Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617

Lei Peng, Yingxia Hu, Madeleine C. Mankowski, Ping Ren, Rita E. Chen, Jin Wei, Min Zhao, Tongqing Li, Therese Tripler, Lupeng Ye, Ryan D. Chow, Zhenhao Fang, Chunxiang Wu, Matthew B. Dong, Matthew Cook, Guilin Wang, Paul Clark, Bryce Nelson, Daryl Klein, Richard Sutton, Michael S. Diamond, Craig B. Wilen (), Yong Xiong () and Sidi Chen ()
Additional contact information
Lei Peng: Yale University School of Medicine
Yingxia Hu: Yale University
Madeleine C. Mankowski: Yale University
Ping Ren: Yale University School of Medicine
Rita E. Chen: Washington University School of Medicine in St. Louis
Jin Wei: Yale University
Min Zhao: Yale University
Tongqing Li: Yale University School of Medicine
Therese Tripler: Yale University
Lupeng Ye: Yale University School of Medicine
Ryan D. Chow: Yale University School of Medicine
Zhenhao Fang: Yale University School of Medicine
Chunxiang Wu: Yale University
Matthew B. Dong: Yale University School of Medicine
Matthew Cook: Yale University
Guilin Wang: Yale University
Paul Clark: Yale University School of Medicine
Bryce Nelson: Yale University School of Medicine
Daryl Klein: Yale University School of Medicine
Richard Sutton: Yale University
Michael S. Diamond: Washington University School of Medicine in St. Louis
Craig B. Wilen: Yale University
Yong Xiong: Yale University
Sidi Chen: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solve several cryo-EM structures at ~3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and reveal distinct epitopes, binding patterns, and conformations. The lead clones also show potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generate and characterize a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.

Date: 2022
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DOI: 10.1038/s41467-022-29288-3

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