Discovery and characterization of potent pan-variant SARS-CoV-2 neutralizing antibodies from individuals with Omicron breakthrough infection

Guo, Yu; Zhang, Guangshun; Yang, Qi; Xie, Xiaowei; Yang, Lingling; Cheng, Xuelian; Wang, Hui; Liang, Jingxi; Tang, Jielin; Gao, Yuxin; Shang, Han Lin; Dai, Jun; Shi, Yongxia; Zhou, Jiaxi; Zhou, Jun; Guo, Hangtian; Yang, Haitao; Qi, Jianwei; Liu, Lijun; Ma, Shihui; Zhang, Biao; Huo, Qianyu; Xie, Yi; Wu, Junping; Fang, Dong; Zhang, Song; Lou, Zhiyong; Gao, Yan; Song, Zidan; Wang, Wenming; Sun, Zhenli; Yang, Xiaoming; Xiong, Dongsheng; Liu, Fengjiang; Chen, Xinwen; Zhu, Ping; Wang, Ximo; Cheng, Tao; Rao, Zihe

doi:10.1038/s41467-023-39267-x

Cited by 11 publications

(5 citation statements)

References 54 publications

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“…The cellular antiviral activity of GZNL-P36 was examined by a cell protection assay. In this assay, the cytopathic effect (CPE) of SARS-CoV- 2-infected Vero E6 cells with or without treatment by the compounds was assessed using Celigo Image Cytometer 39 . The cells were challenged with WT SARS-CoV-2 and two other variants Omicron BA.5 and XBB.1.…”

Section: Resultsmentioning

confidence: 99%

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

Lu,

Yang,

Ran

et al. 2024

Preprint

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The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLproinhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLprofrom SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discovered a series of novel potent non-covalent PLproinhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLprowith leads revealed that the residues E164 and Q269 around the S2 site are critical for improving the inhibitor's potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50of 81.6 nM and 2.66 μM, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLproinhibitor is a promising SARS-CoV-2 therapy.

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Section: Resultsmentioning

confidence: 99%

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

Lu,

Yang,

Ran

et al. 2024

Preprint

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“…Indeed, we observed more somatic mutations in IGHV3-53 mAbs isolated from breakthrough infection donors than those isolated from ancestral SARS-CoV-2 infection. Recently, several studies showed that the affinity maturated IGHV3-53 mAbs, such as P5S-2B10 (from WT convalescents) [ 56 ], 10-5B (from inactivated vaccinees) [ 57 ], and TH132 (from BA.1 breakthrough infected donors) [ 58 ], are able to protect K18-hACE2 mice from the challenge of Omicron BA.1, BA.2, and BA.5, respectively. Collectively, our analysis provides a holistic view of the kinetics of the spike-specific antibody response and identifies which of them is induced by ancestral SARS-CoV-2 infection or vaccination that will create long-term or/and cross-reactive B-cell memory.…”

Section: Discussionmentioning

confidence: 99%

Deep immunoglobulin repertoire sequencing depicts a comprehensive atlas of spike-specific antibody lineages shared among COVID-19 convalescents

Yan,

Zhang,

Hou

et al. 2024

Emerging Microbes & Infections

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Neutralizing antibodies are a key component in protective humoral immunity against SARS-CoV-2. Currently, available technologies cannot track epitope-specific antibodies in global antibody repertoires. Thus, the comprehensive repertoire of spike-specific neutralizing antibodies elicited by SARS-CoV-2 infection is not fully understood. We therefore combined high-throughput immunoglobulin heavy chain (IgH) repertoire sequencing, and structural and bioinformatics analysis to establish an antibodyomics pipeline, which enables tracking spike-specific antibody lineages that target certain neutralizing epitopes. We mapped the neutralizing epitopes on the spike and determined the epitope-preferential antibody lineages. This analysis also revealed numerous overlaps between immunodominant neutralizing antibody-binding sites and mutation hotspots on spikes as observed so far in SARS-CoV-2 variants. By clustering 2677 spike-specific antibodies with 360 million IgH sequences that we sequenced, a total of 329 shared spike-specific antibody clonotypes were identified from 33 COVID-19 convalescents and 24 SARS-CoV-2-naïve individuals. Epitope mapping showed that the shared antibody responses target not only neutralizing epitopes on RBD and NTD but also non-neutralizing epitopes on S2. The immunodominance of neutralizing antibody response is determined by the occurrence of specific precursors in human naïve B-cell repertoires. We identified that only 28 out of the 329 shared spike-specific antibody clonotypes persisted for at least 12 months. Among them, long-lived IGHV3-53 antibodies are likely to evolve cross-reactivity to Omicron variants through accumulating somatic hypermutations. Altogether, we created a comprehensive atlas of spike-targeting antibody lineages in COVID-19 convalescents and antibody precursors in human naïve B cell repertoires, providing a valuable reference for future vaccine design and evaluation.

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“…Although the decision process for clinical development would likely be delayed initially, as input data may not be available, the inclusion of in silico generated data, next to classic neutralization potency, affinity, and developability, may result in longer lasting clinical efficacy. Another strategy against viral escape by new strains is to develop pan-variant reactive antibodies, although their mode of action is not necessarily neutralization [ 43 ], or several infections or vaccinations of an individual are needed to develop such an immune response [ 44 , 45 ] or the epitopes to target. Nevertheless, in an urgent pandemic setting, the question remains if such strategies would be economically viable compared to the obvious strategy of isolating neutralizing antibodies from survivors of the initial pandemic phase.…”

Section: Discussionmentioning

confidence: 99%

Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

Hillenbrand,

Esslinger,

Seidenberg

et al. 2024

Viruses

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As the COVID-19 pandemic revealed, rapid development of vaccines and therapeutic antibodies are crucial to guarantee a quick return to the status quo of society. In early 2020, we deployed our droplet microfluidic single-cell-based platform DROPZYLLA® for the generation of cognate antibody repertoires of convalescent COVID-19 donors. Discovery of SARS-CoV-2-specific antibodies was performed upon display of antibodies on the surface of HEK293T cells by antigen-specific sorting using binding to the SARS-CoV-2 spike and absence of binding to huACE2 as the sort criteria. This efficiently yielded antibodies within 3–6 weeks, of which up to 100% were neutralizing. One of these, MTX-COVAB, displaying low picomolar neutralization IC50 of SARS-CoV-2 and with a neutralization potency on par with the Regeneron antibodies, was selected for GMP manufacturing and clinical development in June 2020. MTX-COVAB showed strong efficacy in vivo and neutralized all identified clinically relevant variants of SARS-CoV-2 at the time of its selection. MTX-COVAB completed GMP manufacturing by the end of 2020, but clinical development was stopped when the Omicron variant emerged, a variant that proved to be detrimental to all monoclonal antibodies already approved. The present study describes the capabilities of the DROPZYLLA® platform to identify antibodies of high virus-neutralizing capacity rapidly and directly.

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Discovery and characterization of potent pan-variant SARS-CoV-2 neutralizing antibodies from individuals with Omicron breakthrough infection

Cited by 11 publications

References 54 publications

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

Deep immunoglobulin repertoire sequencing depicts a comprehensive atlas of spike-specific antibody lineages shared among COVID-19 convalescents

Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

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