Development of neutralizing nanobodies against SARS-CoV-2

在2020财年，何博士评估了开发针对SARS-Cov-2的抗体疗法的现状和挑战，并撰写了一篇综述/观点文章[Ho antibody therapeutics 2020；PMID: 32566896)。SARS-CoV-2通过其刺突(S)蛋白与血管紧张素转换酶2 （ACE2）结合进入人体细胞。因此，S蛋白的受体结合域（RBD）是中和抗体的主要靶点。选择抗SARS-CoV-2和SARS-CoV的广泛中和抗体是有吸引力的，可能不仅对治疗COVID-19有用，而且对未来的sars相关CoV感染也有用。据报道，广谱中和抗体靶向S1亚基RBD中的一个保守区域。病毒膜融合所需的S2亚基可能是另一个目标。结合两种（或更多）抗体的鸡尾酒策略可以识别病毒表面与人体细胞相互作用的不同部分，这可能是最有效的。在2020财年，我们在Ho实验室使用噬菌体展示技术的试点筛选已经确定了一组骆驼纳米体，可以识别RBD的不同构象。一些可能结合RBD的“开放”构象，这可能阻断与人类细胞上ACE2的相互作用，而另一些可能结合“关闭”构象，这可能将其构象锁定在关闭状态。正在进行的研究将使我们的纳米体成为一个新的抗病毒药物家族，用于治疗COVID-19和潜在的未来人类冠状病毒感染。

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.