Two human monoclonal SARS-CoV-2 antibodies that maintain neutralizing potency against the SARS-CoV-2 Omicron BA.1 and BA.2 variants.
Two human monoclonal SARS-CoV-2 antibodies that maintain neutralizing potency against the SARS-CoV-2 Omicron BA.1 and BA.2 variants.
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两种人单克隆 SARS-CoV-2 抗体，对 SARS-CoV-2 Omicron BA.1 和 BA.2 变种保持中和效力。
DOI：
10.1016/j.gendis.2022.05.027
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发表时间：
2023-05
期刊：
影响因子：
6.8
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Zheng, Qianqian;Duan, Liangwei;Jiang, Zhihua;Gu, Tingxuan;Zhang, Bojie;Li, Jiaoyang;Zhang, Yang;Zhang, Shiyu;Liang, Yinming;Wang, Hui
由严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）引起的大流行继续席卷地球仪，对人类生命和世界经济造成毁灭性后果。作为一种RNA病毒，SARS-CoV-2具有相对较高的突变率，并且正在迅速进化。因此，新的SARS-CoV-2变异株不断出现，其中5种被世界卫生组织（WHO）指定为关注变异株（VOCs），即α（B. 1.1. 7）、β（B. 1.351）、伽马（P. 1）、德尔塔（B. 1.617. 2），最近，Omicron（B. 1.1. 529）。1 2021年11月在博茨瓦纳和南非首次发现，原Omicron，BA。1，然后传播到世界的每一个角落，并迅速取代以前占主导地位的德尔塔毒株，成为世界上最流行的SARS-CoV-2流行变种。BA.据报道，1逃避大多数针对SARS-CoV-2的治疗性单克隆抗体。2一致的是，来自恢复期供体和接种个体的血清含有非常低至不可检测水平的抗BA中和抗体。1.因此，迫切需要新的治疗药物。本研究采用噬菌体展示技术，从本课题组完全免疫或加强免疫个体外周血淋巴细胞中提取RNA，构建抗体库。将SARS-CoV-2刺突糖蛋白的重组野生型（WT）受体结合结构域（RBD）用作靶蛋白以筛选噬菌体抗体库中的潜在命中。鉴定了一组单链可变片段（scFv）形式的RBD的高亲和力结合物，并将两种高亲和力候选scFv转化为两种全尺寸IgG1抗体XK01和XK02并表达为两种全尺寸IgG1抗体。XK01和XK02与WT SARS-CoV-2 RBD的结合强度很强，通过酶联免疫吸附试验（ELISA）测得的半数最大有效浓度（EC50）值分别为0.012和0.018 μ g/mL，表明两种单克隆抗体的结合亲合力均高于ACE 2（EC50 Z 0.048 μ g/mL）（图1 AeC）。为了验证这一结果并进一步评价结合亲和力，我们通过表面等离子体共振（SPR）监测了XK01和XK02与WT SARS-CoV-2 RBD（RBDWT）结合的实时缔合和解离。XK01和XK02与RBDWT紧密结合，XK01和XK02的平衡解离常数（KD）分别为93 nM和109 nM，均优于ACE 2与RBDWT的结合（KD Z 348 nM）（图1 DeF）。ELISA和SPR结果表明，XK01和XK02单克隆抗体对SARS-CoV-2具有潜在的中和作用。正如预期的，两种抗体均显示出针对用WT SARS-CoV-2 S假型化的病毒的有效中和活性，其中XK01的半数最大抑制浓度（IC 50）值为0.098 μ g/mL，XK02的半数最大抑制浓度（IC 50）值为0.072 μ g/mL（图1G，H）。1，Omicron SARS-CoV-2 RBD（RBDBA. 1)用SPR法测定了RBDBA对ACE 2受体的作用，结果表明RBDBA. 1与ACE 2有效结合。RBDBA的KD值。1与ACE 2的结合亲和力分别为245 nM（XKO1）和438 nM（XKO2）（图11，J），表明两种抗体对RBDBA的结合亲和力。1的亲和力高于ACE2受体的亲和力（KD Z 527 nM）（图1K）。值得注意的是，这一观察结果与RBDWT的观察结果非常相似。出乎意料的是，两种单克隆抗体均未显示出损失，但增加了针对BA的中和效力。1S假型病毒，XK01和XK02的IC50值分别为0.011 μ g/mL和0.024 μ g/mL（图1 L，M）。在出现后不久，和...
