EMD-16481
Structure of the SARS-CoV-2 spike glycoprotein in complex with the 10D12 heavy-chain-only antibody (2 RBDs up)
EMD-16481
Single-particle3.3 Å
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Map released: 22/02/2023
Last modified: 13/12/2023
Sample Organism:
Severe acute respiratory syndrome coronavirus 2,
Mus musculus
Sample: SARS-CoV-2 spike glycoprotein in complex with the 10D12 heavy-chain-only antibody
Deposition Authors: Serna Martin I
,
Hurdiss DL
Sample: SARS-CoV-2 spike glycoprotein in complex with the 10D12 heavy-chain-only antibody
Deposition Authors: Serna Martin I
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Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants.
Du W
,
Janssens R,
Mykytyn AZ,
Li W
,
Drabek D,
van Haperen R,
Chatziandreou M,
Rissmann M,
van der Lee J,
van Dortmondt M,
Martin IS,
van Kuppeveld FJM,
Hurdiss DL
,
Haagmans BL
,
Grosveld F,
Bosch BJ
(2023) Front Immunol , 14 , 1111385 - 1111385
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(2023) Front Immunol , 14 , 1111385 - 1111385
Abstract:
Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants. Here we describe the design of a biparatopic heavy-chain-only antibody consisting of six antigen binding sites recognizing two distinct epitopes in the spike protein NTD and RBD. The hexavalent antibody showed potent neutralizing activity against SARS-CoV-2 and variants of concern, including the Omicron sub-lineages BA.1, BA.2, BA.4 and BA.5, whereas the parental components had lost Omicron neutralization potency. We demonstrate that the tethered design mitigates the substantial decrease in spike trimer affinity seen for escape mutations for the hexamer components. The hexavalent antibody protected against SARS-CoV-2 infection in a hamster model. This work provides a framework for designing therapeutic antibodies to overcome antibody neutralization escape of emerging SARS-CoV-2 variants.
Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants. Here we describe the design of a biparatopic heavy-chain-only antibody consisting of six antigen binding sites recognizing two distinct epitopes in the spike protein NTD and RBD. The hexavalent antibody showed potent neutralizing activity against SARS-CoV-2 and variants of concern, including the Omicron sub-lineages BA.1, BA.2, BA.4 and BA.5, whereas the parental components had lost Omicron neutralization potency. We demonstrate that the tethered design mitigates the substantial decrease in spike trimer affinity seen for escape mutations for the hexamer components. The hexavalent antibody protected against SARS-CoV-2 infection in a hamster model. This work provides a framework for designing therapeutic antibodies to overcome antibody neutralization escape of emerging SARS-CoV-2 variants.