Multivalent Anti-ACE2 Nanobodies Confer Broad Pan-Sarbecovirus Protection
- 1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065
Abstract
The continual emergence of SARS-CoV-2 variants that rapidly evade conventional spike-directed neutralizing antibodies, together with the ongoing risk of cross-species spillover and new sarbecovirus outbreaks, underscores the need to develop broadly acting, escape-resistant therapeutic agents. Here, we optimized a nanobody discovery pipeline incorporating competition-based yeast surface display assays to isolate single-chain variable heavy chain-only antibody domains (VHHs or nanobodies) that bind human ACE2 and inhibit SARS-CoV-2 entry. Dimeric VHHs, as well as bivalent and tetravalent Fc-fusion proteins exhibited markedly increased antiviral activity, blocking a broad panel of SARS-CoV-2 variants and diverse sarbecoviruses at low-nanomolar to picomolar concentrations. These agents did not affect ACE2 enzymatic function or cell surface expression. The VHH-Fc fusion proteins had favorable pharmacokinetics and conferred prophylactic protection in mouse models of both SARS-CoV-2 and SARS-CoV infection, showcasing their potential as broadly acting receptor-targeted biologics against pandemic-threat viruses.
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BibTeX
@misc{bakasis2026multivalent,
title = {{Multivalent Anti-ACE2 Nanobodies Confer Broad Pan-Sarbecovirus Protection}},
author = {A. D. Bakasis and R. Patejak and P. C. Fridy and J. Jenkins and M. Aldis and V. A. Baharani and L. Sriram and K. R. Molloy and B. T. Chait and M. P. Rout and F. R. Cross and P. D. Bieniasz and T. Hatziioannou},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748598},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748598v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multivalent Anti-ACE2 Nanobodies Confer Broad Pan-Sarbecovirus Protection
AU - A. D. Bakasis
AU - R. Patejak
AU - P. C. Fridy
AU - J. Jenkins
AU - M. Aldis
AU - V. A. Baharani
AU - L. Sriram
AU - K. R. Molloy
AU - B. T. Chait
AU - M. P. Rout
AU - F. R. Cross
AU - P. D. Bieniasz
AU - T. Hatziioannou
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748598
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748598v1
AB - The continual emergence of SARS-CoV-2 variants that rapidly evade conventional spike-directed neutralizing antibodies, together with the ongoing risk of cross-species spillover and new sarbecovirus outbreaks, underscores the need to develop broadly acting, escape-resistant therapeutic agents. Here, we optimized a nanobody discovery pipeline incorporating competition-based yeast surface display assays to isolate single-chain variable heavy chain-only antibody domains (VHHs or nanobodies) that bind human ACE2 and inhibit SARS-CoV-2 entry. Dimeric VHHs, as well as bivalent and tetravalent Fc-fusion proteins exhibited markedly increased antiviral activity, blocking a broad panel of SARS-CoV-2 variants and diverse sarbecoviruses at low-nanomolar to picomolar concentrations. These agents did not affect ACE2 enzymatic function or cell surface expression. The VHH-Fc fusion proteins had favorable pharmacokinetics and conferred prophylactic protection in mouse models of both SARS-CoV-2 and SARS-CoV infection, showcasing their potential as broadly acting receptor-targeted biologics against pandemic-threat viruses.
ER -