A highly potent antibody effective against SARS-CoV-2 variants of concern

Fenwick, Craig; Turelli, Priscilla; Perez, Laurent; Pellaton, Céline; Esteves-Leuenberger, Line; Farina, A.; Campos, Jérémy; Lana, Erica; Fiscalini, Flurin; Raclot, Charlène; Pojer, Florence; Lau, Kelvin; Demurtas, Davide; Descatoire, Marc; Joo, Victor; Foglierini, Mathilde; Noto, Alessandra; Abdelnabi, Rana; Foo, Caroline S.; Vangeel, Laura; Neyts, Johan; Du, Wenjuan; Bosch, Berend-Jan; Veldman, Geertruida M.; Leyssen, Pieter; Thiel, Volker; Legrand, R.; Lévy, Yves; Trono, Didier; Pantaleo, Giuseppe

doi:10.1016/j.celrep.2021.109814

Cited by 43 publications

(44 citation statements)

References 67 publications

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“…Such strategies have shown potent prophylactic and therapeutic activity in mouse models of infection as well as hamsters [ 47 , 48 ]. Alternatively, monoclonal antibodies such as COVA1-18 and P5C3 with broad neutralizing activities have also shown prophylactic effect in hamsters, hACE2 mice, and cynomolgus macaques and potent reduction of virus replication postexposure [ 49 , 50 ]. P5C3 has also shown neutralization of all known VOCs to date at picomolar concentrations [ 50 ].…”

Section: Animal Models and Voc Prophylaxis And Therapymentioning

confidence: 99%

“…Alternatively, monoclonal antibodies such as COVA1-18 and P5C3 with broad neutralizing activities have also shown prophylactic effect in hamsters, hACE2 mice, and cynomolgus macaques and potent reduction of virus replication postexposure [ 49 , 50 ]. P5C3 has also shown neutralization of all known VOCs to date at picomolar concentrations [ 50 ]. Neutralizing single domain antibodies (nanobodies) can be administered intranasally and have also shown to greatly reduce SARS-CoV-2 replication in hamsters [ 51 , 52 ].…”

Section: Animal Models and Voc Prophylaxis And Therapymentioning

confidence: 99%

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Advances and gaps in SARS-CoV-2 infection models

et al. 2022

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The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

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Section: Animal Models and Voc Prophylaxis And Therapymentioning

confidence: 99%

Section: Animal Models and Voc Prophylaxis And Therapymentioning

confidence: 99%

Advances and gaps in SARS-CoV-2 infection models

et al. 2022

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“…K417N has been shown experimentally to lead to reduction in REGN10933 binding by various degrees, ranging from 4.4-to >100-fold reductions, 29,39,41-45 while reduced binding by 0.8- to 6.7-fold has been reported for the cocktail with REGN10987. 23,29,39,42 S477N was reported to lead to 0.9- to 3.4-fold reduction in REGN10933 binding 43,45-47 and 1.5-fold reduction for the cocktail. 23,46 Finally, Q493R led to a 70-fold reduction in REGN10933 binding.…”

Section: Resultsmentioning

confidence: 99%

Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces

Lubin

Markosian

Balamurugan

et al. 2021

Preprint

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There is enormous ongoing interest in characterizing the binding properties of the SARS-CoV-2 Omicron Variant of Concern (VOC) (B.1.1.529), which continues to spread towards potential dominance worldwide. To aid these studies, based on the wealth of available structural information about several SARS-CoV-2 variants in the Protein Data Bank (PDB) and a modeling pipeline we have previously developed for tracking the ongoing global evolution of SARS-CoV-2 proteins, we provide a set of computed structural models (henceforth models) of the Omicron VOC receptor-binding domain (omRBD) bound to its corresponding receptor Angiotensin-Converting Enzyme (ACE2) and a variety of therapeutic entities, including neutralizing and therapeutic antibodies targeting previously-detected viral strains. We generated bound omRBD models using both experimentally-determined structures in the PDB as well as machine learningbased structure predictions as starting points. Examination of ACE2-bound omRBD models reveals an interdigitated multi-residue interaction network formed by omRBD-specific substituted residues (R493, S496, Y501, R498) and ACE2 residues at the interface, which was not present in the original Wuhan-Hu-1 RBD-ACE2 complex. Emergence of this interaction network suggests optimization of a key region of the binding interface, and positive cooperativity among various sites of residue substitutions in omRBD mediating ACE2 binding. Examination of neutralizing antibody complexes for Barnes Class 1 and Class 2 antibodies modeled with omRBD highlights an overall loss of interfacial interactions (with gain of new interactions in rare cases) mediated by substituted residues. Many of these substitutions have previously been found to independently dampen or even ablate antibody binding, and perhaps mediate antibody-mediated neutralization escape (e.g., K417N). We observe little compensation of corresponding interaction loss at interfaces when potential escape substitutions occur in combination. A few selected antibodies (e.g., Barnes Class 3 S309), however, feature largely unaltered or modestly affected protein-protein interfaces. While we stress that only qualitative insights can be obtained directly from our models at this time, we anticipate that they can provide starting points for more detailed and quantitative computational characterization, and, if needed, redesign of monoclonal antibodies for targeting the Omicron VOC Spike protein. In the broader context, the computational pipeline we developed provides a framework for rapidly and efficiently generating retrospective and prospective models for other novel variants of SARS-CoV-2 bound to entities of virological and therapeutic interest, in the setting of a global pandemic.

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“…It should be noted that B1.182.1 is highly similar to S2E12, including sharing the same germline families and a high degree of sequence identity [ 391 ]. A very newly described antibody, P5C3, also likely belongs to the RBD-2 epitope group [ 441 ]. Similar to S2E12, B.1-182.1, and tixagevimab (AZD8895, COV2-2196), P5C3 is fully active against all VOCs prior to Omicron, including variant Beta [ 441 ], to which the first generation RBD-2 epitope antibodies, casirivimab (REGN10933) and bamlanivimab (LY-CoV555), are inactive.…”

Section: Epitope Classes Of Sars-cov-2 Antibodiesmentioning

confidence: 99%

“…A very newly described antibody, P5C3, also likely belongs to the RBD-2 epitope group [ 441 ]. Similar to S2E12, B.1-182.1, and tixagevimab (AZD8895, COV2-2196), P5C3 is fully active against all VOCs prior to Omicron, including variant Beta [ 441 ], to which the first generation RBD-2 epitope antibodies, casirivimab (REGN10933) and bamlanivimab (LY-CoV555), are inactive. Thus, it is becoming clear that a subset of RBD-2 antibodies is fully capable of neutralizing VOCs Alpha, Beta, Gamma, and Delta.…”

Section: Epitope Classes Of Sars-cov-2 Antibodiesmentioning

confidence: 99%

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

Strohl

et al. 2022

BioDrugs

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The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly’s bamlanivimab and etesevimab, Regeneron’s mixture of imdevimab and casirivimab, Vir’s sotrovimab, Celltrion’s regdanvimab, and Lilly’s bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-022-00529-7.

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A highly potent antibody effective against SARS-CoV-2 variants of concern

Cited by 43 publications

References 67 publications

Advances and gaps in SARS-CoV-2 infection models

Advances and gaps in SARS-CoV-2 infection models

Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

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