Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA.
Cell Rep. 2023 Sep 26;42(9):113150. doi: 10.1016/j.celrep.2023.113150. Epub 2023 Sep 13.
The pairing of antibody genes IGHV2-5/IGLV2-14 is established as a public immune response that potently cross-neutralizes SARS-CoV-2 variants, including Omicron, by targeting class-3/RBD-5 epitopes in the receptor binding domain (RBD). LY-CoV1404 (bebtelovimab) exemplifies this, displaying exceptional potency against Omicron sub-variants up to BA.5. Here, we report a human antibody, 002-S21B10, encoded by the public clonotype IGHV2-5/IGLV2-14. While 002-S21B10 neutralized key SARS-CoV-2 variants, it did not neutralize Omicron, despite sharing >92% sequence similarity with LY-CoV1404. The structure of 002-S21B10 in complex with spike trimer plus structural and sequence comparisons with LY-CoV1404 and other IGHV2-5/IGLV2-14 antibodies revealed significant variations in light-chain orientation, paratope residues, and epitope-paratope interactions that enable some antibodies to neutralize Omicron but not others. Confirming this, replacing the light chain of 002-S21B10 with the light chain of LY-CoV1404 restored 002-S21B10's binding to Omicron. Understanding such Omicron evasion from public response is vital for guiding therapeutics and vaccine design.
IGHV2-5/IGLV2-14 抗体基因的配对被确立为一种公共免疫反应，能够通过靶向受体结合域（RBD）中的第 3 类/RBD-5 表位，有力地中和包括奥密克戎在内的 SARS-CoV-2 变体。LY-CoV1404（贝替洛维单抗）就是一个很好的例子，它对奥密克戎亚变体的效力甚至高达 BA.5。在这里，我们报告了一种人类抗体 002-S21B10，它由公共克隆型 IGHV2-5/IGLV2-14 编码。虽然 002-S21B10 中和了关键的 SARS-CoV-2 变体，但它不能中和奥密克戎，尽管与 LY-CoV1404 共享超过 92%的序列相似性。002-S21B10 与 Spike 三聚体复合物的结构以及与 LY-CoV1404 和其他 IGHV2-5/IGLV2-14 抗体的结构和序列比较表明，轻链取向、互补位残基和表位-互补位相互作用存在显著差异，这些差异使一些抗体能够中和奥密克戎，而另一些则不能。证实了这一点，用 LY-CoV1404 的轻链替换 002-S21B10 的轻链，恢复了 002-S21B10 对奥密克戎的结合。了解这种对公共反应的奥密克戎逃避对于指导治疗和疫苗设计至关重要。
