The molecular reach of antibodies crucially underpins their viral neutralisation capacity

Anna Huhn, Daniel Nissley, Daniel B. Wilson, Mikhail A. Kutuzov, Robert Donat, Tiong Kit Tan, Ying Zhang, Michael I. Barton, Chang Liu, Wanwisa Dejnirattisai, Piyada Supasa, Juthathip Mongkolsapaya, Alain Townsend, William James, Gavin Screaton, P. Anton van der Merwe, Charlotte M. Deane (), Samuel A. Isaacson () and Omer Dushek ()
Additional contact information
Anna Huhn: University of Oxford
Daniel Nissley: University of Oxford
Daniel B. Wilson: University of Oxford
Mikhail A. Kutuzov: University of Oxford
Robert Donat: University of Oxford
Tiong Kit Tan: University of Oxford
Ying Zhang: Boston University
Michael I. Barton: University of Oxford
Chang Liu: University of Oxford
Wanwisa Dejnirattisai: University of Oxford
Piyada Supasa: University of Oxford
Juthathip Mongkolsapaya: University of Oxford
Alain Townsend: University of Oxford
William James: University of Oxford
Gavin Screaton: University of Oxford
P. Anton van der Merwe: University of Oxford
Charlotte M. Deane: University of Oxford
Samuel A. Isaacson: Boston University
Omer Dushek: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. The model provides the standard monovalent affinity/kinetics and new bivalent parameters, including the molecular reach: the maximum antigen separation enabling bivalent binding. We find large variations in these parameters across antibodies, including reach variations (22–46 nm) that exceed the physical antibody size (~15 nm). By using antigens of different physical sizes, we show that these large molecular reaches are the result of both the antibody and antigen sizes. Although viral neutralisation correlates poorly with affinity, a striking correlation is observed with molecular reach. Indeed, the molecular reach explains differences in neutralisation for antibodies binding with the same affinity to the same RBD-epitope. Thus, antibodies within an isotype class binding the same antigen can display differences in molecular reach, substantially modulating their binding and functional properties.

Date: 2025
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DOI: 10.1038/s41467-024-54916-5

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