Download MendeleyThe therapeutic antibody sacituzumab induces trophoblast cell-surface antigen-2 conformational rearrangement.
Ferrao, R., Zhang, J., Chou, C.C., Nieto, A., Langeslay, D., Chatterjee, M., Jin, D., Hung, M., Scott, I., Nagel, M., Xing, W., Letarte, S., Wang, J., Ambrogelly, A., Lansdon, E.B.(2025) Structure
- PubMed: 41314216
- DOI: https://doi.org/10.1016/j.str.2025.11.002
- Primary Citation of Related Structures:
9PI9 - PubMed Abstract:
Sacituzumab govitecan (SG) is a therapeutic antibody-drug conjugate globally approved for the treatment of breast cancer. SG targets the trophoblast cell-surface antigen-2 (Trop2) at the surface of cancer cells to deliver the cytotoxic topoisomerase I inhibitor SN-38 to the tumor microenvironment. SN-38 is covalently linked to the humanized monoclonal antibody (mAb) sacituzumab via a hydrolyzable linker. Here, we describe the 1.56-Å X-ray crystal structure and stoichiometry of the human Trop2 ectodomain in complex with a sacituzumab (hRS7) antigen-binding Fab fragment. The complex reveals a 2:2 stoichiometry where two sacituzumab Fabs bind across the two Trop2 dimer subunits, inducing a conformational change compared to the apo-structure. Cryo-electron microscopy (cryoEM) and size-exclusion chromatography in combination with multi-angle light scattering (SEC-MALS) analysis of the intact sacituzumab mAb bound to the Trop2 ECD reveals a complex whereby sacituzumab engages two Trop2 dimers in a 2:4 stoichiometry.
- Gilead Sciences Inc., Structural Biology and Chemistry, 333 Lakeside Dr., Foster City, CA 94404, USA.
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