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

Ye, Gang; Gallant, Joseph P.; Massey, Christopher; Shi, Ke; Tai, Wanbo; Zheng, Jian; Odle, Abby E.; Vickers, Molly A.; Shang, Jian; Wan, Yushun; Drelich, Aleksandra; Kempaiah, Kempaiah R.; Tat, Vivian; Perlman, Stanley; Du, Lanying; Tseng, Chien-Te; Aihara, Hideki; LeBeau, Aaron M.; Li, Fang

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 K(d) of 15.7picomolar (~3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND(50) 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.