Light chain of a public SARS-CoV-2 class-3 antibody modulates neutralization against Omicron

Cell Rep. 2023 Sep 13;42(9):113150. doi: 10.1016/j.celrep.2023.113150. Online ahead of print.ABSTRACTThe 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.PMID:37708028 | DOI:10.1016/j.celrep.2023.113150

Source: Cell Research - September 14, 2023 Category: Cytology Authors: Anamika Patel Sanjeev Kumar Lilin Lai Meredith Keen Rajesh Valanparambil Chennareddy Chakravarthy Zane Laughlin Filipp Frank Narayanaiah Cheedarla Hans P Verkerke Andrew S Neish John D Roback Carl W Davis Jens Wrammert Amit Sharma Rafi Ahmed Mehul S Sutha Source Type: research