Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain DOI Creative Commons
Zhaoyong Zhang, Yuanyuan Zhang, Yuting Zhang

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(12)

Published: Nov. 28, 2024

Abstract Research on virus/receptor interactions has uncovered various mechanisms of antibody‐mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, understanding by antibodies targeting the silent face, which recognize epitopes glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a face neutralizing antibody, 3711, targets non‐supersite N‐terminal domain (NTD) spike protein. Cryo‐EM structure determination 3711 Fab complex reveals novel epitope shielded glycans spike's face. Antibody inhibits interaction between receptor‐binding (RBD) human angiotensin‐converting enzyme (hACE2) through steric hindrance exhibits superior effects compared to other reported NTD‐targeted monoclonal (mAbs). Competition assays antibody repertoire analysis indicate rarity 3711‐related SARS‐CoV‐2 convalescents, suggesting infrequency NTD face‐targeted during infection. As first SARS‐CoV‐2, identification mAb with its mechanism, enhances our shields elucidates epitope‐guided viral mutations that evade specific antibodies.

Language: Английский

Cross-reactive sarbecovirus antibodies induced by mosaic RBD-nanoparticles DOI Creative Commons
Chengcheng Fan, Jennifer R. Keeffe,

Kathryn E. Malecek

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Therapeutic monoclonal antibodies (mAbs) against SARS-CoV-2 become obsolete as spike substitutions reduce antibody binding. To induce conserved receptor-binding domain (RBD) regions for protection variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD-nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges viruses whose were matched or mismatched to those nanoparticles. Here, describe neutralizing mAbs mosaic-8b-immunized rabbits, some par with Pemgarda (the only currently FDA-approved therapeutic mAb). Deep mutational scanning, in vitro selection resistance mutations, cryo-EM structures spike-antibody complexes demonstrated targeting epitopes. Rabbit included critical D-gene segment features common human anti-RBD mAbs, despite rabbit genomes lacking an equivalent segment. Thus, mosaic RBD-nanoparticle immunization coupled multiplexed screening represent efficient way generate select pan-sarbecovirus pan-SARS-2 variant mAbs.

Language: Английский

Citations

1
Challenges and compromises: Predicting unbound antibody structures with deep learning DOI Creative Commons
Alexander Greenshields‐Watson, Odysseas Vavourakis, Fabian C. Spoendlin

et al.

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 90, P. 102983 - 102983

Published: Jan. 24, 2025

Language: Английский

Citations

1
Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain DOI Creative Commons

Rajeshwer S. Sankhala,

Vincent Dussupt, Wei‐Hung Chen

et al.

Structure, Journal Year: 2023, Volume and Issue: 32(2), P. 131 - 147.e7

Published: Dec. 28, 2023

Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants concern (VoCs), immunotherapeutics that target conserved epitopes on spike (S) glycoprotein have therapeutic advantages. Here, we report crystal structure SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility distinct conformations angiotensin-converting enzyme (ACE2)-binding site. We identify a set SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including Omicron subvariants, SARS-CoV-1, other sarbecoviruses determine structures mAb-RBD complexes Ab246 CR3022 mAbs targeting class IV site, WRAIR-2134, which binds recently designated V epitope, WRAIR-2123, I ACE2-binding The reactivity to regions VoCs sarbecovirus provides framework for long-term immunotherapeutic development strategies.

Language: Английский

Citations

15
The D Gene in CDR H3 Determines a Public Class of Human Antibodies to SARS-CoV-2 DOI Creative Commons
Meng Yuan, Ian A. Wilson

Vaccines, Journal Year: 2024, Volume and Issue: 12(5), P. 467 - 467

Published: April 27, 2024

Public antibody responses have been found against many infectious agents. Structural convergence of public antibodies is usually determined by immunoglobulin V genes. Recently, a human class SARS-CoV-2 was reported, where the D gene (IGHD3-22) encodes common YYDxxG motif in heavy-chain complementarity-determining region 3 (CDR H3), which determines specificity for receptor-binding domain (RBD). In this review, we discuss isolation, structural characterization, and genetic analyses antibodies, isolated from various cohorts COVID-19 convalescents vaccinees. All eleven with available structures target RBD similar binding mode, CDR H3 dominates interaction antigen. The conserved site on that does not overlap site, but their particular angle approach results direct steric hindrance to receptor binding, enables both neutralization potency breadth. We also review properties H3-dominant other viruses. Overall, unlike most are identified usage, newly discovered dominated D-gene-encoded uncovers further opportunities germline-targeting vaccine design.

