State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China.
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China.
Protein Cell. 2024 Feb 1;15(2):121-134. doi: 10.1093/procel/pwad040.
Continual evolution of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs (bnAbs) and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two angiotensin-converting enzyme 2 competing nAbs-8H12 and 3E2-with synergistic neutralization but evaded by some Omicron subvariants. Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.
严重急性呼吸综合征冠状病毒（SARS-CoV-2）的不断进化使其能够逐渐逃避针对自然感染或接种而产生的中和抗体（nAbs）。这些变化的快速性质促使人们需要开发更优越的广谱 nAbs（bnAbs）和/或合理设计能够抵御突变病毒株的抗体鸡尾酒。在这里，我们报告了两种血管紧张素转换酶 2 竞争 nAbs-8H12 和 3E2-具有协同中和作用，但被一些奥密克戎亚变体逃避。冷冻电镜显示，这两种 nAbs 通过受体结合域中 472-489 环的重排允许严格配对来协同中和病毒，从而避免空间冲突。基于这两种 nAbs 的双特异性抗体极大地扩展了中和广度，并恢复了对最近变体的中和作用，包括目前占主导地位的 XBB.1.5。总的来说，这些发现扩展了我们对中和 SARS-CoV-2 变体的潜在策略的理解，以设计广谱抗体治疗药物和疫苗。
