LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Westendorf, Kathryn; Žentelis, Stefanie; Wang, Lingshu; Foster, Denisa; Vaillancourt, Peter; Wiggin, Matthew; Lovett, Erica; Lee, Robin van der; Hendle, J.; Pustilnik, Anna; Sauder, J.M.; Kraft, Lucas; Hwang, Yuri; Siegel, Robert W.; Chen, Jinbiao; Heinz, Beverly A.; Higgs, Richard E.; Kallewaard, Nicole L.; Jepson, Kevin; Goya, Rodrigo; Smith, Maia A.; Collins, David W.; Pellacani, Davide; Xiang, Ping; Puyraimond, Valentine de; Řičicová, Markéta; DeVorkin, Lindsay; Pritchard, Caitlin; O’Neill, Aoise; Dalal, Kush; Panwar, Pankaj; Dhupar, Harveer; Garces, Fabian A.; Cohen, Courtney A.; Dye, John M.; Huie, Kathleen E.; Badger, Catherine V.; Kobasa, Darwyn; Audet, Jonathan; Freitas, Joshua J.; Hassanali, Saleema; Hughes, Ina; Muñoz, Luis J.; Palma, Holly C.; Ramamurthy, Bharathi; Cross, Robert W.; Geisbert, Thomas W.; Menacherry, Vineet; Lokugamage, Kumari G.; Borisevich, Viktoriya; Lanz, Iliana; Anderson, Lisa K.; Sipahimalani, Payal; Corbett, Kizzmekia S.; Yang, Eun Sung; Zhang, Yi; Shi, Wei; Zhou, Tongqing; Choe, Misook; Misasi, John; Kwong, Peter D.; Sullivan, Nancy J.; Graham, Barney S.; Fernandez, Tara L.; Hansen, Carl L.; Falconer, Ester; Mascola, John R.; Jones, Bryan E.; Barnhart, Bryan C.

doi:10.1016/j.celrep.2022.110812

Cited by 373 publications

(387 citation statements)

References 68 publications

Supporting

Mentioning

370

Contrasting

Order By: Relevance

“…Additionally, C5G2 could inhibit the infection of most of the virus of concern(VOC), especially Omicron variant in the pseudovirus assay with similar or higher potency, implying its broad spectrum neutralising capacity. C5G2 is one of the few reported broad-spectrum antibodies so far[51-53] that neutralize Omicron variant in addition to the wild type virus. In terms of the potency(i.e.…”

Section: Discussionmentioning

confidence: 99%

A potent synthetic nanobody with broad-spectrum activity neutralizes SARS-Cov-2 virus and Omicron variant through a unique binding mode

Huang¹,

Tao

et al. 2022

Preprint

View full text Add to dashboard Cite

COVID-19 continues to be a severe public health thread worldwide. The major challenge to control this pandemic is the rapid mutation rate of the SARS-Cov-2 virus, leading to the escape of the protection of vaccines and most of the neutralizing antibodies to date. Thus, it is pivotal to develop neutralizing antibodies with broad-spectrum activity targeting multiple SARS-Cov-2 variants. In this study, we first got a synthetic nanobody (named C5) which could interfere with ACE2 binding to SARS-Cov-2 spike protein and its RBD domain. The affinity matured format of C5 clone, named C5G2, has a single digit nanomolar affinity to RBD domain and inhibit its binding to ACE2 with an IC50 of 3.7 nM. Pseudovirus assay indicated that the monovalent C5G2 could protect the cells from the infection of SARS-Cov-2 wild type virus as well as most of the virus of concern, i.e. Alpha, Beta, Gamma and Omicron variants. Strikingly, C5G2 has the highest potency against omicron among all the variants with the IC50 of 4.9ng/ml (0.3 nM). We further solved the Cryo-EM structure of C5G2 in complex with the Spike trimer. The structure data showed that C5G2 bind to RBD mainly through its CDR3 at a vast region that not overlapping with the ACE2 binding surface. Surprisingly, C5G2 also bind to a distinct epitope residing in the NTD domain of spike protein through the same CDR3 loop, which may further increase its potency against the virus infection. Thus, this bi-paratopic nanobody may be served as an effective drug for the prophylaxis and therapy of the Omicron infection.

