@article{04ce8e7f3f9e44f6933b1e8726c5ff91,
title = "Widespread impact of immunoglobulin V-gene allelic polymorphisms on antibody reactivity",
abstract = "The ability of the human immune system to generate antibodies to any given antigen can be strongly influenced by immunoglobulin V-gene allelic polymorphisms. However, previous studies have provided only limited examples. Therefore, the prevalence of this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many V-gene allelic polymorphisms in antibody paratopes are determinants for antibody binding activity. Biolayer interferometry experiments further demonstrate that paratope allelic polymorphisms on both heavy and light chains often abolish antibody binding. We also illustrate the importance of minor V-gene allelic polymorphisms with low frequency in several broadly neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus. Overall, this study not only highlights the pervasive impact of V-gene allelic polymorphisms on antibody binding but also provides mechanistic insights into the variability of antibody repertoires across individuals, which in turn have important implications for vaccine development and antibody discovery.",
keywords = "B cells, CP: Immunology, allelic polymorphism, antibody, immunoglobulin V gene, paratope, structural biology, virus",
author = "Meng Yuan and Ziqi Feng and Huibin Lv and Natalie So and Shen, {Ivana R.} and Tan, {Timothy J.C.} and Teo, {Qi Wen} and Ouyang, {Wenhao O.} and Logan Talmage and Wilson, {Ian A.} and Wu, {Nicholas C.}",
note = "We thank Jeanne Matteson and Beverly Ellis for contribution to mammalian cell culture and Wenli Yu, Xueyong Zhu, Re{\textquoteright}em Moskovitz, Tossapol Pholcharee, and T.K. Yen Nguyen for assistance in protein production. We are grateful for the SARS-CoV-2 spike (HexaPro) plasmid from Jason McLellan from The University of Texas at Austin. This work was supported by the National Institutes of Health (NIH) R01 AI167910 (N.C.W.), DP2 AT011966 (N.C.W.), and UM1 AI144462 (I.A.W.); the Department of Health and Human Services under contract number 75N93021C00015 (I.A.W. and N.C.W.), the Bill and Melinda Gates Foundation INV-004923 (I.A.W.), and the Searle Scholars Program (N.C.W.). We thank Jeanne Matteson and Beverly Ellis for contribution to mammalian cell culture and Wenli Yu, Xueyong Zhu, Re'em Moskovitz, Tossapol Pholcharee, and T.K. Yen Nguyen for assistance in protein production. We are grateful for the SARS-CoV-2 spike (HexaPro) plasmid from Jason McLellan from The University of Texas at Austin. This work was supported by the National Institutes of Health (NIH) R01 AI167910 (N.C.W.), DP2 AT011966 (N.C.W.), and UM1 AI144462 (I.A.W.); the Department of Health and Human Services under contract number 75N93021C00015 (I.A.W. and N.C.W.), the Bill and Melinda Gates Foundation INV-004923 (I.A.W.), and the Searle Scholars Program (N.C.W.). M.Y. and N.C.W. conceived and designed the study. N.S. and N.C.W. analyzed the antibody structure database and performed mutational stability analysis. M.Y. and N.C.W. performed the structural analysis. M.Y. Z.F. H.L. I.R.S. T.J.C.T. Q.W.T. W.O.O. and L.T. expressed and purified the antibodies and antigens. M.Y. and Z.F. performed the BLI experiment. N.C.W. and I.A.W. provided resources and support. M.Y. and N.C.W. wrote the paper, and all authors reviewed and/or edited the paper. N.C.W. consults for HeliXon.",
year = "2023",
month = oct,
day = "31",
doi = "10.1016/j.celrep.2023.113194",
language = "English (US)",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}