Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors.
Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors.
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DOI：
10.1038/s41589-022-01140-1
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发表时间：
2022-11
影响因子：
14.8
通讯作者：
Kim, Peter S.
中科院分区：
文献类型：
--
作者：
Weidenbacher, Payton A. -B.;Waltari, Eric;de los Rios Kobara, Izumi;Bell, Benjamin N.;Morris, Mary Kate;Cheng, Ya-Chen;Hanson, Carl;Pak, John E.;Kim, Peter S.
Omicron及其亚变体已使大多数经授权的基于单克隆抗体的严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）治疗无效，突出了对能够克服SARS-CoV-2进化的生物制剂的需求。这些大多无效的抗体靶向可变表位。在这里，我们描述了广谱SARS-CoV-2抑制剂，通过将SARS-CoV-2受体，血管紧张素转换酶2（ACE 2），与已知的非中和抗体结合，靶向病毒刺突蛋白中高度保守的表位。这些抑制剂被称为受体阻断保守非中和抗体（ReconnAbs），有效地中和所有SARS-CoV-2相关变体（VOC），包括Omicron。当连接结合和抑制性ReconnAb组分的接头被切断时，中和效力丧失。此外，通过将ACE 2连接至靶向本文定义的两个非重叠保守表位的双特异性抗体制备的双功能ReconnAb显示出针对所有VOC（包括Omicron和BA）的亚纳摩尔中和活性。鉴于其保守的靶标和模块化的性质，ReconnAbs具有作为广谱治疗剂对抗SARS-CoV-2和其他新出现的大流行性疾病的潜力。通过与SARS-CoV-2受体ACE 2偶联，SARS-CoV-2刺突导向的非中和抗体被转化为广谱抑制剂，从而产生靶向所有检测的SARS-CoV-2变异体的融合蛋白。
Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases. SARS-CoV-2 spike-directed, non-neutralizing antibodies were converted into broad-spectrum inhibitors by conjugation to the SARS-CoV-2 receptor, ACE2, resulting in fusion proteins that target all SARS-CoV-2 variants of concern tested.
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影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
6.8
作者：
Gai, S. Annie;Wittrup, K. Dane
通讯作者：
Wittrup, K. Dane
DOI：
10.1038/s41577-020-00471-1
发表时间：
2020-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Khoury DS;Wheatley AK;Ramuta MD;Reynaldi A;Cromer D;Subbarao K;O'Connor DH;Kent SJ;Davenport MP
通讯作者：
Davenport MP
DOI：
10.1073/pnas.2016093117
发表时间：
2020-11-10
影响因子：
11.1
作者：
Glasgow A;Glasgow J;Limonta D;Solomon P;Lui I;Zhang Y;Nix MA;Rettko NJ;Zha S;Yamin R;Kao K;Rosenberg OS;Ravetch JV;Wiita AP;Leung KK;Lim SA;Zhou XX;Hobman TC;Kortemme T;Wells JA
通讯作者：
Wells JA
影响因子：
5.3
作者：
Lim SA;Gramespacher JA;Pance K;Rettko NJ;Solomon P;Jin J;Lui I;Elledge SK;Liu J;Bracken CJ;Simmons G;Zhou XX;Leung KK;Wells JA
通讯作者：
Wells JA