Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2.
Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2.
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DOI：
10.7150/thno.65563
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Stuart DI
中科院分区：
文献类型：
--
作者：
Huang KA;Zhou D;Tan TK;Chen C;Duyvesteyn HME;Zhao Y;Ginn HM;Qin L;Rijal P;Schimanski L;Donat R;Harding A;Gilbert-Jaramillo J;James W;Tree JA;Buttigieg K;Carroll M;Charlton S;Lien CE;Lin MY;Chen CP;Cheng SH;Chen X;Lin TY;Fry EE;Ren J;Ma C;Townsend AR;Stuart DI
背景：有效的抗受体结合域（RBD）单克隆抗体已被证明可减少病毒脱落并减少SARS-CoV-2感染患者的住院时间。然而，有效的人抗rbd单克隆抗体的结构-功能分析及其与抗体鸡尾酒配方的联系在很大程度上仍然难以捉摸。方法：先从恢复期患者中分离出一组抗rbd的中和性单克隆抗体，并在体外验证其中和效果。在这里，我们阐明了抗体的作用机制，并在表位水平上解剖抗体，从而形成一种有效的抗体鸡尾酒。结果：我们发现针对非重叠表位的代表性抗体对野生型病毒和最近出现的关注变体有效，同时由很少体细胞突变的抗体基因编码。中和作用与抑制病毒RBD与ACE2的结合以及随后的融合过程有关。通过冷冻电镜和晶体学对代表性抗体进行结构分析，发现它们具有一些具有潜在价值的独特方面，同时与先前报道的中和性单克隆抗体具有一些共同特征。例如，一个人有一个常见的VH 3-53公共可变区，但对RBD残基501的突变具有不同寻常的弹性。我们在叙利亚仓鼠模型中评估了由两种强效非竞争性抗rbd抗体组成的抗体鸡尾酒的体内功效。我们证明，鸡尾酒预防体重减轻，减少肺病毒载量和减轻肺部炎症的仓鼠在预防和治疗设置。虽然其中一种抗体的中和作用被变异B.1.351的突变所废除，但也有可能产生一种双价鸡尾酒抗体，这两种抗体都对变异B.1.1.7、B.1.351和B.1.617.2具有弹性。结论：这些发现支持了抗rbd抗体鸡尾酒作为COVID-19候选治疗方案的最新和合理设计。
Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remains largely elusive. Methods: Previously, we isolated a panel of neutralizing anti-RBD monoclonal antibodies from convalescent patients and showed their neutralization efficacy in vitro. Here, we elucidate the mechanism of action of antibodies and dissect antibodies at the epitope level, which leads to a formation of a potent antibody cocktail. Results: We found that representative antibodies which target non-overlapping epitopes are effective against wild type virus and recently emerging variants of concern, whilst being encoded by antibody genes with few somatic mutations. Neutralization is associated with the inhibition of binding of viral RBD to ACE2 and possibly of the subsequent fusion process. Structural analysis of representative antibodies, by cryo-electron microscopy and crystallography, reveals that they have some unique aspects that are of potential value while sharing some features in common with previously reported neutralizing monoclonal antibodies. For instance, one has a common VH 3-53 public variable region yet is unusually resilient to mutation at residue 501 of the RBD. We evaluate the in vivo efficacy of an antibody cocktail consisting of two potent non-competing anti-RBD antibodies in a Syrian hamster model. We demonstrate that the cocktail prevents weight loss, reduces lung viral load and attenuates pulmonary inflammation in hamsters in both prophylactic and therapeutic settings. Although neutralization of one of these antibodies is abrogated by the mutations of variant B.1.351, it is also possible to produce a bi-valent cocktail of antibodies both of which are resilient to variants B.1.1.7, B.1.351 and B.1.617.2. Conclusions: These findings support the up-to-date and rational design of an anti-RBD antibody cocktail as a therapeutic candidate against COVID-19.
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影响因子：
64.8
作者：
Plante JA;Liu Y;Liu J;Xia H;Johnson BA;Lokugamage KG;Zhang X;Muruato AE;Zou J;Fontes-Garfias CR;Mirchandani D;Scharton D;Bilello JP;Ku Z;An Z;Kalveram B;Freiberg AN;Menachery VD;Xie X;Plante KS;Weaver SC;Shi PY
通讯作者：
Shi PY
DOI：
10.1056/nejmoa1604330
发表时间：
2016-10-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
PREVAIL II Writing Group;Multi-National PREVAIL II Study Team;Davey RT Jr;Dodd L;Proschan MA;Neaton J;Neuhaus Nordwall J;Koopmeiners JS;Beigel J;Tierney J;Lane HC;Fauci AS;Massaquoi MBF;Sahr F;Malvy D
通讯作者：
Malvy D
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：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K