Language: Английский

Citations

3
Structural Immunology of SARS‐CoV‐2 DOI Creative Commons
Meng Yuan, Ian A. Wilson

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 27, 2024

The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, escape mechanisms. Antibodies receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in variants. contrast, conserved regions, such as S2 stem helix fusion peptide, broader reactivity generally lower potency. However, several broadly have demonstrated exceptional efficacy against emerging variants, including latest omicron subvariants, underscoring potential vulnerable sites RBS-A RBS-D/CR3022. We also highlight public classes different protein. targeted present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent effective vaccines remains crucial combating future This review emphasizes importance identifying key utilizing antibody affinity maturation inform therapeutic design.

Language: Английский

Citations

3
Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV DOI Creative Commons
Naveenchandra Suryadevara, Nurgun Kose, Sandhya Bangaru

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 135(3)

Published: Nov. 26, 2024

The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target SARS-CoV-2 NTD potently neutralize virus. This finding suggests may contribute, part, to protective immunity. Pansarbecovirus are desirable for broad protection, but region SARS-CoV and exhibit a high level sequence divergence; therefore, cross-reactive NTD-specific unexpected, there no structure antibody complex with NTD. Here, we report monoclonal COV1-65, encoded by IGHV1-69 gene, recognizes S protein. A prophylaxis study showed mAb COV1-65 prevented disease when administered before challenge BALB/c mice, an effect requires intact fragment crystallizable (Fc) effector functions optimal protection vivo. footprint on near functional components S2 fusion machinery, selection escape mutant viruses identified critical residues Y886H Q974H, which likely affect epitope through allosteric effects. Structural features COV1-65-SARS-CoV antigen interaction suggest antigenic determinants should be considered rational design sarbecovirus vaccine candidates.

Language: Английский

Citations

2
Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain DOI Creative Commons
Denise Guerra, Laura Radić, Mitch Brinkkemper

et al.

Human Vaccines & Immunotherapeutics, Journal Year: 2024, Volume and Issue: 20(1)

Published: Aug. 20, 2024

Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only few sarbecovirus strains. Therefore, there is growing interest bispecific (bsAbs) which can simultaneously target different spike epitopes thereby increase breadth prevent viral escape. Here, we generate characterize panel of 30 novel broadly reactive bsAbs using efficient controlled Fab-arm exchange protocol. We specifically combine some the broadest described far, conserved on receptor binding domain (RBD). Several show superior cross-binding neutralization compared parental cocktails sarbecoviruses from diverse clades, including recent variants. BsAbs include mAb COVA2–02 among potent broad combinations. As result, study unknown epitope that this targets distinct region at base RBD, could be when designing next-generation bsAb constructs contribute better pandemic preparedness.

Language: Английский

Citations

1
Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain DOI Open Access
Denise Guerra, Laura Radić, Mitch Brinkkemper

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 9, 2024

Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only few sarbecovirus strains. Therefore, there is growing interest bispecific (bsAbs) which can simultaneously target different spike epitopes thereby increase breadth prevent viral escape. Here, we generate characterize panel of 30 novel broadly reactive bsAbs using efficient controlled Fab-arm exchange protocol. We specifically combine some the broadest described far, conserved on receptor binding domain (RBD). Several show superior cross-binding neutralization compared parental sarbecoviruses from diverse clades, including recent variants. BsAbs include mAb COVA2-02 among potent broad combinations. As result, study unknown epitope that this targets distinct region at base RBD, could be when designing next-generation bsAb constructs contribute better pandemic preparedness.

Language: Английский

Citations

0
Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain DOI Creative Commons
Zhaoyong Zhang, Yuanyuan Zhang, Yuting Zhang

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(12)

Published: Nov. 28, 2024

Abstract Research on virus/receptor interactions has uncovered various mechanisms of antibody‐mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, understanding by antibodies targeting the silent face, which recognize epitopes glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a face neutralizing antibody, 3711, targets non‐supersite N‐terminal domain (NTD) spike protein. Cryo‐EM structure determination 3711 Fab complex reveals novel epitope shielded glycans spike's face. Antibody inhibits interaction between receptor‐binding (RBD) human angiotensin‐converting enzyme (hACE2) through steric hindrance exhibits superior effects compared to other reported NTD‐targeted monoclonal (mAbs). Competition assays antibody repertoire analysis indicate rarity 3711‐related SARS‐CoV‐2 convalescents, suggesting infrequency NTD face‐targeted during infection. As first SARS‐CoV‐2, identification mAb with its mechanism, enhances our shields elucidates epitope‐guided viral mutations that evade specific antibodies.

Language: Английский

Citations

0