show abstract

Section: Discussionmentioning

confidence: 99%

A potent synthetic nanobody with broad-spectrum activity neutralizes SARS-Cov-2 virus and Omicron variant through a unique binding mode

Huang¹,

Tao

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Structural comparison of the 002-S21F2 epitope with other class-3 mAbs, including the two available therapeutic mAbs effective against Omicron -Ly-CoV1404 (Bebtelovimab) and S309 (Sotrovimab), show some similarities between the 002-S21F2 and C135 binding sites (Fig. 2J) (16,17). However, C135 is unable to neutralize Omicron as a lysine mutation at RBD site N440 position would sterically clash with the C135 heavy chain CDR2 (Fig.…”

Section: S5 and S6mentioning

confidence: 98%

Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody

Kumar

Patel

Lai

et al. 2022

Preprint

View full text Add to dashboard Cite

The SARS-CoV-2 BA.1 and BA.2 (Omicron) variants contain more than 30 mutations within the spike protein and evade therapeutic monoclonal antibodies (mAbs). Here, we report a receptor-binding domain (RBD) targeting human antibody (002-S21F2) that effectively neutralizes live viral isolates of SARS-CoV-2 variants of concern (VOCs) including Alpha, Beta, Gamma, Delta, and Omicron (BA.1 and BA.2) with IC50 ranging from 0.02 – 0.05 μg/ml. This near germline antibody 002-S21F2 has unique genetic features that are distinct from any reported SARS-CoV-2 mAbs. Structural studies of the full-length IgG in complex with spike trimers (Omicron and WA.1) reveal that 002-S21F2 recognizes an epitope on the outer face of RBD (class-3 surface), outside the ACE2 binding motif and its unique molecular features enable it to overcome mutations found in the Omicron variants. The discovery and comprehensive structural analysis of 002-S21F2 provide valuable insight for broad and potent neutralization of SARS-CoV-2 Omicron variants BA.1 and BA.2.

show abstract

“…The search for broadly neutralizing mAbs is being pursued. Novel antibodies active against all variants of concern (VOCs), including the currently prevalent omicron lineage, have been described (Cameroni et al, 2022; Gruell et al, 2022; Westendorf et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Potent Human Broadly SARS-CoV-2 Neutralizing IgA and IgG Antibodies Effective Against Omicron BA.1 and BA.2

Planchais

Fernández

Bruel

et al. 2022

Preprint

View full text Add to dashboard Cite

Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. Here, wide SARS-CoV-2 immunoprofiling in COVID-19 convalescents combining serological, cellular and monoclonal antibody explorations, revealed humoral immunity coordination. Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions. The latter were influenced by the targeted spike region with strong Fc-dependent effectors to the S2 subunit and potent neutralizers to the receptor binding domain. Amongst those, Cv2.1169 and Cv2.3194 antibodies cross-neutralized SARS-CoV-2 variants of concern including Omicron BA.1 and BA.2. Cv2.1169, isolated from a mucosa-derived IgA memory B cell, demonstrated potency boost as IgA dimers and therapeutic efficacy as IgG antibodies in animal models. Structural data provided mechanistic clues to Cv2.1169 potency and breadth. Thus, potent broadly neutralizing IgA antibodies elicited in mucosal tissues can stem SARS-CoV-2 infection, and Cv2.1169 and Cv2.3194 are prime candidates for COVID-19 prevention and treatment.

show abstract

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Cited by 373 publications

References 68 publications

A potent synthetic nanobody with broad-spectrum activity neutralizes SARS-Cov-2 virus and Omicron variant through a unique binding mode

A potent synthetic nanobody with broad-spectrum activity neutralizes SARS-Cov-2 virus and Omicron variant through a unique binding mode

Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody

Potent Human Broadly SARS-CoV-2 Neutralizing IgA and IgG Antibodies Effective Against Omicron BA.1 and BA.2

Contact Info

Product

Resources

About