一种新型双特异性抗体靶向 RBD 中的两个重叠表位,提高了对 SARS-CoV-2 的中和效力和广度。

A novel bispecific antibody targeting two overlapping epitopes in RBD improves neutralizing potency and breadth against SARS-CoV-2.

机构信息

Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, People's Republic of China.

Center for Infectious Disease Research, Research Center for Industries of the Future, Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Institute of Biology, Westlake Institute for Advanced Study, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, People's Republic of China.

出版信息

Emerg Microbes Infect. 2024 Dec;13(1):2373307. doi: 10.1080/22221751.2024.2373307. Epub 2024 Jul 12.

Abstract

SARS-CoV-2 has been evolving into a large number of variants, including the highly pathogenic Delta variant, and the currently prevalent Omicron subvariants with extensive evasion capability, which raises an urgent need to develop new broad-spectrum neutralizing antibodies. Herein, we engineer two IgG-(scFv) form bispecific antibodies with overlapping epitopes (bsAb1) or non-overlapping epitopes (bsAb2). Both bsAbs are significantly superior to the parental monoclonal antibodies in terms of their antigen-binding and virus-neutralizing activities against all tested circulating SARS-CoV-2 variants including currently dominant JN.1. The bsAb1 can efficiently neutralize all variants insensitive to parental monoclonal antibodies or the cocktail with IC lower than 20 ng/mL, even slightly better than bsAb2. Furthermore, the cryo-EM structures of bsAb1 in complex with the Omicron spike protein revealed that bsAb1 with overlapping epitopes effectively locked the S protein, which accounts for its conserved neutralization against Omicron variants. The bispecific antibody strategy engineered from overlapping epitopes provides a novel solution for dealing with viral immune evasion.

摘要

SARS-CoV-2 已经进化出大量变体,包括高致病性的 Delta 变体,以及目前广泛传播的具有广泛逃逸能力的奥密克戎亚变体,这就迫切需要开发新的广谱中和抗体。在此,我们设计了两种具有重叠表位的 IgG-(scFv)形式双特异性抗体(bsAb1)或非重叠表位的双特异性抗体(bsAb2)。与亲本单克隆抗体相比,这两种 bsAb 在针对所有测试的循环 SARS-CoV-2 变体(包括目前占主导地位的 JN.1)的抗原结合和病毒中和活性方面都具有显著优势。bsAb1 可以有效中和所有对亲本单克隆抗体或鸡尾酒不敏感的变体,其 IC 低于 20ng/ml,甚至略优于 bsAb2。此外,bsAb1 与奥密克戎刺突蛋白复合物的冷冻电镜结构表明,具有重叠表位的 bsAb1 可以有效地锁定 S 蛋白,这解释了其对奥密克戎变体的保守中和作用。从重叠表位设计的双特异性抗体策略为应对病毒免疫逃逸提供了一种新的解决方案。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b2f/11249148/f8e219df5b46/TEMI_A_2373307_F0001_OC.jpg

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