broadly reactive neutralizing antibodies (nAbs) may overcome SARS-CoV-2 variant escape•mRNA display is used to rapidly identify SARS-CoV-2 spike (S)-protein-directed nAbs•Structural studies reveal distinct binding modes for several identified antibodies•An engineered nAb sustains binding to variant Gamma E484K and Delta L452R spikes Tanaka et al. identify a set of SARS-CoV-2 spike (S)-targeted potentially neutralizing antibodies (nAbs) by mRNA display. Structural analyses reveal distinct binding modes, including the targeting of rare cryptic S receptor-binding domain epitopes. A further engineered ACE2-blocking nAb shows sustained binding to S RBD with the E484K and L452R substitutions.