Sun Yaping, Ho Mitchell
Antibody Engineering Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Antib Ther. 2020 Nov 24;3(4):246-256. doi: 10.1093/abt/tbaa025. eCollection 2020 Dec.
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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）抗体疗法正处于临床和临床前评估阶段。截至2020年10月11日，13种靶向SARS-CoV-2刺突蛋白的人源单克隆抗体已进入临床试验，其中3种（REGN-COV2、LY3819253/LY-CoV555和VIR-7831/VIR-7832）处于3期试验。2020年11月9日，美国食品药品监督管理局发布了巴瑞替尼单抗（LY3819253/LY-CoV555）用于治疗轻至中度新型冠状病毒肺炎（COVID-19）的紧急使用授权。本综述概述了针对SARS-CoV-2的中和抗体的研发情况，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。靶向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是唯一处于临床后期开发阶段的抗体，它可以中和SARS-CoV-2和SARS-CoV，尽管它不能直接阻断病毒受体结合。迄今为止，唯一也是受体结合阻断剂的交叉中和抗体是纳米抗体VHH-72。开发纳米抗体作为吸入药物治疗COVID-19和其他呼吸道疾病的可行性是一个值得探索和测试的有吸引力的想法。一种如REGN-COV2的鸡尾酒策略，或工程化的多价和多特异性分子，结合两种或更多抗体，可能会提高疗效并防止因病毒逃逸突变体产生的耐药性。除了受体结合结构域，其他病毒抗原，如刺突蛋白的S2亚基，以及宿主细胞上的病毒附着位点，如硫酸乙酰肝素蛋白聚糖，也值得研究。
