Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants

Wenjuan Du; Rick Janssens; Anna Z Mykytyn; Wentao Li; Dubravka Drabek; Rien van Haperen; Marianthi Chatziandreou; Melanie Rissmann; Joline van der Lee; Melissa van Dortmondt; Itziar Serna Martin; Frank J M van Kuppeveld; Daniel L Hurdiss; Bart L Haagmans; Frank Grosveld; Berend-Jan Bosch

doi:10.3389/fimmu.2023.1111385

Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants

Wenjuan Du
, Rick Janssens
, Anna Z Mykytyn
, Wentao Li
, Dubravka Drabek
, Rien van Haperen
, Marianthi Chatziandreou
, Melanie Rissmann
, Joline van der Lee
, Melissa van Dortmondt
, Itziar Serna Martin
, Frank J M van Kuppeveld
, Daniel L Hurdiss
, Bart L Haagmans
, Frank Grosveld
, Berend-Jan Bosch

Erasmus University Medical Center Rotterdam

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	1111385
Number of pages	13
Journal	Frontiers in Immunology
Volume	14
DOIs	https://doi.org/10.3389/fimmu.2023.1111385
Publication status	Published - 21 Feb 2023

Bibliographical note

Funding Information:
The collaboration project is co-funded by the PPP Allowance made available by Health~Holland (Grant no. LSHM20037). This work is supported by the Netherlands Electron Microscopy Infrastructure (NEMI), project number 184.034.014 of the National Roadmap for Large-Scale Research Infrastructure of the Dutch Research Council (NWO). This work made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to DH. Acknowledgments

Publisher Copyright:
Copyright © 2023 Du, Janssens, Mykytyn, Li, Drabek, van Haperen, Chatziandreou, Rissmann, van der Lee, van Dortmondt, Martin, van Kuppeveld, Hurdiss, Haagmans, Grosveld and Bosch.

Keywords

SARS-CoV-2
antibody-mediated neutralization
avidity
heavy-chain-only antibody
neutralization escape

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10.3389/fimmu.2023.1111385Licence: CC BY

fimmu-14-1111385Final published version, 3.17 MBLicence: CC BY

Cite this

Du, W., Janssens, R., Mykytyn, A. Z., Li, W., Drabek, D., van Haperen, R., Chatziandreou, M., Rissmann, M., van der Lee, J., van Dortmondt, M., Martin, I. S., van Kuppeveld, F. J. M., Hurdiss, D. L., Haagmans, B. L., Grosveld, F., & Bosch, B.-J. (2023). Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants. Frontiers in Immunology, 14, Article 1111385. https://doi.org/10.3389/fimmu.2023.1111385

@article{bd77c1680f0148e1b185466ccb408191,

title = "Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants",

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.",

keywords = "SARS-CoV-2, antibody-mediated neutralization, avidity, heavy-chain-only antibody, neutralization escape",

author = "Wenjuan Du and Rick Janssens and Mykytyn, \{Anna Z\} and Wentao Li and Dubravka Drabek and \{van Haperen\}, Rien and Marianthi Chatziandreou and Melanie Rissmann and \{van der Lee\}, Joline and \{van Dortmondt\}, Melissa and Martin, \{Itziar Serna\} and \{van Kuppeveld\}, \{Frank J M\} and Hurdiss, \{Daniel L\} and Haagmans, \{Bart L\} and Frank Grosveld and Berend-Jan Bosch",

note = "Funding Information: The collaboration project is co-funded by the PPP Allowance made available by Health\textasciitilde{}Holland (Grant no. LSHM20037). This work is supported by the Netherlands Electron Microscopy Infrastructure (NEMI), project number 184.034.014 of the National Roadmap for Large-Scale Research Infrastructure of the Dutch Research Council (NWO). This work made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to DH. Acknowledgments Publisher Copyright: Copyright {\textcopyright} 2023 Du, Janssens, Mykytyn, Li, Drabek, van Haperen, Chatziandreou, Rissmann, van der Lee, van Dortmondt, Martin, van Kuppeveld, Hurdiss, Haagmans, Grosveld and Bosch.",

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month = feb,

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doi = "10.3389/fimmu.2023.1111385",

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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, B-J 2023, 'Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants', Frontiers in Immunology, vol. 14, 1111385. https://doi.org/10.3389/fimmu.2023.1111385

TY - JOUR

T1 - Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants

AU - Du, Wenjuan

AU - Janssens, Rick

AU - Mykytyn, Anna Z

AU - Li, Wentao

AU - Drabek, Dubravka

AU - van Haperen, Rien

AU - Chatziandreou, Marianthi

AU - Rissmann, Melanie

AU - van der Lee, Joline

AU - van Dortmondt, Melissa

AU - Martin, Itziar Serna

AU - van Kuppeveld, Frank J M

AU - Hurdiss, Daniel L

AU - Haagmans, Bart L

AU - Grosveld, Frank

AU - Bosch, Berend-Jan

N1 - Funding Information: The collaboration project is co-funded by the PPP Allowance made available by Health~Holland (Grant no. LSHM20037). This work is supported by the Netherlands Electron Microscopy Infrastructure (NEMI), project number 184.034.014 of the National Roadmap for Large-Scale Research Infrastructure of the Dutch Research Council (NWO). This work made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to DH. Acknowledgments Publisher Copyright: Copyright © 2023 Du, Janssens, Mykytyn, Li, Drabek, van Haperen, Chatziandreou, Rissmann, van der Lee, van Dortmondt, Martin, van Kuppeveld, Hurdiss, Haagmans, Grosveld and Bosch.

PY - 2023/2/21

Y1 - 2023/2/21

N2 - 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.

AB - 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.

KW - SARS-CoV-2

KW - antibody-mediated neutralization

KW - avidity

KW - heavy-chain-only antibody

KW - neutralization escape

UR - https://www.scopus.com/pages/publications/85149683321

U2 - 10.3389/fimmu.2023.1111385

DO - 10.3389/fimmu.2023.1111385

M3 - Article

C2 - 36895554

SN - 1664-3224

VL - 14

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1111385

ER -

Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants

Abstract

Bibliographical note

Keywords

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