Department of Biomedical Sciences, Graduate School, Korea University, Seoul 02841, Republic of Korea.
BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea.
Mol Pharm. 2024 Sep 2;21(9):4336-4346. doi: 10.1021/acs.molpharmaceut.4c00297. Epub 2024 Jul 26.
Given the previous SARS-CoV-2 pandemic and the inherent unpredictability of viral antigenic drift and shift, preemptive development of diverse neutralizing antibodies targeting a broad spectrum of epitopes is essential to ensure immediate therapeutic and prophylactic interventions during emerging outbreaks. In this study, we present a monoclonal antibody engineered for cross-reactivity to both wild-type and Delta RBDs, which, surprisingly, demonstrates enhanced neutralizing activity against the Omicron variant despite a significant number of mutations. Using an inner membrane display of a human naïve antibody library, we identified antibodies specific to the wild-type SARS-CoV-2 receptor binding domain (RBD). Subsequent directed evolution via yeast surface display yielded JS18.1, an antibody with high binding affinity for both the Delta and Kappa RBDs, as well as enhanced binding to other RBDs (wild-type, Alpha, Beta, Gamma, Kappa, and Mu). Notably, JS18.1 (engineered for wild-type and Delta RBDs) exhibits enhanced neutralizing capability against the Omicron variant and binds to RBDs noncompetitively with ACE2, distinguishing it from other previously reported antibodies. This underscores the potential of pre-existing antibodies to neutralize emerging SARS-CoV-2 strains and offers insights into strategies to combat emerging viruses.
鉴于之前的 SARS-CoV-2 大流行以及病毒抗原漂移和转变的固有不可预测性，抢先开发针对广泛表位的多样化中和抗体对于确保在新出现的疫情爆发期间立即进行治疗和预防干预至关重要。在这项研究中，我们介绍了一种针对野生型和 Delta RBD 均具有交叉反应性的单克隆抗体，令人惊讶的是，尽管发生了大量突变，该抗体对奥密克戎变异株仍表现出增强的中和活性。我们使用人幼稚抗体文库的内膜展示技术，鉴定出了针对野生型 SARS-CoV-2 受体结合域（RBD）的抗体。随后通过酵母表面展示进行定向进化，得到了 JS18.1，该抗体对 Delta 和 Kappa RBD 具有高亲和力，并且对其他 RBD（野生型、Alpha、Beta、Gamma、Kappa 和 Mu）的结合能力也得到了增强。值得注意的是，JS18.1（针对野生型和 Delta RBD 进行了工程改造）对奥密克戎变异株表现出增强的中和能力，并且与 ACE2 非竞争性地结合 RBD，这使其有别于其他先前报道的抗体。这突显了先前存在的抗体中和新出现的 SARS-CoV-2 株的潜力，并为应对新兴病毒提供了策略上的见解。
