Development of neutralizing nanobodies against SARS-CoV-2

在2020财年，何博士评估了针对SARS-CoV-2的抗体疗法的发展现状和挑战，并撰写了一篇综述/展望文章[Ho抗体疗法2020；PMID：32566896]。SARS-CoV-2通过其尖峰蛋白(S)与血管紧张素转换酶2(ACE2)结合而进入人类细胞。因此，S蛋白的受体结合区是中和抗体的主要靶点。筛选针对SARS-CoV-2和SARS-CoV的广谱中和抗体是有吸引力的，不仅可能用于治疗新冠肺炎，也可能用于治疗未来与SARS相关的CoV感染。据报道，广谱中和抗体针对的是S1亚单位RBD中的保守区。病毒膜融合所需的S2亚基可能是另一个靶点。将识别与人类细胞相互作用的病毒表面不同部分的两种(或更多)抗体结合在一起的鸡尾酒策略可能是最有效的。在2020财年，我们在Ho实验室使用噬菌体展示技术的试点屏幕已经识别出一组骆驼纳米体，它们可能识别RBD的不同构象。一些可能与RBD的“开放”构象结合，这可能阻止与人细胞上ACE2的相互作用，而另一些可能结合“关闭”构象，可能将其构象锁定在关闭状态。正在进行的研究将建立我们的纳米体作为一个新的抗病毒药物家族，用于治疗新冠肺炎和未来可能在人类身上的冠状病毒感染。

In FY20, Dr Ho has evaluated the current status and challenges for developing antibody therapeutics targeting SARS-Cov-2 and wrote a review/perspective article [Ho Antibody Therapeutics 2020; PMID: 32566896]. SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective. In FY2020, our pilot screen in the Ho lab using phage display technology has identified a panel of camel nanobodies that might recognize diverse conformations of the RBD. Some might bind an "open" conformation of the RBD, which might block the interaction with the ACE2 on human cell, while others might bind a "close" conformation, which might lock its conformation in the off state. Ongoing studies will establish our nanobodies as a new family of anti-viral drugs for treating COVID-19 and potentially future coronavirus infections in humans.