Immunity
. 2021 Aug 24;S1074-7613(21)00359-9.
doi: 10.1016/j.immuni.2021.08.025. Online ahead of print.
A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site
Taishi Onodera 1 , Shunsuke Kita 2 , Yu Adachi 1 , Saya Moriyama 1 , Akihiko Sato 3 , Takao Nomura 2 , Shuhei Sakakibara 4 , Takeshi Inoue 5 , Takashi Tadokoro 2 , Yuki Anraku 2 , Kohei Yumoto 2 , Cong Tian 2 , Hideo Fukuhara 6 , Michihito Sasaki 7 , Yasuko Orba 7 , Nozomi Shiwa 8 , Naoko Iwata 8 , Noriyo Nagata 8 , Tateki Suzuki 9 , Jiei Sasaki 9 , Tsuyoshi Sekizuka 10 , Keisuke Tonouchi 11 , Lin Sun 1 , Shuetsu Fukushi 12 , Hiroyuki Satofuka 13 , Yasuhiro Kazuki 14 , Mitsuo Oshimura 15 , Tomohiro Kurosaki 5 , Makoto Kuroda 10 , Yoshiharu Matsuura 16 , Tadaki Suzuki 8 , Hirofumi Sawa 7 , Takao Hashiguchi 17 , Katsumi Maenaka 18 , Yoshimasa Takahashi 19
Affiliations
- PMID: 34508662
- DOI: 10.1016/j.immuni.2021.08.025
Abstract
Potent 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 angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (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 broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.
Keywords: IgG3; SARS-CoV; SARS-CoV-2; X-ray crystallography; neutralizing antibody; receptor-binding domain; variants of concern.