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/观点文章[Ho抗体疗法2020年；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蛋白是中和抗体的主要靶点。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2021财年，Ho实验室利用噬菌体展示技术鉴定了一组骆驼纳米体，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。这些纳米体在病毒刺突蛋白上的表位图谱显示了两个不同的结合表位，一个直接参与ACE2结合，另一个在SARS-CoV-2和SARS-CoV之间保守。识别这两个不同表位的最佳候选者对SARS-CoV-2变异体B.1.1.7和B.1.351显示出强大的中和活性。这两组纳米体的2合1鸡尾酒疗法在小鼠身上显示了对B.1.351变体的有效保护，这表明有希望在预防和治疗新冠肺炎方面具有治疗潜力。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。我们正在积极寻找行业合作伙伴，在临床上开发我们针对SARS-CoV-2的新型纳米体，用于治疗新冠肺炎大流行。

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.