In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains.
1区 · 综合性期刊
作者: Rita E Chen ; Emma S Winkler ; James Brett Case ; Ishmael D Aziati ; Traci L Bricker ; Astha Joshi ; Tamarand L Darling ; Baoling Ying ; John M Errico ; Swathi Shrihari ; Laura A VanBlargan ; Xuping Xie ; Pavlo Gilchuk ; Seth J Zost ; Lindsay Droit ; Zhuoming Liu ; Spencer Stumpf ; David Wang ; Scott A Handley ; W Blaine Stine ; Pei-Yong Shi ; Meredith E Davis-Gardner ; Mehul S Suthar ; Miguel Garcia Knight ; Raul Andino ; Charles Y Chiu ; Ali H Ellebedy ; Daved H Fremont ; Sean P J Whelan ; James E Crowe ; Lisa Purcell ; Davide Corti ; Adrianus C M Boon ; Michael S Diamond
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies against variant strains of SARS-CoV-21-3, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.
2021-05-06·Science advances1区 · 综合性期刊
Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11.
1区 · 综合性期刊
作者: Juliette Fedry ; Daniel L Hurdiss ; Chunyan Wang ; Wentao Li ; Gonzalo Obal ; Ieva Drulyte ; Wenjuan Du ; Stuart C Howes ; Frank J M van Kuppeveld ; Friedrich Förster ; Berend-Jan Bosch
The emergence of SARS-CoV-2 antibody escape-mutations highlights the urgent clinical need for broadly neutralizing therapeutics. We previously identified a potent human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV, and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of trimeric SARS-CoV and SARS-CoV-2 spike ectodomains in complex with the 47D11 Fab. 47D11 binds specifically to the closed conformation of the receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a conserved and mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies that target the exposed receptor-binding motif. Altogether, these results reveal a cross-protective epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or post-exposure therapy for COVID-19.
Perspectives on the development of neutralizing antibodies against SARS-CoV-2.
作者: Mitchell Ho
SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies, such as 47D11, S309, and VHH-72, have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. Due to their small size and high stability, single-domain antibodies might have the ability to be administered by an inhaler making them potentially attractive therapeutics for respiratory infections. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective.