scholarly journals The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody

2020 ◽  
Author(s):  
Conrad E.Z. Chan ◽  
Shirley G.K. Seah ◽  
De Hoe Chye ◽  
Shane Massey ◽  
Maricela Torres ◽  
...  
Keyword(s):  
Viral Load ◽  
Therapeutic Efficacy ◽  
Neutralizing Antibodies ◽  
Inflammatory Responses ◽  
Systemic Disease ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Effector Functions ◽  
Igg1 Antibody

AbstractSARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is known about the mechanisms of action of these antibodies or their effective dosing windows. We report the discovery and development of SC31, a potent SARS-CoV-2 neutralizing IgG1 antibody, originally isolated from a convalescent patient at day 27 after the onset of symptoms. Neutralization occurs via a binding epitope that maps within the ACE2 interface of the SARS-CoV-2 Spike protein, conserved across all common circulating SARS-CoV-2 mutants. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, SC31 demonstrated potent survival benefit by dramatically reducing viral load concomitant with attenuated pro-inflammatory responses linked to severe systemic disease, such as IL-6. Comparison with a Fc-null LALA variant of SC31 demonstrated that optimal therapeutic efficacy of SC31 requires intact Fc-mediated effector functions that can further induce an IFNγ-driven anti-viral immune response. Dose-dependent efficacy for SC31 was observed down to 5mg/kg when dosed before the activation of lung inflammatory responses. Importantly, despite FcγR binding, no evidence of antibody dependent enhancement was observed with the Fc-competent SC31 even at sub-therapeutic doses. Therapeutic efficacy was confirmed in SARS-CoV-2-infected hamsters, where SC31 again significantly reduced viral load, decreased lung lesions and inhibited progression to severe disease manifestations. This study underlines the potential for significant COVID-19 patient benefit for the SC31 antibody that justifies rapid advancement to the clinic, as well as highlighting the importance of appropriate mechanistic and functional studies during development.One Sentence SummaryAnti-SARS-CoV-2 IgG1 antibody SC31 controls infection in vivo by blocking SP:ACE2 binding and triggering a Fc-mediated anti-viral response.

scholarly journals The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253487
Author(s):  
Conrad E. Z. Chan ◽  
Shirley G. K. Seah ◽  
De Hoe Chye ◽  
Shane Massey ◽  
Maricela Torres ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Neutralizing Antibodies ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Effector Functions ◽  
Viral Loads ◽  
Therapeutic Doses ◽  
Dose Dependent

Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.

scholarly journals Differential Association of Viral Dynamics With Disease Severity Depending on Patients’ Age Group in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuri Kim ◽  
Shinhyea Cheon ◽  
Hyeongseok Jeong ◽  
Uni Park ◽  
Na-Young Ha ◽  
...  
Keyword(s):  
Viral Load ◽  
Elderly Patients ◽  
Disease Severity ◽  
Acute Phase ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
The Elderly ◽  
Clinical Severity ◽  
Younger Patients

Despite a clear association of patient’s age with COVID-19 severity, there has been conflicting data on the association of viral load with disease severity. Here, we investigated the association of viral load dynamics with patient’s age and severity of COVID-19 using a set of respiratory specimens longitudinally collected (mean: 4.8 times/patient) from 64 patients with broad distribution of clinical severity and age during acute phase. Higher viral burden was positively associated with inflammatory responses, as assessed by IL-6, C-reactive protein, and lactate dehydrogenase levels in patients’ plasma collected on the same day, primarily in the younger cohort (≤59 years old) and in mild cases of all ages, whereas these were barely detectable in elderly patients (≥60 years old) with critical disease. In addition, viral load dynamics in elderly patients were not significantly different between mild and critical cases, even though more enhanced inflammation was consistently observed in the elderly group when compared to the younger group during the acute phase of infection. The positive correlation of viral load with disease severity in younger patients may explain the increased therapeutic responsiveness to current antiviral drugs and neutralizing antibody therapies in younger patients compared to elderly patients. More careful intervention against aging-associated inflammation might be required to mitigate severe disease progression and reduce fatality in COVID-19 patients more than 60 years old.

scholarly journals An anti-SARS-CoV-2 non-neutralizing antibody with Fc-effector function defines a new NTD epitope and delays neuroinvasion and death in K18-hACE2 mice

2021 ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Yaozong Chen ◽  
Irfan Ullah ◽  
Jérémie Prévost ◽  
William D. Tolbert ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Animal Models ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Transgenic Mouse Model ◽  
Effector Function ◽  
Effector Functions

SummaryEmerging evidence in animal models indicate that both neutralizing activity and Fc- mediated effector functions of neutralizing antibodies contribute to protection against SARS-CoV-2. It is unclear if antibody effector functions alone could protect against SARS-CoV-2. Here we isolated CV3-13, a non-neutralizing antibody from a convalescent individual with potent Fc-mediated effector functions that targeted the N- terminal domain (NTD) of SARS-CoV-2 Spike. The cryo-EM structure of CV3-13 in complex with SAR-CoV-2 spike revealed that the antibody bound from a distinct angle of approach to a novel NTD epitope that partially overlapped with a frequently mutated NTD supersite in SARS-CoV-2 variants. While CV3-13 did not alter the replication dynamics of SARS-CoV-2 in a K18-hACE2 transgenic mouse model, an Fc-enhanced CV3-13 significantly delayed neuroinvasion and death in prophylactic settings. Thus, we demonstrate that efficient Fc-mediated effector functions can contribute to the in vivo efficacy of anti-SARS-CoV-2 monoclonal antibodies in the absence of neutralization.

scholarly journals Systematic assessment of antiviral potency, breadth, and synergy of triple broadly neutralizing antibody combinations against Simian-Human Immunodeficiency Viruses

2020 ◽  
Author(s):  
Stella J Berendam ◽  
Tiffany M Styles ◽  
Papa K Morgan-Asiedu ◽  
DeAnna Tenney ◽  
Amit Kumar ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Systematic Assessment ◽  
Effector Functions ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Antiviral Activities

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term HIV remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the ability of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and non-neutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain-dependent. Moreover, we observe a strong correlation between the neutralization potencies and non-neutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprised of CD4 binding site, V2-glycan, and gp120-gp41 interface targeting bNAbs that are capable of mediating, synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.

scholarly journals Live imaging of SARS-CoV-2 infection in mice reveals neutralizing antibodies require Fc function for optimal efficacy

2021 ◽  
Author(s):  
Irfan Ullah ◽  
Jeremie Prevost ◽  
Mark S. Ladinsky ◽  
Helen Stone ◽  
Maolin Lu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Bioluminescence Imaging ◽  
Inflammatory Responses ◽  
Immune Protection ◽  
In Vivo Efficacy ◽  
Effector Functions ◽  
Systemic Spread ◽  
The Brain ◽  
Established Infection

Neutralizing antibodies (NAbs) are effective in treating COVID-19 but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment in prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. We visualized sequential spread of virus from the nasal cavity to the lungs followed by systemic spread to various organs including the brain, culminating in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days of infection. In addition to direct neutralization, in vivo efficacy required Fc effector functions of NAbs, with contributions from monocytes, neutrophils and natural killer cells, to dampen inflammatory responses and limit immunopathology. Thus, our study highlights the requirement of both Fab and Fc effector functions for an optimal in vivo efficacy afforded by NAbs against SARS-CoV-2.

scholarly journals Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

2021 ◽  
Vol 118 (30) ◽  
pp. e2104651118
Author(s):  
Matthijs Meijers ◽  
Kanika Vanshylla ◽  
Henning Gruell ◽  
Florian Klein ◽  
Michael Lässig
Keyword(s):  
Viral Load ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Treatment ◽  
Trade Off ◽  
Escape Dynamics ◽  
Resistance Evolution ◽  
Hiv 1

Broadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map a fitness model of HIV-1 interacting with broadly neutralizing antibodies using in vivo data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary trade-off between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance–cost trade-off curves as a measure of antibody performance in the presence of resistance evolution.

scholarly journals Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

2020 ◽  
Author(s):  
Matthijs Meijers ◽  
Kanika Vanshylla ◽  
Henning Gruell ◽  
Florian Klein ◽  
Michael Lässig
Keyword(s):  
Viral Load ◽  
Neutralizing Antibodies ◽  
Fitness Landscape ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Treatment ◽  
Escape Dynamics ◽  
Resistance Evolution ◽  
Hiv 1

ABSTRACTBroadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map an in vivo fitness landscape of HIV-1 interacting with broadly neutralizing antibodies, using data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary tradeoff between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance-cost tradeoff curves as a measure of antibody performance in the presence of resistance evolution.

scholarly journals Contribution to HIV Prevention and Treatment by Antibody-Mediated Effector Function and Advances in Broadly Neutralizing Antibody Delivery by Vectored Immunoprophylaxis

2021 ◽  
Vol 12 ◽  
Author(s):  
Meredith Phelps ◽  
Alejandro Benjamin Balazs
Keyword(s):  
Hiv Prevention ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Passive Transfer ◽  
Viral Envelope ◽  
Viral Clearance ◽  
Effector Functions ◽  
Transient Nature ◽  
Antibody Delivery

HIV-1 broadly neutralizing antibodies (bNAbs) targeting the viral envelope have shown significant promise in both HIV prevention and viral clearance, including pivotal results against sensitive strains in the recent Antibody Mediated Prevention (AMP) trial. Studies of bNAb passive transfer in infected patients have demonstrated transient reduction of viral load at high concentrations that rebounds as bNAb is cleared from circulation. While neutralization is a crucial component of therapeutic efficacy, numerous studies have demonstrated that bNAbs can also mediate effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). These functions have been shown to contribute towards protection in several models of HIV acquisition and in viral clearance during chronic infection, however the role of target epitope in facilitating these functions, as well as the contribution of individual innate functions in protection and viral clearance remain areas of active investigation. Despite their potential, the transient nature of antibody passive transfer limits the widespread use of bNAbs. To overcome this, we and others have demonstrated vectored antibody delivery capable of yielding long-lasting expression of bNAbs in vivo. Two clinical trials have shown that adeno-associated virus (AAV) delivery of bNAbs is safe and capable of sustained bNAb expression for over 18 months following a single intramuscular administration. Here, we review key concepts of effector functions mediated by bNAbs against HIV infection and the potential for vectored immunoprophylaxis as a means of producing bNAbs in patients.

scholarly journals Transcriptomic Analysis of Inbred Chicken Lines Reveals Infectious Bursal Disease Severity Is Associated with Greater Bursal Inflammation In Vivo and More Rapid Induction of Pro-Inflammatory Responses in Primary Bursal Cells Stimulated Ex Vivo

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 933
Author(s):  
Amin S. Asfor ◽  
Salik Nazki ◽  
Vishwanatha R.A.P. Reddy ◽  
Elle Campbell ◽  
Katherine L. Dulwich ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Severe Disease ◽  
Infectious Bursal Disease ◽  
Rna Seq ◽  
Rapid Induction ◽  
Cytoskeletal Regulation ◽  
Bursal Disease

In order to better understand differences in the outcome of infectious bursal disease virus (IBDV) infection, we inoculated a very virulent (vv) strain into White Leghorn chickens of inbred line W that was previously reported to experience over 24% flock mortality, and three inbred lines (15I, C.B4 and 0) that were previously reported to display no mortality. Within each experimental group, some individuals experienced more severe disease than others but line 15I birds experienced milder disease based on average clinical scores, percentage of birds with gross pathology, average bursal lesion scores and average peak bursal virus titre. RNA-Seq analysis revealed that more severe disease in line W was associated with significant up-regulation of pathways involved in inflammation, cytoskeletal regulation by Rho GTPases, nicotinic acetylcholine receptor signaling, and Wnt signaling in the bursa compared to line 15I. Primary bursal cell populations isolated from uninfected line W birds contained a significantly greater percentage of KUL01+ macrophages than cells isolated from line 15I birds (p < 0.01) and, when stimulated ex vivo with LPS, showed more rapid up-regulation of pro-inflammatory gene expression than those from line 15I birds. We hypothesize that a more rapid induction of pro-inflammatory cytokine responses in bursal cells following IBDV infection leads to more severe disease in line W birds than in line 15I.

scholarly journals Neutralizing Antibody Therapeutics for COVID-19

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 628
Author(s):  
Aeron C. Hurt ◽  
Adam K. Wheatley
Keyword(s):  
High Risk ◽  
Neutralizing Antibodies ◽  
Controlled Trial ◽  
Antiviral Treatment ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Supplemental Oxygen ◽  
European Medicines Agency ◽  
Global Public Health ◽  
Public Health Burden

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant “escape” mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.

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