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Paired heavy and light chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

Bailey B Banach et al. bioRxiv. .

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  • Paired heavy- and light-chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses.
    Banach BB, Cerutti G, Fahad AS, Shen CH, Oliveira De Souza M, Katsamba PS, Tsybovsky Y, Wang P, Nair MS, Huang Y, Francino-Urdániz IM, Steiner PJ, Gutiérrez-González M, Liu L, López Acevedo SN, Nazzari AF, Wolfe JR, Luo Y, Olia AS, Teng IT, Yu J, Zhou T, Reddem ER, Bimela J, Pan X, Madan B, Laflin AD, Nimrania R, Yuen KY, Whitehead TA, Ho DD, Kwong PD, Shapiro L, DeKosky BJ. Banach BB, et al. Cell Rep. 2021 Oct 5;37(1):109771. doi: 10.1016/j.celrep.2021.109771. Epub 2021 Sep 28. Cell Rep. 2021. PMID: 34587480 Free PMC article.

Abstract

Understanding protective mechanisms of antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We discovered a new antibody, 910-30, that targets the SARS-CoV-2 ACE2 receptor binding site as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. We performed sequence and structural analyses to explore how antibody features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer revealed its binding interactions and ability to disassemble spike. Despite heavy chain sequence similarity, biophysical analyses of IGHV3-53/3-66 antibodies highlighted the importance of native heavy:light pairings for ACE2 binding competition and for SARS-CoV-2 neutralization. We defined paired heavy:light sequence signatures and determined antibody precursor prevalence to be ~1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These data reveal key structural and functional neutralization features in the IGHV3-53/3-66 public antibody class to accelerate antibody-based medical interventions against SARS-CoV-2.

Highlights: A molecular study of IGHV3-53/3-66 public antibody responses reveals critical heavy and light chain features for potent neutralizationCryo-EM analyses detail the structure of a novel public antibody class member, antibody 910-30, in complex with SARS-CoV-2 spike trimerCryo-EM data reveal that 910-30 can both bind assembled trimer and can disassemble the SARS-CoV-2 spikeSequence-structure-function signatures defined for IGHV3-53/3-66 class antibodies including both heavy and light chainsIGHV3-53/3-66 class precursors have a prevalence of 1:44,000 B cells in healthy human antibody repertoires.

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