Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Case, J. B.; Chen, R. E.; Cao, L.; Ying, B.; Winkler, E. S.; Goreshnik, I.; Shrihari, S.; Kafai, N. M.; Bailey, A. L.; Xie, X.; Shi, P.-Y.; Ravichandran, R.; Carter, L.; Stewart, L.; Baker, D.; Diamond, M. S.

doi:10.1101/2021.03.01.433110

bioRxiv · 10.1101/2021.03.01.433110

Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Case, J. B.·Chen, R. E.·Cao, L.·Ying, B.·Winkler, E. S.·Goreshnik, I.·Shrihari, S.·Kafai, N. M.·Bailey, A. L.·Xie, X.·Shi, P.-Y.·Ravichandran, R.·Carter, L.·Stewart, L.·Baker, D.·Diamond, M. S.

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Abstract

Despite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to rise. Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 receptor binding domain. Here, we investigated the capacity of modified versions of one lead binder, LCB1, to protect against SARS-CoV-2-mediated lung disease in human ACE2-expressing transgenic mice. Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung even when given as many as five days before or two days after virus inoculation. Importantly, LCB1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support development of LCB1v1.3 for prevention or treatment of SARS-CoV-2 infection.

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Case, J. B., Chen, R. E., Cao, L., Ying, B., Winkler, E. S., Goreshnik, I., Shrihari, S., Kafai, N. M., Bailey, A. L., Xie, X., Shi, P.-Y., Ravichandran, R., Carter, L., Stewart, L., Baker, D., Diamond, M. S.. 2021-03-01. Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice. https://doi.org/10.1101/2021.03.01.433110

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