RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

Gagne, M.; Flynn, B. J.; Honeycutt, C. C.; Flebbe, D. R.; Andrew, S. F.; Provost, S. J.; McCormick, L.; Van Ry, A.; McCarthy, E.; Todd, J.-P. M.; Bao, S.; Teng, I.-T.; Marciano, S.; Rudich, Y.; Li, C.; Pessaint, L.; Dodson, A.; Cook, A.; Lewis, M. G.; Andersen, H.; Zahradnik, J.; Nason, M. C.; Foulds, K. E.; Kwong, P. D.; Roederer, M.; Schreiber, G.; Seder, R. A.; Douek, D. C.

doi:10.1101/2023.06.09.544432

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bioRxiv · 10.1101/2023.06.09.544432

RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

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Abstract

SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

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Gagne, M., Flynn, B. J., Honeycutt, C. C., Flebbe, D. R., Andrew, S. F., Provost, S. J., McCormick, L., Van Ry, A., McCarthy, E., Todd, J.-P. M., Bao, S., Teng, I.-T., Marciano, S., Rudich, Y., Li, C., Pessaint, L., Dodson, A., Cook, A., Lewis, M. G., Andersen, H., Zahradnik, J., Nason, M. C., Foulds, K. E., Kwong, P. D., Roederer, M., Schreiber, G., Seder, R. A., Douek, D. C.. 2023-06-12. RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways. https://doi.org/10.1101/2023.06.09.544432

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