Dissociation kinetics and avidity gate SARS-CoV-2 neutralization by HR2 stem helix antibodies
- 1Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
Abstract
SARS-CoV-2 evolution has reduced the efficacy of clinical monoclonal antibodies, underscoring the need for therapeutics targeting conserved viral regions. The Spike (S) heptad repeat 2 (HR2) stem helix is highly conserved across SARS-CoV-2 variants and related betacoronaviruses. Although antibodies to this region can neutralize infection, their natural occurrence and evolution remain poorly understood. We previously identified human neutralizing antibodies to a conserved peptide within this region (HR2 coldspot). Here, we show that plasma IgG reactivity to this region remains rare, even after repeated antigen exposure. Longitudinal analysis over 30 months revealed continued somatic hypermutation of HR2-specific antibodies, yet none surpassed the potency or breadth of hr2.016, which emerged shortly after primary infection. Crystal structures of four HR2 stem helix antibodies revealed convergent recognition across distinct antibody lineages. Comparison of hr2.016 with its non-neutralizing clonal relative hr2.086 showed that structural convergence masks distinct binding kinetics. Surface plasmon resonance and molecular dynamics simulations revealed a more stable interaction network for hr2.016, with slower dissociation and prolonged S residence time. Neutralization required the IgG format, supporting an avidity-driven mechanism. Together, these findings define kinetic and avidity constraints governing neutralization at the HR2 stem helix and position hr2.016 as a resilient therapeutic candidate.
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BibTeX
@misc{crivelli2026dissociation,
title = {{Dissociation kinetics and avidity gate SARS-CoV-2 neutralization by HR2 stem helix antibodies}},
author = {V. Crivelli and C. Guerra and M. E. Abernathy and J. Sgrignani and G. Zoppi and M. L. Greeson and A. Sanga and P. Locatelli and J. Cantergiani and B. Cena and T. Cervantes Rincon and Y. E. Lee and M. Eso and D. Jarrossay and M. Biggiogero and V. Calvaruso and A. Franzetti Pellanda and C. Garzoni and E. Tamagnini and S. Lestani and L. Varani and S. Sommer and D. Fernandez and G. Barba Spaeth and E. G. Niejadlik and S. Bournazos and D. F. Robbiani and C. O. Barnes and A. Cavalli},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.17.745160},
url = {https://www.biorxiv.org/content/10.64898/2026.08.17.745160v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Dissociation kinetics and avidity gate SARS-CoV-2 neutralization by HR2 stem helix antibodies
AU - V. Crivelli
AU - C. Guerra
AU - M. E. Abernathy
AU - J. Sgrignani
AU - G. Zoppi
AU - M. L. Greeson
AU - A. Sanga
AU - P. Locatelli
AU - J. Cantergiani
AU - B. Cena
AU - T. Cervantes Rincon
AU - Y. E. Lee
AU - M. Eso
AU - D. Jarrossay
AU - M. Biggiogero
AU - V. Calvaruso
AU - A. Franzetti Pellanda
AU - C. Garzoni
AU - E. Tamagnini
AU - S. Lestani
AU - L. Varani
AU - S. Sommer
AU - D. Fernandez
AU - G. Barba Spaeth
AU - E. G. Niejadlik
AU - S. Bournazos
AU - D. F. Robbiani
AU - C. O. Barnes
AU - A. Cavalli
PY - 2026
DA - 2026/08/17
PB - bioRxiv
DO - 10.64898/2026.08.17.745160
UR - https://www.biorxiv.org/content/10.64898/2026.08.17.745160v2
AB - SARS-CoV-2 evolution has reduced the efficacy of clinical monoclonal antibodies, underscoring the need for therapeutics targeting conserved viral regions. The Spike (S) heptad repeat 2 (HR2) stem helix is highly conserved across SARS-CoV-2 variants and related betacoronaviruses. Although antibodies to this region can neutralize infection, their natural occurrence and evolution remain poorly understood. We previously identified human neutralizing antibodies to a conserved peptide within this region (HR2 coldspot). Here, we show that plasma IgG reactivity to this region remains rare, even after repeated antigen exposure. Longitudinal analysis over 30 months revealed continued somatic hypermutation of HR2-specific antibodies, yet none surpassed the potency or breadth of hr2.016, which emerged shortly after primary infection. Crystal structures of four HR2 stem helix antibodies revealed convergent recognition across distinct antibody lineages. Comparison of hr2.016 with its non-neutralizing clonal relative hr2.086 showed that structural convergence masks distinct binding kinetics. Surface plasmon resonance and molecular dynamics simulations revealed a more stable interaction network for hr2.016, with slower dissociation and prolonged S residence time. Neutralization required the IgG format, supporting an avidity-driven mechanism. Together, these findings define kinetic and avidity constraints governing neutralization at the HR2 stem helix and position hr2.016 as a resilient therapeutic candidate.
ER -