Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD.,Protein & Cell

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Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD.
Protein & Cell ( IF 21.1 ) Pub Date : 2023-07-20 , DOI: 10.1093/procel/pwad040
Hui Sun _{1,

2,

3} , Tingting Deng _{1,

2,

3} , Yali Zhang _{1,

2,

3,

4} , Yanling Lin _{1,

2,

3} , Yanan Jiang _{1,

2,

3} , Yichao Jiang _{1,

2,

3} , Yang Huang _{1,

2,

3} , Shuo Song _{5,

6} , Lingyan Cui _{1,

2,

3} , Tingting Li _{1,

2,

3,

4} , Hualong Xiong _{1,

2,

3,

4} , Miaolin Lan _{1,

2,

3} , Liqin Liu _{1,

2,

3} , Yu Li _{1,

2,

3} , Qianjiao Fang _{1,

2,

3} , Kunyu Yu _{1,

2,

3} , Wenling Jiang _{1,

2,

3} , Lizhi Zhou _{1,

2,

3,

4} , Yuqiong Que _{1,

2,

3,

4} , Tianying Zhang _{1,

2,

3,

4} , Quan Yuan _{1,

2,

3,

4} , Tong Cheng _{1,

2,

3,

4} , Zheng Zhang _{5,

6} , Hai Yu _{1,

2,

3,

4} , Jun Zhang _{1,

2,

3,

4} , Wenxin Luo _{1,

2,

3,

4} , Shaowei Li _{1,

2,

3,

4} , Qingbing Zheng _{1,

2,

3,

4} , Ying Gu _{1,

2,

3,

4} , Ningshao Xia _{1,

2,

3,

4,

7}

Affiliation

Continual evolution of the 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 and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two ACE2 competing nAbs-8H12 and 3E2-with synergistic neutralization but evaded by some Omicron subvariants. Cryo-EM reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the RBD 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.

中文翻译：

两种抗体通过诱导 RBD 内的构象变化，对 SARS-CoV-2 变体表现出广泛的协同中和作用。

SARS-CoV-2 病毒的不断进化使其能够逐渐逃避因自然感染或疫苗接种而产生的中和抗体 (nAb)。这些变化的快速性质激发了对开发优质广泛的 nAb 和/或合理设计可预防突变病毒株的抗体混合物的需求。在这里，我们报告了两种 ACE2 竞争性 nAbs-8H12 和 3E2-具有协同中和作用，但被一些 Omicron 亚变体所回避。Cryo-EM 通过 RBD 中 472-489 环重排以避免空间冲突而允许的严格配对揭示了两种 nAb 协同中和病毒。基于这两种 nAb 的双特异性抗体极大地扩展了中和广度，并恢复了针对最新变体（包括目前占主导地位的 XBB.1.5）的中和作用。总之，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，从而设计出广泛作用的抗体疗法和疫苗。

更新日期：2023-07-20

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