Paired heavy- and light-chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

Banach, Bailey B; Cerutti, Gabriele; Fahad, Ahmed S.; Shen, Chen‐Hsiang; Souza, Matheus Oliveira de; Katsamba, Phinikoula S.; Tsybovsky, Yaroslav; Wang, Pengfei; Nair, Manoj S.; Huang, Yaoxing; Francino-Urdániz, Irene M.; Steiner, Paul J; Gutiérrez-González, Matías; Liu, Lihong; Acevedo, Sheila N. López; Nazzari, Alexandra; Wolfe, Jacy R.; Luo, Yang; Olia, Adam S.; Teng, I-Ting; Yu, Jian; Zhou, Tongqing; Bimela, Jude; Pan, Xiaoli; Madan, Bharat; Laflin, Amy D.; Nimrania, Rajani; Yuen, Kwok‐Yung; Whitehead, Timothy A.; Ho, David D.; Kwong, Peter D.; Shapiro, Lawrence; DeKosky, Brandon J.

doi:10.1016/j.celrep.2021.109771

Cited by 43 publications

(18 citation statements)

References 91 publications

(167 reference statements)

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“…Banach et al . realised that many of the coronavirus-binding antibodies deriving from the IGHV3–53/IGHV3–66 genes possess a conserved set of structural motifs that enable complementarity to a SARS-CoV-2 RBD epitope [ 60 ]. Our updated analysis reiterates the importance of these V gene origins in engaging this highly conserved binding site: 19/22 (86%) of the antibodies align closest to the IGHV3–53 gene, while the remaining 3 align closest to IGHV3–66.…”

Section: Resultsmentioning

confidence: 99%

“…In most cases where multiple clonotypes are found in the same structural cluster, it is due to significant differences in the CDRH3 sequence. However, some clusters such as SC134 (which pools COV2-2490 (60) with H712061+K711727 (61)), contain many differences across the entirety of the sequence (26 differences across VH, 27 across VL) and align closest to different heavy V (IGHV3-7 vs. IGHV3-30) and light V (IGKV1-5 vs. IGKV1D-16) genes.…”

Section: (Sc57)mentioning

confidence: 99%

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Epitope profiling using computational structural modelling demonstrated on coronavirus-binding antibodies

et al. 2021

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Identifying the epitope of an antibody is a key step in understanding its function and its potential as a therapeutic. Sequence-based clonal clustering can identify antibodies with similar epitope complementarity, however, antibodies from markedly different lineages but with similar structures can engage the same epitope. We describe a novel computational method for epitope profiling based on structural modelling and clustering. Using the method, we demonstrate that sequence dissimilar but functionally similar antibodies can be found across the Coronavirus Antibody Database, with high accuracy (92% of antibodies in multiple-occupancy structural clusters bind to consistent domains). Our approach functionally links antibodies with distinct genetic lineages, species origins, and coronavirus specificities. This indicates greater convergence exists in the immune responses to coronaviruses than is suggested by sequence-based approaches. Our results show that applying structural analytics to large class-specific antibody databases will enable high confidence structure-function relationships to be drawn, yielding new opportunities to identify functional convergence hitherto missed by sequence-only analysis.

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Section: Resultsmentioning

confidence: 99%

Section: (Sc57)mentioning

confidence: 99%

Epitope profiling using computational structural modelling demonstrated on coronavirus-binding antibodies

et al. 2021

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“…The activity of S309 declined modestly, whereas Brii-198 was spared. All mAbs in RBD class 4 lost neutralization potency against B.1.1.529 by at least 10-fold, as did mAb directed to the antigenic supersite 26 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) or the alternate site 23 (5-7) on NTD. Strikingly, all four combination mAb drugs in clinical use lost substantial activity against B.1.1.529, likely abolishing or impairing their efficacy in patients.…”

Section: Monoclonal Antibody Neutralization Of B11529mentioning

confidence: 97%

“…We also included other mAbs of interest: 910-30 18 , ADG-2 19 , DH1047 20 , S2X259 21 , and our antibodies 1-20, 2-15, 2-7, 4-18, 5-7, and 10-40 [22][23][24] . The footprints of mAbs with structures available were drawn in relation to the mutations found in B.1.1.529 RBD (Fig.…”

Section: Monoclonal Antibody Neutralization Of B11529mentioning

confidence: 99%

Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2

Liu

Iketani

Guo

et al. 2021

Preprint

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The Omicron (B.1.1.529) variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally1. It is expected to become dominant in the coming weeks2, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies4. This concern is amplified by the findings from our study. We found B.1.1.529 to be markedly resistant to neutralization by serum not only from convalescent patients, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, we noted that the activity of 18 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients. In addition, we also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.

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“…Overlap extension RT-PCR was used to transform separate heavy (VH) and light (VL) variable genes into a single, physically linked VH:VL cDNA amplicons. cDNA amplicons encoding heavy and kappa light chain variable regions were cloned into a yeast display vector for expressing antibody VH:VL genes as Fabs for functional screening via FACS and NGS as previously reported [16, 39, 51, 52]. Briefly, AWY101 yeast expressing Fabs were cultured in SGCAA media (Teknova) with 2 g/L dextrose (SGDCAA) for 36 hrs at 20°C to induce Fab expression for surface display.…”

Section: Methodsmentioning

confidence: 99%

Molecular probes of spike ectodomain and its subdomains for SARS-CoV-2 variants, Alpha through Omicron

Teng

Nazzari

Choe

et al. 2021

Preprint

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Since the outbreak of the COVID-19 pandemic, widespread infections have allowed SARS-CoV-2 to evolve in human, leading to the emergence of multiple circulating variants. Some of these variants show increased resistance to vaccines, convalescent plasma, or monoclonal antibodies. In particular, mutations in the SARS-CoV-2 spike have drawn attention. To facilitate the isolation of neutralizing antibodies and the monitoring the vaccine effectiveness against these variants, we designed and produced biotin-labeled molecular probes of variant SARS-CoV-2 spikes and their subdomains, using a structure-based construct design that incorporated an N-terminal purification tag, a specific amino acid sequence for protease cleavage, the variant spike-based region of interest, and a C-terminal sequence targeted by biotin ligase. These probes could be produced by a single step using in-process biotinylation and purification. We characterized the physical properties and antigenicity of these probes, comprising the N-terminal domain (NTD), the receptor-binding domain (RBD), the RBD and subdomain 1 (RBD-SD1), and the prefusion-stabilized spike ectodomain (S2P) with sequences from SARS-CoV-2 variants of concern or of interest, including variants Alpha, Beta, Gamma, Epsilon, Iota, Kappa, Delta, Lambda, Mu, and Omicron. We functionally validated probes by using yeast expressing a panel of nine SARS-CoV-2 spike-binding antibodies and confirmed sorting capabilities of variant probes using yeast displaying libraries of plasma antibodies from COVID-19 convalescent donors. We deposited these constructs to Addgene to enable their dissemination. Overall, this study describes a matrix of SARS-CoV-2 variant molecular probes that allow for assessment of immune responses, identification of serum antibody specificity, and isolation and characterization of neutralizing antibodies.

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Paired heavy- and light-chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

Cited by 43 publications

References 91 publications

Epitope profiling using computational structural modelling demonstrated on coronavirus-binding antibodies

Epitope profiling using computational structural modelling demonstrated on coronavirus-binding antibodies

Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2

Molecular probes of spike ectodomain and its subdomains for SARS-CoV-2 variants, Alpha through Omicron

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