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to sweep the globe with devastating consequences on human lives and world economy. As an RNA virus, SARS-CoV-2 has a relatively high mutation rate and is rapidly evolving. Thus, new SARS-CoV-2 variants continued to emerge, 5 of which were designated by the World Health Organization (WHO) as variants of concern (VOCs), Alpha (B. 1.1. 7), Beta (B. 1.351), Gamma (P. 1), Delta (B. 1.617. 2), and, recently, Omicron (B. 1.1. 529). 1 First identified in Botswana and South Africa in November 2021, the original Omicron, BA. 1, then spread to every corner of the world and quickly replaced the previously dominant Delta strain to become the most prevalent SARS-CoV-2 circulating variant across the world. BA. 1 is reported to escape most therapeutic monoclonal antibodies against SARS-CoV-2. 2 Consistently, sera from convalescent donors and vaccinated individuals contain very low to undetectable levels of neutralizing antibodies against BA. 1. 3 Therefore, new therapeutic agents are urgently needed. By phage display technique, antibody libraries generated from RNAs extracted from peripheral lymphocytes of fully or booster-vaccinated individuals in our research group were constructed. The recombinant wild-type (WT) receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein was used as the target protein to screen the phage antibody library for potential hits. A panel of highaffinity binders to the RBD in single chain variable fragment (scFv) format were identified and two high-affinity candidate scFvs were converted into and expressed as two fullsize IgG1 antibodies, XK01 and XK02. XK01 and XK02 bound strongly to the WT SARS-CoV-2 RBD with half-maximal effective concentration (EC50) values of 0.012 and0.018 μg/mL, respectively, as measured by enzyme-linked immunosorbent assay (ELISA), suggesting both monoclonal antibodies have a higher binding avidity than that of ACE2 (EC50 Z 0.048 μg/mL)(Fig. 1 AeC). To verify this result and further evaluate the binding affinity, we monitored realetime association and dissociation of XK01 and XK02 binding to the WT SARS-CoV-2 RBD (RBDWT) by surface plasmon resonance (SPR). XK01 and XK02 exhibited tight binding to RBDWT with equilibrium dissociation constants (KD) of 93 nM for XK01 and of 109 nM for XK02, respectively, both of which are superior to that of ACE2 with RBDWT (KD Z 348 nM)(Fig. 1 DeF). Based on the data obtained by ELISA and SPR, both XK01 and XK02 monoclonal antibodies probably have potential neutralization efficacy against SARS-CoV-2. As expected, both antibodies showed potent neutralizing activities against virus pseudotyped with the WT SARS-CoV-2 S with half-maximal inhibitory concentration (IC50) values of 0.098 μg/mL for XK01 and 0.072 μg/mL for XK02, respectively (Fig. 1 G, H).In the case of BA. 1, the binding kinetics of the Omicron SARS-CoV-2 RBD (RBDBA. 1) to the ACE2 receptor was measured by SPR, which showed that RBDBA. 1 bound potently to ACE2. The KD values of RBDBA. 1 with ACE2 were 245 nM for XK01 and 438 nM for XK02, respectively (Fig. 1 I, J), indicating the binding affinity of both antibodies for RBDBA. 1 was higher than that of the ACE2 receptor (KD Z 527 nM)(Fig. 1 K). Notably, this observation is very similar to that is observed for RBDWT. Unexpectedly, both monoclonal antibodies showed no loss but increased potency of neutralization against BA. 1 S pseudotyped virus with IC50 values of 0.011 μg/mL for XK01 and 0.024 μg/mL for XK02, respectively (Fig. 1 L, M). Soon after the emergence and …
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