Emerging antibody-based therapeutics against SARS-CoV-2 during the global pandemic.
Emerging antibody-based therapeutics against SARS-CoV-2 during the global pandemic.
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DOI：
10.1093/abt/tbaa025
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发表时间：
2020-12
影响因子：
--
通讯作者：
Ho M
中科院分区：
文献类型：
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作者：
Sun Y;Ho M
SARS-CoV-2抗体疗法正在临床和临床前阶段进行评估。截至2020年10月11日，已有13种靶向SARS-CoV-2刺突蛋白的人源单克隆抗体进入临床试验，其中3种（REGN-COV 2、LY 3819253/LY-CoV 555和VIR-7831/VIR-7832）处于3期。于2020年11月9日，美国食品药品监督管理局（FDA）发出bamlanivimab（LY 3819253/LY-CoV 555）用于治疗轻至中度COVID-19的紧急使用授权。本文综述了抗SARS-CoV-2中和抗体的研究进展，重点讨论了各种抗体发现策略（动物免疫、噬菌体展示和B细胞克隆），描述了结合表位并比较了中和活性。针对SARS-CoV-2和SARS-CoV刺突蛋白的广泛中和抗体可能有助于治疗COVID-19和未来的感染。基于S309的VIR-7831/7832是唯一处于后期临床开发阶段的抗体，尽管其不直接阻断病毒受体结合，但可中和SARS-CoV-2和SARS-CoV。到目前为止，唯一的交叉中和抗体也是受体结合阻断剂是纳米抗体VHH-72。开发纳米抗体作为治疗COVID-19和其他呼吸系统疾病的吸入药物的可行性是一个值得探索和测试的有吸引力的想法。鸡尾酒策略，如REGN-COV 2，或工程化的多价和多特异性分子，组合两种或更多种抗体可能会提高疗效，并防止由于病毒逃逸突变体引起的耐药性。除了受体结合结构域之外，其他病毒抗原如刺突蛋白的S2亚基和病毒附着位点如宿主细胞上的硫酸乙酰肝素蛋白聚糖也值得研究。
SARS-CoV-2 antibody therapeutics are being evaluated in clinical and preclinical stages. As of 11 October 2020, 13 human monoclonal antibodies targeting the SARS-CoV-2 spike protein have entered clinical trials with three (REGN-COV2, LY3819253/LY-CoV555, and VIR-7831/VIR-7832) in phase 3. On 9 November 2020, the US Food and Drug Administration issued an emergency use authorization for bamlanivimab (LY3819253/LY-CoV555) for the treatment of mild-to-moderate COVID-19. This review outlines the development of neutralizing antibodies against SARS-CoV-2, with a focus on discussing various antibody discovery strategies (animal immunization, phage display and B cell cloning), describing binding epitopes and comparing neutralizing activities. Broad-neutralizing antibodies targeting the spike proteins of SARS-CoV-2 and SARS-CoV might be helpful for treating COVID-19 and future infections. VIR-7831/7832 based on S309 is the only antibody in late clinical development, which can neutralize both SARS-CoV-2 and SARS-CoV although it does not directly block virus receptor binding. Thus far, the only cross-neutralizing antibody that is also a receptor binding blocker is nanobody VHH-72. The feasibility of developing nanobodies as inhaled drugs for treating COVID-19 and other respiratory diseases is an attractive idea that is worth exploring and testing. A cocktail strategy such as REGN-COV2, or engineered multivalent and multispecific molecules, combining two or more antibodies might improve the efficacy and protect against resistance due to virus escape mutants. Besides the receptor-binding domain, other viral antigens such as the S2 subunit of the spike protein and the viral attachment sites such as heparan sulfate proteoglycans that are on the host cells are worth investigating.