Broadening a SARS-CoV-1–neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.; IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.; Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.
- Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.
- IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.; IAVI, New York, NY 10004, USA.
- Department of Pathology, George Washington University, Washington, DC 20052, USA.
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.; Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.; Center for Viral Systems Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.; IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.; Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.; IAVI, New York, NY 10004, USA.
- IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.; Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.; Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA.; Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.; IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.; Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for strategies to rapidly develop neutralizing monoclonal antibodies that can function as prophylactic and therapeutic agents and to help guide vaccine design. Here, we demonstrate that engineering approaches can be used to refocus an existing antibody that neutralizes one virus but not a related virus. Through a rapid affinity maturation strategy, we engineered CR3022, a SARS-CoV-1–neutralizing antibody, to bind to the receptor binding domain of SARS-CoV-2 with >1000-fold increased affinity. The engineered CR3022 neutralized SARS-CoV-2 and provided prophylactic protection from viral challenge in a small animal model of SARS-CoV-2 infection. Deep sequencing throughout the engineering process paired with crystallographic analysis of engineered CR3022 elucidated the molecular mechanisms by which the antibody can accommodate sequence differences in the epitopes between SARS-CoV-1 and SARS-CoV-2. This workflow provides a blueprint for the rapid broadening of neutralization of an antibody from one virus to closely related but resistant viruses.
- Research Organization:
- SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC02-76SF00515
- OSTI ID:
- 2423886
- Journal Information:
- Science Signaling, Journal Name: Science Signaling Journal Issue: 798 Vol. 16; ISSN 1945-0877
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- English