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

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 Suthar, Kaja Murali-Krishna, Anmol Chandele, Eric Ortlund

Cell reports 2023 Sep 13

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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. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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PMID: 37708028

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