A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site

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

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.

Highlights

The coronavirus disease 2019 (COVID-19) pandemic, triggered by the novel virus SARS-CoV-2 (CoV2), has caused more than 198 million infections and more than 4.2 million deaths worldwide as of August 3, 2021
NT-108 and NT-193 potently neutralize SARS-CoV-2 despite atypical VH usage Here, we used TC-mAb mice, which stably maintain an engineered chromosome containing the loci of the entire human Ig heavy and kappa chains in a murine Ig knockout background (Satofuka et al, 2020)
After sequential immunization with spike/receptor-binding domain (RBD) antigens from CoV2, CoV1, and MERS (Middle East respiratory syndrome)-CoV, B cells binding to the CoV2 RBD were sorted for single-cell culture as previously described (Figure 1A) (Adachi et al, 2019)

Summary

Introduction

The coronavirus disease 2019 (COVID-19) pandemic, triggered by the novel virus SARS-CoV-2 (CoV2), has caused more than 198 million infections and more than 4.2 million deaths worldwide as of August 3, 2021 (https://www.who.int/). Major epitopes for CoV2-neutralizing antibodies reside in the receptor-binding domain (RBD) of spike (S) protein (Andreano et al, 2021; Piccoli et al, 2020). Many RBS antibodies are vulnerable to CoV2 escape mutations under monotherapeutic usage (Baum et al, 2020b; Li et al, 2020; Weisblum et al, 2020) because of the antigenic drift of the RBS epitopes (Piccoli et al, 2020; Starr et al, 2021). Similar to antibodies to other mutating RNA viruses, potent neutralizing activity and breadth to antigenically divergent viruses are incompatible characters in most CoV2-neutralizing antibodies

Methods

Results

Discussion

Conclusion