Structural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants

Saya Moriyama (), Yuki Anraku, Shunta Taminishi, Yu Adachi, Daisuke Kuroda, Shunsuke Kita, Yusuke Higuchi, Yuhei Kirita, Ryutaro Kotaki, Keisuke Tonouchi, Kohei Yumoto, Tateki Suzuki, Taiyou Someya, Hideo Fukuhara, Yudai Kuroda, Tsukasa Yamamoto, Taishi Onodera, Shuetsu Fukushi, Ken Maeda, Fukumi Nakamura-Uchiyama, Takao Hashiguchi, Atsushi Hoshino, Katsumi Maenaka and Yoshimasa Takahashi ()
Additional contact information
Saya Moriyama: National Institute of Infectious Diseases; Shinjuku-ku
Yuki Anraku: Hokkaido University; Sapporo
Shunta Taminishi: Kyoto Prefectural University of Medicine; Kyoto
Yu Adachi: National Institute of Infectious Diseases; Shinjuku-ku
Daisuke Kuroda: National Institute of Infectious Diseases; Shinjuku-ku
Shunsuke Kita: Hokkaido University; Sapporo
Yusuke Higuchi: Kyoto Prefectural University of Medicine; Kyoto
Yuhei Kirita: Kyoto Prefectural University of Medicine; Kyoto
Ryutaro Kotaki: National Institute of Infectious Diseases; Shinjuku-ku
Keisuke Tonouchi: National Institute of Infectious Diseases; Shinjuku-ku
Kohei Yumoto: National Institute of Infectious Diseases; Shinjuku-ku
Tateki Suzuki: Kyoto University; Kyoto
Taiyou Someya: Hokkaido University; Sapporo
Hideo Fukuhara: Hokkaido University
Yudai Kuroda: National Institute of Infectious Diseases; Shinjuku-ku
Tsukasa Yamamoto: National Institute of Infectious Diseases; Shinjuku-ku
Taishi Onodera: National Institute of Infectious Diseases; Shinjuku-ku
Shuetsu Fukushi: National Institute of Infectious Diseases; Shinjuku-ku
Ken Maeda: National Institute of Infectious Diseases; Shinjuku-ku
Fukumi Nakamura-Uchiyama: Tokyo Metropolitan Bokutoh Hospital; Sumida-ku
Takao Hashiguchi: Kyoto University; Kyoto
Atsushi Hoshino: Kyoto Prefectural University of Medicine; Kyoto
Katsumi Maenaka: Hokkaido University; Sapporo
Yoshimasa Takahashi: National Institute of Infectious Diseases; Shinjuku-ku

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract SARS-CoV-2 Omicron subvariants have evolved to evade receptor-binding site (RBS) antibodies that exist in diverse individuals as public antibody clones. We rationally selected RBS antibodies resilient to mutations in emerging Omicron subvariants. Y489 was identified as a site of virus vulnerability and a common footprint of broadly neutralizing antibodies against the subvariants. Multiple Y489-binding antibodies were encoded by public clonotypes and additionally recognized F486, potentially accounting for the emergence of Omicron subvariants harboring the F486V mutation. However, a subclass of antibodies broadly neutralized BA.4/BA.5 variants via hydrophobic binding sites of rare clonotypes along with high mutation-resilience under escape mutation screening. A computationally designed antibody based on one of the Y489-binding antibodies, NIV-10/FD03, was able to bind XBB with any 486 mutation and neutralized XBB.1.5. The structural basis for the mutation-resilience of this Y489-binding antibody group may provide important insights into the design of therapeutics resistant to viral escape.

Date: 2023
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DOI: 10.1038/s41467-023-39890-8

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