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The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody

Soliman, Caroline; Chua, Jia Xin; Vankemmelbeke, Mireille; McIntosh, Richard S.; Guy, Andrew J.; Spendlove, Ian; Durrant, Lindy G.; Ramsland, Paul A.

The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody Thumbnail


Authors

Caroline Soliman

Jia Xin Chua

Mireille Vankemmelbeke

Richard S. McIntosh

Andrew J. Guy

Lindy G. Durrant

Paul A. Ramsland



Abstract

Cancer remains a leading cause of morbidity and mortality worldwide, requiring ongoing development of targeted therapeutics such as monoclonal antibodies. Carbohydrates on embryonic cells are often highly expressed in cancer and are therefore attractive targets for antibodies. Stage-specific embryonic antigen-4 (SSEA-4) is one such glycolipid target expressed in many cancers, including breast and ovarian carcinomas. Here, we defined the structural basis for recognition of SSEA-4 by a novel monospecific chimeric antibody (ch28/11). Five X-ray structures of ch28/11 Fab complexes with the SSEA-4 glycan headgroup, determined at 1.5–2.7 Å resolutions, displayed highly similar three-dimensional structures indicating a stable binding mode. The structures also revealed that by adopting a horseshoe-shaped conformation in a deep groove, the glycan headgroup likely sits flat against the membrane to allow the antibody to interact with SSEA-4 on cancer cells. Moreover, we found that the terminal sialic acid of SSEA-4 plays a dominant role in dictating the exquisite specificity of the ch28/11 antibody. This observation was further supported by molecular dynamics simulations of the ch28/11-glycan complex, which show that SSEA-4 is stabilized by its terminal sialic acid, unlike SSEA-3, which lacks this sialic acid modification. These high-resolution views of how a glycolipid interacts with an antibody may help to advance a new class of cancer-targeting immunotherapy.

Citation

Soliman, C., Chua, J. X., Vankemmelbeke, M., McIntosh, R. S., Guy, A. J., Spendlove, I., …Ramsland, P. A. (2020). The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody. Journal of Biological Chemistry, 295(4), 1009-1020. https://doi.org/10.1074/jbc.ra119.011518

Journal Article Type Article
Acceptance Date Dec 12, 2019
Online Publication Date Dec 12, 2019
Publication Date Jan 24, 2020
Deposit Date Nov 26, 2020
Publicly Available Date Mar 28, 2024
Journal Journal of Biological Chemistry
Print ISSN 0021-9258
Electronic ISSN 1083-351X
Publisher American Society for Biochemistry and Molecular Biology
Peer Reviewed Peer Reviewed
Volume 295
Issue 4
Pages 1009-1020
DOI https://doi.org/10.1074/jbc.ra119.011518
Keywords Cell Biology; Biochemistry; Molecular Biology
Public URL https://nottingham-repository.worktribe.com/output/5071876
Publisher URL https://www.jbc.org/content/295/4/1009
Additional Information This research was originally published in the Journal of Biological Chemistry. Caroline Soliman, Jia Xin Chua, Mireille Vankemmelbeke, Richard S. McIntosh, Andrew J. Guy, Ian Spendlove, Lindy G. Durrant and Paul A. Ramsland. The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody. J Biol Chem. 2020; 295, 1009-1020. © 2020 Soliman et al.

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