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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
20 Downloads (Pure)


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 languageEnglish
Article number1111385
JournalFrontiers in Immunology
Publication statusPublished - 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.


Dive into the research topics of 'Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants'. Together they form a unique fingerprint.

Cite this