Payload-Free [89Zr]Zr-DFO*-sq-Enfortumab ImmunoPET for Imaging Nectin-4 Expression in Bladder Cancer.

Authors

Marian N Aziz, Tianyuan Wang, Jiawen Lang, Mickey Glover, Abhilash Boppana, Sashi Debnath, Jui Wan Loh, Jeon Lee, Sean Yan, Ningyan Zhang, Xiankai Sun, Jer-Tsong Hsieh, Jue Wang, Li Liu, Guiyang Hao

Published in

Molecular pharmaceutics. Volume 23. Issue 9. Pages 4758-4769. Sep 07, 2026.

Abstract

Nectin-4-targeted imaging has emerged as a promising strategy for patient stratification in urothelial carcinoma, yet currently available radiotracers remain limited by rapid renal clearance, urinary background activity, or potential pharmacologic confounding associated with antibody-drug conjugate (ADC)-based constructs. To overcome some of these limitations, we developed a payload-free immunoPET radiotracer based on the native enfortumab antibody conjugated with the bifunctional chelator DFO*-sq and radiolabeled with zirconium-89 (89Zr). The resulting [89Zr]Zr-DFO*-sq-Enfortumab preserved Nectin-4-specific targeting while demonstrating high radiochemical stability in human serum (>99% through Day 12). In vitro studies showed efficient antigen-specific cellular internalization (80-85%), prolonged intracellular retention, and evidence consistent with partial recycling of antibody-associated species. In vivo, [89Zr]Zr-DFO*-sq-Enfortumab exhibited sustained tumor uptake reaching 17.4 ± 2.8% ID/g in high Nectin-4-expressing xenografts and correlated with differential Nectin-4 expression across multiple bladder cancer models. Importantly, the full-length antibody platform enabled high-contrast visualization of pulmonary metastatic lesions and orthotopic bladder tumors despite some urinary background activity. Together, these findings demonstrate that payload-free [89Zr]Zr-DFO*-sq-Enfortumab provides a biologically relevant immunoPET platform for noninvasive assessment of variable Nectin-4 expression and support its further evaluation as a companion imaging strategy for Enfortumab Vedotin-based therapies.

PMID:
42704134
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.