9PI9

Sacituzumab Fab bound to Trop2 Dimer

Summary for 9PI9

• Entry DOI: 10.2210/pdb9pi9/pdb
• Descriptor: Sacituzumab Heavy Chain, Sacituzumab Light Chain, Tumor-associated calcium signal transducer 2, ... (9 entities in total)
• Functional Keywords: antibody drug conjugate, immune complex, dimer, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 153729.38

Authors

Ferrao, R.,Lansdon, E.B. (deposition date: 2025-07-10, release date: 2025-12-10, Last modification date: 2026-02-18)

Primary citation

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.
The therapeutic antibody sacituzumab induces trophoblast cell-surface antigen-2 conformational rearrangement.
Structure, 34:264-, 2026

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.

PubMed: 41314216
DOI: 10.1016/j.str.2025.11.002

Experimental method

X-RAY DIFFRACTION (1.56 Å)