A SARS-CoV-2 Antibody Broadly Neutralizes SARS-related Coronaviruses and Variants by Coordinated Recognition of a Virus Vulnerable Site

Onodera, Taishi; Kita, Shunsuke; Adachi, Yu; Moriyama, Saya; Sato, Akihiko; Nomura, Takao; Sakakibara, Shuhei; Inoue, Takeshi; Tadokoro, Takashi; Anraku, Yuki; Yumoto, Kohei; Tian, Cong; Fukuhara, Hideo; Sasaki, Michihito; Orba, Yasuko; Shiwa, Nozomi; Iwata, Naoko; Nagata, Noriyo; Suzuki, Tateki; Sasaki, Jiei; Sekizuka, Tsuyoshi; Tonouchi, Keisuke; Sun, Lin; Fukushi, Shuetsu; Satofuka, Hiroyuki; Kazuki, Yasuhiro; Oshimura, Mitsuo; Kurosaki, Tomohiro; Kuroda, Makoto; Matsuura, Yoshiharu; Suzuki, Tadaki; Sawa, Hirofumi; Hashiguchi, Takao; Maenaka, Katsumi; Takahashi, Yoshimasa

Potently neutralizing SARS-CoV-2 antibodies often target the spike protein receptor binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the ACE2 receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by IgG3 class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broadly neutralizing activity may inform the design of broad spectrum of therapeutics and vaccines.