Dataset Information

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

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants.

SUBMITTER: Westendorf K

PROVIDER: S-EPMC9035363 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Westendorf Kathryn K Žentelis Stefanie S Wang Lingshu L Foster Denisa D Vaillancourt Peter P Wiggin Matthew M Lovett Erica E van der Lee Robin R Hendle Jörg J Pustilnik Anna A Sauder J Michael JM Kraft Lucas L Hwang Yuri Y Siegel Robert W RW Chen Jinbiao J Heinz Beverly A BA Higgs Richard E RE Kallewaard Nicole L NL Jepson Kevin K Goya Rodrigo R Smith Maia A MA Collins David W DW Pellacani Davide D Xiang Ping P de Puyraimond Valentine V Ricicova Marketa M Devorkin Lindsay L Pritchard Caitlin C O'Neill Aoise A Dalal Kush K Panwar Pankaj P Dhupar Harveer H Garces Fabian A FA Cohen Courtney A CA Dye John M JM Huie Kathleen E KE Badger Catherine V CV Kobasa Darwyn D Audet Jonathan J Freitas Joshua J JJ Hassanali Saleema S Hughes Ina I Munoz Luis L Palma Holly C HC Ramamurthy Bharathi B Cross Robert W RW Geisbert Thomas W TW Menachery Vineet V Lokugamage Kumari K Borisevich Viktoriya V Lanz Iliana I Anderson Lisa L Sipahimalani Payal P Corbett Kizzmekia S KS Yang Eun Sung ES Zhang Yi Y Shi Wei W Zhou Tongqing T Choe Misook M Misasi John J Kwong Peter D PD Sullivan Nancy J NJ Graham Barney S BS Fernandez Tara L TL Hansen Carl L CL Falconer Ester E Mascola John R JR Jones Bryan E BE Barnhart Bryan C BC

Cell reports 20220425 7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific anti ...[more]

PMID: 35568025

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Project description:Emerging severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants, especially the Omicron variant, have impaired the efficacy of existing vaccines and most therapeutic antibodies, highlighting the need for additional antibody-based tools that can efficiently neutralize emerging SARS-CoV-2 variants. The use of a "single" agent to simultaneously target multiple distinct epitopes on the spike is desirable in overcoming the neutralizing escape of SARS-CoV-2 variants. Herein, we generated a human-derived IgG-like bispecific antibody (bsAb), Bi-Nab35B5-47D10, which successfully retained parental specificity and simultaneously bound to the two distinct epitopes on receptor-binding domain (RBD) and S2. Bi-Nab35B5-47D10 showed improved spike binding breadth among wild-type (WT) SARS-CoV-2, variants of concern (VOCs), and variants being monitored (VBMs) compared with its parental monoclonal antibodies (MAbs). Furthermore, pseudotyped virus neutralization demonstrated that Bi-Nab35B5-47D10 can efficiently neutralize VBMs, including Alpha (B.1.1.7), Beta (B.1.351), and Kappa (B.1.617.1), as well as VOCs, including Delta (B.1.617.2), Omicron BA.1, and Omicron BA.2. Crucially, Bi-Nab35B5-47D10 substantially improved neutralizing activity against Omicron BA.1 (IC50 = 0.15 nM) and Omicron BA.2 (IC50 = 0.67 nM) compared with its parental MAbs. Therefore, Bi-Nab35B5-47D10 represents a potential effective countermeasure against SARS-CoV-2 Omicron and other variants of concern. IMPORTANCE The new, highly contagious SARS-CoV-2 Omicron variant caused substantial breakthrough infections and has become the dominant strain in countries across the world. Omicron variants usually bear high mutations in the spike protein and exhibit considerable escape of most potent neutralization monoclonal antibodies and reduced efficacy of current COVID-19 vaccines. The development of neutralizing antibodies with potent efficacy against the Omicron variant is still an urgent priority. Here, we generated a bsAb, Bi-Nab35B5-47D10, which simultaneously targets SARS-CoV-2 RBD and S2 and improves the neutralizing potency and breadth against SARS-CoV-2 WT and the tested variants compared with their parental antibodies. Notably, Bi-Nab35B5-47D10 has more potent neutralizing activity against the VOC Omicron pseudotyped virus. Therefore, Bi-Nab35B5-47D10 is a feasible and potentially effective strategy by which to treat and prevent COVID-19.

Dataset Information

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

Publications

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

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