Development of neutralizing nanobodies against SARS-CoV-2

在大流行期间，何博士评估了开发针对SARS-Cov-2的抗体疗法的挑战，并撰写了一篇综述/展望文章[Ho Antibody Therapeutics 2020; PMID：32566896]。SARS-CoV-2通过与血管紧张素转换酶2（ACE 2）结合的刺突蛋白（S）进入人体细胞。因此，S蛋白是中和抗体的主要靶标。将两种（或更多种）抗体结合起来的鸡尾酒策略可能是最有效的，这些抗体可以识别与人类细胞相互作用的病毒表面的不同部分。于2021财政年度，Ho实验室利用噬菌体展示技术鉴定了一组骆驼纳米抗体，其可能识别RBD的不同构象。一些可能结合RBD的“开放”构象，这可能会阻止与人类细胞上的ACE 2的相互作用，而另一些可能结合“封闭”构象，这可能会将其构象锁定在关闭状态。这些纳米抗体在病毒刺突蛋白上的表位作图揭示了两个不同的结合表位，一个直接参与ACE 2结合，另一个在SARS-CoV-2和SARS-CoV之间是保守的。识别这两种不同表位的最佳候选物显示出对SARS-CoV-2变体B.1.1.7和B.1.351的有效中和活性。这两组纳米抗体的二合一混合治疗显示出对小鼠B.1.351变体的有效保护作用，这表明预防和治疗COVID-19的治疗潜力很有希望。正在进行的研究将使我们的纳米抗体成为一种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。我们正在积极寻找行业合作伙伴，以临床开发我们针对SARS-CoV-2的新型纳米抗体，用于治疗COVID-19大流行。

During the pandemic, Dr Ho has evaluated the 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 S protein is the primary target for neutralizing antibodies. 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 FY2021, 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. Epitope mapping of these nanobodies on the viral spike protein reveals two distinct binding epitopes, one is directly involved in the ACE2 binding and the other is conserved between SARS-CoV-2 and SARS-CoV. The top candidates that recognize these two distinct epitopes shows potent neutralization activities against SARS-CoV-2 variants B.1.1.7 and B.1.351. The 2-in-1 cocktail treatment with these two groups of nanobodies shows potent protection against the B.1.351 variant in mice, suggesting promising therapeutic potential to prevent and treat COVID-19. 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. We are actively searching for industry partners to clinically develop our novel nanobodies targeting SARS-CoV-2 for treating COVID-19 pandemic.