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Dec 24, 2021;

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, Sidi Chen
Author Information
  1. Lei Peng: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  2. Yingxia Hu: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  3. Madeleine C Mankowski: Department of Laboratory Medicine, Yale University, New Haven, CT, USA.
  4. Ping Ren: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  5. Rita E Chen: Departments of Medicine and Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  6. Jin Wei: Department of Laboratory Medicine, Yale University, New Haven, CT, USA.
  7. Min Zhao: Section of Infectious Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA.
  8. Tongqing Li: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  9. Therese Tripler: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  10. Lupeng Ye: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  11. Ryan D Chow: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  12. Zhenhao Fang: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  13. Chunxiang Wu: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  14. Matthew B Dong: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  15. Matthew Cook: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  16. Guilin Wang: Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
  17. Paul Clark: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  18. Bryce Nelson: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  19. Daryl Klein: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  20. Richard Sutton: Section of Infectious Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA.
  21. Michael S Diamond: Departments of Medicine and Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  22. Craig B Wilen: Department of Laboratory Medicine, Yale University, New Haven, CT, USA.
  23. Yong Xiong: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  24. Sidi Chen: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
PMID: 34981065 DOI: 10.1101/2021.12.21.473733

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 identified two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generated a bispecific antibody. Lead antibodies showed strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solved several cryo-EM structures at ∼3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and revealed distinct epitopes, binding patterns, and conformations. The lead clones also showed potent efficacy against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generated and characterized 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.

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Grants

  1. R01 AI157155/NIAID NIH HHS
  2. S10 OD018521/NIH HHS
  3. R01 AI148467/NIAID NIH HHS
  4. R01 AI150334/NIAID NIH HHS
  5. K08 AI128043/NIAID NIH HHS
Preprint

Links to CNCB-NGDC Resources

GEN: GEND000371 (Development, Cryo-EM structure and function of potent monospecific and bispecific monoclonal antibodies that neutralize SARS-CoV-2 and variant B.1.351)

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