TROP2
May 2026
Several recent developments highlight growing momentum around trophoblast cell surface antigen-2 (TROP2): an anti-cancer drug target with antibody-drug conjugates (ADCs) moving into earlier treatment lines and new therapeutic strategies emerging.
Recent pharma news from early 2026 includes:
TROP2 ADCs move toward first lines: Gilead’s sacituzumab govitecan (Trodelvy) has recently been incorporated into Category 1 preferred regimens for metastatic triple-negative breast cancer (TNBC), both as monotherapy and in combination with pembrolizumab. This marks a shift toward the earlier use of TROP2-directed ADCs in standard of care.
New modalities: Astellas presented preclinical data on ASP2998, a TROP2-targeted ADC combining a TOP1 inhibitor with a STING agonist payload. The program showed strong efficacy and favorable safety, with first-in-human studies planned. This reflects a shift toward multi-mechanistic ADC designs that combine cytotoxic and immune-modulating effects.
Focus on next-generation drugs: Eli Lilly acquired CrossBridge Bio (~$300M deal), gaining access to a dual-payload TROP2 ADC expected to enter the clinic in 2026. This highlights pharma consolidation around next-gen TROP2 ADC designs, driven by linker and payload innovation.
Despite these advances, TROP2-directed ADCs still face key limitations, including variable efficacy and class-associated toxicities. What new findings could help optimize TROP2-targeted therapies to improve their therapeutic index?
Novel biological insights to guide next-generation therapies
TROP2 is a type I transmembrane glycoprotein broadly expressed across epithelial tumors, making it a relevant therapeutic target for cancer. Sacituzumab govitecan (SG) is an ADC composed of the anti-TROP2 monoclonal antibody (mAb) sacituzumab (hRS7) conjugated via a labile linker to the SN-38 topoisomerase I inhibitor. Upon binding with TROP2, SG is rapidly internalized, enabling efficient delivery of its cytotoxic payload into tumor cells.
However, crucial challenges remain: heterogeneous expression, regulated proteolysis, and controlling uptake to optimize payload exposure while managing its potential effects on surrounding cells (bystander effects).
Understanding the limitations requires a closer look at how TROP2 interacts with therapeutic ADCs at the structural level. The first resolved X-ray structure of the sacituzumab–TROP2 complex (1.56 Å; PDB 9PI9) reveals key features — including epitope location, binding geometry, and antibody-induced conformational changes — that directly influence ADC performance.
Key structural findings include:
Binding stoichiometry/geometry: The sacituzumab Fab binds TROP2 as a 2:2 complex. Two Fab fragments span a single TROP2 dimer, engaging both monomers simultaneously in a V-shaped arrangement. The resulting binding site is composite and present only in the dimeric state.
Two sacituzumab Fabs bind across two TROP2 dimer subunits.
Conformational change: Fab binding induces a large rotation (~26°) between the two TROP2 ectodomains compared to the unbound dimer. This rearrangement is enabled by pronounced conformational changes in the TY‑loop (S81–G102), which adopts a symmetric conformation distinct from the asymmetric, apo state. Modeling shows that without this shift, two Fabs would sterically clash, indicating that Fab‑induced rearrangement is required for bivalency.
Notably, sacituzumab Fab binding reduces TROP2 proteolysis through a dual mechanism:
Physically blockage of protease access to cleavage sites and
Stabilization of the dimer in a specific conformation that further buries key cleavage residues within the dimer interface,
thereby preventing TROP2 shedding and supporting more efficient ADC internalization.
Upon Fab binding, the TY-loop of TROP2 (in red) shifts compared to the unbound state (in blue)
Key interactions: Sacituzumab’s Heavy Chain (HC) CDR3 is the dominant binding hotspot at the TROP2 interface. In particular, three HC‑CDR3 residues (S103, S104, Y105) stabilize the Fab-TROP2 complex, forming multiple hydrogen bonds and polar contacts that bury more surface area than any other region of the antibody. Mutating these key HC‑CDR3 residues drastically reduced binding affinity, while other CDR loop mutations had minimal effect, confirming that HC‑CDR3 serves as the primary anchor for sacituzumab–TROP2 recognition.
Key residues (in white) on HC‑CDR3 responsible for binding affinity
Outlook
TROP2 ADCs have demonstrated meaningful clinical benefit, and the novel sacituzumab–TROP2 structure now provides discovery teams with a clear structural blueprint: composite, dimer-spanning epitope; TROP-2 dimer conformational change; and key residues that dominate complex stabilization.
Together, these insights enable rational epitope selection, paratope engineering, and valency optimization to drive next-generation TROP2 therapies, including bispecific formats.
Reference:
Ferrao, Ryan, et al. “The therapeutic antibody sacituzumab induces trophoblast cell‑surface antigen‑2 conformational rearrangement.” Structure 34 (2026): 264–272. doi:10.1016/j.str.2025.11.002
Structural exploration of the reference paper and images is produced using the 3decision software.