Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection

Winkler, Emma S.; Gilchuk, Pavlo; Yu, Jinsheng; Bailey, Adam L.; Chen, Rita E.; Chong, Zhenlu; Zost, Seth J.; Jang, Hyesun; Huang, Ying; Allen, James D.; Case, James Brett; Sutton, Rachel E.; Carnahan, Robert H.; Darling, Tamarand L.; Boon, Adrianus C. M.; Mack, Matthias; Head, Richard D.; Ross, Ted M.; Diamond, Michael S.

doi:10.1016/j.cell.2021.02.026

Cited by 304 publications

(283 citation statements)

References 95 publications

(119 reference statements)

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“…An S/C of 9 on the Ortho Clinical assay correlated to a neutralizing titer of ~1:100. This is notably similar to the neutralizing titer of 1:104 we found to be sufficient to reduce weight loss in mice (23). Nevertheless, the neutralizing assay used in this study cannot be assumed to perform similarly to the assay used in the BARDA study (14,15) due to non-standardization of SARS-CoV-2 strains, cell lines, and reagents/procedures.…”

Section: Discussionsupporting

confidence: 76%

Assessment of serological assays for identifying high titer convalescent plasma

Farnsworth

Case

Hock

et al. 2021

Preprint

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The COVID-19 pandemic has been accompanied by the largest mobilization of therapeutic convalescent plasma (CCP) in over a century. Initial identification of high titer units was based on dose-response data using the Ortho VITROS IgG assay. The proliferation of SARS-CoV-2 serological assays and non-uniform application has led to uncertainty about their interrelationships. The purpose of this study was to establish correlations and analogous cutoffs between commercially available serological tests (Ortho, Abbott, Roche), a spike ELISA, and a virus neutralization assay using convalescent plasma from a cohort of 79 donors from April 2020. Relationships relative to FDA-approved cutoffs under the CCP EUA were identified by linear regression and receiver operator characteristic curves. Relative to the Ortho VITROS assay, the r2 of the Abbott, Roche, the anti-Spike ELISA and the neutralizing assay were 0.58, 0.5, 0.82, and 0.44, respectively. The best correlative index for establishing high-titer units was 3.82 S/C for the Abbott, 10.89 COI for the Roche, 1:1,202 for the anti-Spike ELISA, and 1:200 by the neutralization assay. The overall agreement using derived cutoffs compared to the CCP EUA Ortho VITROS cutoff of 9.5 was 92.4% for Abbott, 84.8% for Roche, 87.3% for the anti-S ELISA and 78.5% for the neutralization assay. Assays based on antibodies against the nucleoprotein (Roche, Abbott) and neutralizing antibody tests were positively associated with the Ortho assay, although their ability to distinguish FDA high-titer specimens was imperfect. The resulting relationships help reconcile results from the large body of serological data generated during the COVID-19 pandemic.

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Section: Discussionsupporting

confidence: 76%

Assessment of serological assays for identifying high titer convalescent plasma

Farnsworth

Case

Hock

et al. 2021

Preprint

Self Cite

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“…Despite observing differences in serum neutralizing activity against authentic SARS-CoV-2 variant viruses, it remains unclear how this finding translates into effects on protection in the context of secondary infection or infection after vaccination with platforms using historical spike gene sequences. Although serum neutralizing titers are an anticipated correlate of protection 37 , this measurement does not account for Fc effector functions; Fcγ receptor or complement protein engagement by non, weakly, or strongly neutralizing antibodies that bind the SARS-CoV-2 spike protein on the surface of infected cells could confer substantial protection [38][39][40] . Also, the role of memory T or B cells in protection against variant viruses is unknown and could prevent severe infection even in the setting of compromised serum antibody responses [41][42][43] .…”

Section: Discussionmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

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evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 111 million people and causing 2.4 million deaths. Clinical disease in humans ranges from asymptomatic infection to pneumonia, severe respiratory compromise, multi-organ failure and systemic inflammatory syndromes. The rapid expansion and prolonged nature of the COVID-19 pandemic and its accompanying morbidity, mortality and destabilizing socioeconomic effects have made the development of SARS-CoV-2 therapeutics and vaccines an urgent global health priority 1. Indeed, the emergency use authorization and rapid deployment of antibody-based countermeasures, including mAbs, immune plasma therapy and messenger RNA, and inactivated and viral-vectored vaccines has provided hope for curtailing disease and ending the pandemic. The spike protein of the SARS-CoV-2 virion binds the cell-surface receptor angiotensin-converting enzyme 2 (ACE2) to promote entry into human cells 2. Because the spike protein is critical for viral entry, it has been targeted for vaccine development and therapeutic antibody interventions. SARS-CoV-2 S proteins are cleaved to yield S1 and S2 fragments. The S1 protein includes the N-terminal (NTD) and receptor-binding (RBD) domains, whereas the S2 protein promotes membrane fusion. The RBD is recognized by many potently neutralizing monoclonal antibodies 3-7 , protein-based inhibitors 8 and serum antibodies 9. The current suite of antibody therapeutics and vaccines was designed with a spike protein based on strains circulating during the early phases of the pandemic in 2020. More recently, variants with enhanced transmissibility have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248) and elsewhere with multiple substitutions in the spike protein, including in the NTD and the receptor-binding motif (RBM) of the RBD. Preliminary studies with pseudoviruses suggest that neutralization by some antibodies and immune sera may be diminished against variants expressing mutations in the spike gene 10-13. Given these

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“…Indeed, FcγR engagement mediates pleiotropic antiviral immune functions, including the clearance of viral particles 9,10 , the cytotoxic elimination of virus-infected cells 11 , as well as the induction of protective T cell responses that contribute to antiviral immunity [12][13][14] . In the context of SARS-CoV-2 infection, a growing body of experimental evidence from various animal disease models supports that Fc-FcγR interactions are essential for the in vivo antiviral activity of anti-SARS-CoV-2 mAbs, as loss of the capacity of the Fc domain of these mAbs to engage FcγRs is associated with reduced antiviral activity in vivo [15][16][17][18] .…”

mentioning

confidence: 99%

Fc-engineered antibody therapeutics with improved efficacy against COVID-19

Ravetch

Yamin

Jones

et al. 2021

Preprint

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Monoclonal antibodies (mAbs) with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefit in cases of mild to moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these mAbs with limited efficacy in preventing disease complications or mortality among hospitalized COVID-19 patients5. Here we report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease. In several animal models of COVID-19 disease6,7, we demonstrate that selective engagement of activating FcγRs results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection upon SARS-CoV-2 challenge and treatment of pre-infected animals. Our results highlight the importance of FcγR pathways in driving antibody-mediated antiviral immunity, while excluding any pathogenic or disease-enhancing effects of FcγR engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered mAbs with optimal Fc effector function and improved clinical efficacy against COVID-19 disease.

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Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection

Cited by 304 publications

References 95 publications

Assessment of serological assays for identifying high titer convalescent plasma

Assessment of serological assays for identifying high titer convalescent plasma

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Fc-engineered antibody therapeutics with improved efficacy against COVID-19

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