Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection.
Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection.
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DOI：
10.1073/pnas.2010197117
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发表时间：
2020-11-24
影响因子：
11.1
通讯作者：
Dimitrov DS
中科院分区：
文献类型：
--
作者：
Li W;Chen C;Drelich A;Martinez DR;Gralinski LE;Sun Z;Schäfer A;Kulkarni SS;Liu X;Leist SR;Zhelev DV;Zhang L;Kim YJ;Peterson EC;Conard A;Mellors JW;Tseng CK;Falzarano D;Baric RS;Dimitrov DS
COVID-19急需有效的治疗方法。我们迅速（在一周内）从噬菌体展示的文库中鉴定出一种完全人类单克隆种系样抗体（ab1），当在病毒攻毒前给药时，该抗体能有效抑制小鼠适应ACE2的SARS-CoV-2在野生型BALB/c小鼠中的复制，在表达人类ACE2的转基因小鼠中的本地病毒以及在仓鼠中的复制。在仓鼠感染病毒后给药也有效，尽管效果低于预防性使用。Ab1具有高度特异性，不与人细胞膜相关蛋白结合。它还表现出良好的显影性，包括完全不聚集。Ab1具有单独或与其他药物联合预防和治疗COVID-19的潜力。目前迫切需要有效的治疗方法来应对SARS-CoV-2/COVID-19大流行。我们通过筛选SARS-CoV-2刺突(S)糖蛋白的受体结合域（RBD），从大型噬菌体展示的Fab、scFv和VH文库中鉴定出全人源单克隆抗体（mab）。从一个文库中选择一个高亲和力的Fab并转化为全尺寸抗体IgG1 ab1，该抗体与人ACE2竞争与RBD结合。通过两种不同的组织培养测定，它能有效中和具有复制能力的SARS-CoV-2，但不能中和SARS-CoV，以及在BALB/c小鼠中中和具有复制能力的小鼠适应ace2的SARS-CoV-2，在表达hace2的转基因小鼠中中和天然病毒，最低试验剂量为2 mg/kg时显示出活性。IgG1 ab1在SARS-CoV-2感染仓鼠模型中也显示出较高的预防和治疗效果。中和的机制是通过与ACE2竞争，但可能涉及抗体依赖性细胞毒性（ADCC），因为IgG1 ab1在体外具有ADCC活性。ab1序列的体细胞突变数量相对较少，这表明ab1样抗体可以在自然感染SARS-CoV-2期间或通过基于rbd的疫苗快速引发。IgG1 ab1没有聚集，没有表现出其他可发育性缺陷，也没有与5300种人类膜相关蛋白中的任何一种结合。这些结果表明，IgG1 ab1具有治疗和预防SARS-CoV-2感染的潜力。有效单克隆抗体的快速鉴定（在获得抗原后6天内进行筛选）显示了大型抗体库在应对新兴微生物对公共卫生威胁方面的价值。
Effective therapies are urgently needed for COVID-19. We rapidly (within a week) identified a fully human monoclonal germline-like antibody (ab1) from phage-displayed libraries that potently inhibited mouse ACE2-adapted SARS-CoV-2 replication in wild-type BALB/c mice and native virus in transgenic mice expressing human ACE2 as well as in hamsters when administered before virus challenge. It was also effective when administered after virus infection of hamsters, although at lower efficacy than when used prophylactically. Ab1 was highly specific and did not bind to human cell membrane-associated proteins. It also exhibited good developability properties including complete lack of aggregation. Ab1 has potential for prophylaxis and therapy of COVID-19 alone or in combination with other agents. Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.
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