TY - JOUR
T1 - Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617
AU - Peng, Lei
AU - Hu, Yingxia
AU - Mankowski, Madeleine C.
AU - Ren, Ping
AU - Chen, Rita E.
AU - Wei, Jin
AU - Zhao, Min
AU - Li, Tongqing
AU - Tripler, Therese
AU - Ye, Lupeng
AU - Chow, Ryan D.
AU - Fang, Zhenhao
AU - Wu, Chunxiang
AU - Dong, Matthew B.
AU - Cook, Matthew
AU - Wang, Guilin
AU - Clark, Paul
AU - Nelson, Bryce
AU - Klein, Daryl
AU - Sutton, Richard
AU - Diamond, Michael S.
AU - Wilen, Craig B.
AU - Xiong, Yong
AU - Chen, Sidi
N1 - Funding Information:
We thank various members from Chen, Xiong, and Wilen labs for discussions and support. We thank Dr. Bieniasz for providing pseudovirus reporter plasmids. We thank the staff from various Yale core facilities (Keck, YCGA, HPC, Biophysics, YARC, Cryo-EM, CBDS, and others) for technical support. We thank various support from Departments of Genetics, MBB, Laboratory Medicine, Immunobiology, Internal Medicine and Pharmacology; Institutes of Systems Biology and Cancer Biology; Dean’s office of Yale School of Medicine and the office of Vice Provost for Research. This work is supported by DoD PRMRP IIAR (W81XWH-21-1-0019) and discretionary funds to S.C.; discretionary funds to Y.X.; Ludwig Foundation, Mathers Foundation, Burroughs Wellcome Fund, NIH K08 AI128043, NIH R01 AI148467 to C.B.W.; NIH R01 AI157155 to M.S.D.; NIH/NIAID R01 AI150334 to R.S. YCGA / HPC were supported by NIH Award 1S10OD018521. The T200 Biacore instrumentation was supported by NIH Award S10RR026992-0110.
Funding Information:
We thank various members from Chen, Xiong, and Wilen labs for discussions and support. We thank Dr. Bieniasz for providing pseudovirus reporter plasmids. We thank the staff from various Yale core facilities (Keck, YCGA, HPC, Biophysics, YARC, Cryo-EM, CBDS, and others) for technical support. We thank various support from Departments of Genetics, MBB, Laboratory Medicine, Immunobiology, Internal Medicine and Pharmacology; Institutes of Systems Biology and Cancer Biology; Dean’s office of Yale School of Medicine and the office of Vice Provost for Research. This work is supported by DoD PRMRP IIAR (W81XWH-21-1-0019) and discretionary funds to S.C.; discretionary funds to Y.X.; Ludwig Foundation, Mathers Foundation, Burroughs Wellcome Fund, NIH K08 AI128043, NIH R01 AI148467 to C.B.W.; NIH R01 AI157155 to M.S.D.; NIH/NIAID R01 AI150334 to R.S. YCGA / HPC were supported by NIH Award 1S10OD018521. The T200 Biacore instrumentation was supported by NIH Award S10RR026992-0110.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127241733&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29288-3
DO - 10.1038/s41467-022-29288-3
M3 - Article
C2 - 35347138
AN - SCOPUS:85127241733
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1638
ER -