The Development of a Novel Nanobody Therapeutic for SARS-CoV-2

Ye, G.; Gallant, J.; Massey, C.; Shi, K.; Tai, W.; Zheng, J.; Odle, A.; Vickers, M.; Shang, J.; Wan, Y.; Drelich, A.; Kempaiah, K.; Tat, V.; Perlman, S.; Du, L.; Tseng, C.-T.; Aihara, H.; LeBeau, A.; Li, F.

doi:10.1101/2020.11.17.386532

bioRxiv · 10.1101/2020.11.17.386532

The Development of a Novel Nanobody Therapeutic for SARS-CoV-2

Ye, G.·Gallant, J.·Massey, C.·Shi, K.·Tai, W.·Zheng, J.·Odle, A.·Vickers, M.·Shang, J.·Wan, Y.·Drelich, A.·Kempaiah, K.·Tat, V.·Perlman, S.·Du, L.·Tseng, C.-T.·Aihara, H.·LeBeau, A.·Li, F.

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Abstract

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a novel series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking out viral receptor ACE2. The lead drug possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD with a Kd of 15.7picomolar ([~]3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND50 of 0.16microgram/milliliter ([~]6000 times more potently than ACE2 did). Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented a greater than 10-day in vivo half-life efficacy and high tissue bioavailability. Nanosota-1C-Fc is a potentially effective and realistic solution to the COVID-19 pandemic. Impact statementPotent and low-cost Nanosota-1 drugs block SARS-CoV-2 infections both in vitro and in vivo and act both preventively and therapeutically.

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Ye, G., Gallant, J., Massey, C., Shi, K., Tai, W., Zheng, J., Odle, A., Vickers, M., Shang, J., Wan, Y., Drelich, A., Kempaiah, K., Tat, V., Perlman, S., Du, L., Tseng, C.-T., Aihara, H., LeBeau, A., Li, F.. 2020-11-17. The Development of a Novel Nanobody Therapeutic for SARS-CoV-2. https://doi.org/10.1101/2020.11.17.386532

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