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TitleStructural basis for uPAR binding to an antibody developed for targeted cancer therapy. Mechanistic insights into flexibility, ligand recognition, and molecular imaging.
Journal, issue, pagesProtein Sci, Vol. 35, Issue 2, Page e70473, Year 2026
Publish dateJan 23, 2026
AuthorsRex F Anane / Anni Kumari / Hari Venugopal / Sylvain Trépout / James C Whisstock / Lars H Engelholm / Ruby H P Law / Michael Ploug /
PubMed AbstractThe urokinase-type plasminogen activator receptor (uPAR) is currently gaining momentum as a promising molecular target for treatment of various solid cancers. For patient stratification, we developed ...The urokinase-type plasminogen activator receptor (uPAR) is currently gaining momentum as a promising molecular target for treatment of various solid cancers. For patient stratification, we developed a high-affinity uPAR-targeting peptide (AE105) detecting primary cancer lesions as well as occult metastasis by positron emission tomography (PET) imaging. uPAR-targeting by AE105 is also used for optical imaging in fluorescence-guided surgery of, for example, head-and-neck cancers. Recently, we showed that a monoclonal anti-uPAR antibody (FL1), in the form of an antibody-drug conjugate (FL1-ADC), efficiently eradicate pancreatic ductal carcinomas in surrogate mouse models leading to long-term remissions. In the current study, we solved high-resolution cryo-EM structures of FL1 in complex with two different conformational states of uPAR. Combined with comprehensive kinetic data from surface plasmon resonance studies, our cryo-EM structures provide essential insights into how FL1 binding impacts the interdomain flexibility of uPAR by restricting the movement of its N-terminal LU domain. This constraint from the bound FL1 drives uPAR into its open conformation, which leads to a pronounced reduction in the binding affinity for both its natural protease ligand (300-fold) and the PET imaging probe AE105 (25-fold). Collectively, these consequences of FL1-binding on uPAR conformation are considered beneficial for both targeted cancer treatment with FL1-ADCs and for the accompanying evaluation of treatment efficacy by longitudinal AE105-based PET imaging.
External linksProtein Sci / PubMed:41575054 / PubMed Central
MethodsEM (single particle)
Resolution2.94 - 4.8 Å
Structure data

72760

9yc5

EMDB-72760, PDB-9yc5:
Human uPAR bound to the Fab fragment of targeted cancer therapeutic antibody FL1
Method: EM (single particle) / Resolution: 2.94 Å

72761

9yc6

EMDB-72761, PDB-9yc6:
Mutant human uPAR bound to the Fab fragment of the targeted cancer therapeutic antibody FL1
Method: EM (single particle) / Resolution: 4.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / Complex / Targeted cancer therapy / Monoclonal anti-uPAR antibody FL1 / Antibody-drug conjugate

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