Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.
Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.
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DOI：
10.1038/s41421-022-00463-6
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发表时间：
2022-10-07
期刊：
影响因子：
33.5
通讯作者：
Huang, Jinghe
中科院分区：
文献类型：
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作者：
Wang, Yingdan;Zhang, Xiang;Ma, Yunping;Wang, Yanqun;Zhan, Wuqiang;Zheng, Qinwen;Zhang, Meng;Ji, Ping;Liu, Mei;Liu, Qianying;Sun, Tingting;Zhu, Tongyu;Wen, Yumei;Sun, Lei;Zhao, Jincun;Wu, Fan;Chen, Zhenguo;Huang, Jinghe
高度突变和可传播的Omicron（BA.1）及其更具传染性的谱系BA.2引起了人们的严重关注，因为它们对当前COVID-19疫苗的敏感性降低，并且逃避大多数抗SARS-CoV-2中和抗体（NAb）。在这项研究中，我们探索了通过构建基于非Omicron NAb的双特异性抗体来对抗Omicron和BA.2的可能性。我们用非Omicron NAb工程化了10种IgG样双特异性抗体，命名为GW 01、16 L9、4L 12和REGN 10987，方法是通过接头融合两种抗体的单链可变片段（scFvs），然后将它们连接到IgG 1的Fc区。令人惊讶的是，10种双特异性抗体中有8种显示出对Omicron受体结合结构域（RBD）的高结合亲和力，并显示出对假型SARS-CoV-2相关变体（VOC）（包括Omicron和BA.2）的极端广度和效力，50%抑制浓度的几何平均值（GM IC 50）值范围为4.5 ng/mL至103.94 ng/mL，以及正宗的BA.1.1。6株含GW 01的双特异性抗体不仅能中和Omicron和BA.2，而且能中和SARS-CoV和SARS-related coronaviruses（SARS-CoVs）RS3367和WIV 1等肉瘤病毒，其GM IC 50为11.6 ~ 103.9 ng/mL。对Omicron和BA.2的42个刺突（S）变体单突变体的作图分析阐明，这些双特异性抗体容纳S371 L/F突变，其对大多数非Omicron NAb具有抗性。代表性双特异性抗体GW 01 - 16 L9（FD 01）以其天然全长IgG形式与Omicron S三聚体复合的冷冻电子显微镜（cryo-EM）结构研究显示了5种不同的三聚体和一种新的三聚体二聚体构象。16 L9 scFv结合受体结合基序（RBM），而GW 01 scFv结合RBM外部的表位。双特异性抗体的两个scFv协同地诱导RBD-向下构象为3RBD-向上构象，提高IgG与Omicron RBD之间的亲和力，诱导三聚体二聚体的形成，并抑制RBD与ACE 2的结合。三聚体二聚体构象可能诱导病毒粒子聚集并有助于FD 01的中和能力。这些新的双特异性抗体是治疗和预防Omicron、BA.2、VOC和其他肉瘤病毒感染的强有力的候选物。基于非Omicron NAb的工程双特异性抗体可以将大多数NAb变成强大的武器库，以帮助对抗大流行。
The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC50) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC50 ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic.
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影响因子：
16.6
作者：
Kim C;Ryu DK;Lee J;Kim YI;Seo JM;Kim YG;Jeong JH;Kim M;Kim JI;Kim P;Bae JS;Shim EY;Lee MS;Kim MS;Noh H;Park GS;Park JS;Son D;An Y;Lee JN;Kwon KS;Lee JY;Lee H;Yang JS;Kim KC;Kim SS;Woo HM;Kim JW;Park MS;Yu KM;Kim SM;Kim EH;Park SJ;Jeong ST;Yu CH;Song Y;Gu SH;Oh H;Koo BS;Hong JJ;Ryu CM;Park WB;Oh MD;Choi YK;Lee SY
通讯作者：
Lee SY
影响因子：
64.5
作者：
Dejnirattisai W;Zhou D;Ginn HM;Duyvesteyn HME;Supasa P;Case JB;Zhao Y;Walter TS;Mentzer AJ;Liu C;Wang B;Paesen GC;Slon-Campos J;López-Camacho C;Kafai NM;Bailey AL;Chen RE;Ying B;Thompson C;Bolton J;Fyfe A;Gupta S;Tan TK;Gilbert-Jaramillo J;James W;Knight M;Carroll MW;Skelly D;Dold C;Peng Y;Levin R;Dong T;Pollard AJ;Knight JC;Klenerman P;Temperton N;Hall DR;Williams MA;Paterson NG;Bertram FKR;Siebert CA;Clare DK;Howe A;Radecke J;Song Y;Townsend AR;Huang KA;Fry EE;Mongkolsapaya J;Diamond MS;Ren J;Stuart DI;Screaton GR
通讯作者：
Screaton GR
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.
影响因子：
17.1
作者：
Jones BE;Brown-Augsburger PL;Corbett KS;Westendorf K;Davies J;Cujec TP;Wiethoff CM;Blackbourne JL;Heinz BA;Foster D;Higgs RE;Balasubramaniam D;Wang L;Zhang Y;Yang ES;Bidshahri R;Kraft L;Hwang Y;Žentelis S;Jepson KR;Goya R;Smith MA;Collins DW;Hinshaw SJ;Tycho SA;Pellacani D;Xiang P;Muthuraman K;Sobhanifar S;Piper MH;Triana FJ;Hendle J;Pustilnik A;Adams AC;Berens SJ;Baric RS;Martinez DR;Cross RW;Geisbert TW;Borisevich V;Abiona O;Belli HM;de Vries M;Mohamed A;Dittmann M;Samanovic MI;Mulligan MJ;Goldsmith JA;Hsieh CL;Johnson NV;Wrapp D;McLellan JS;Barnhart BC;Graham BS;Mascola JR;Hansen CL;Falconer E
通讯作者：
Falconer E
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD