Development and preclinical evaluation of a novel FGFR3-targeted antibody-drug conjugate in bladder cancer

Abstract

Given the critical shortage of antibody-drug conjugates (ADCs) for bladder cancer (BCa), we developed a novel FGFR3-targeted ADC, LZU-WZLYFG001, composed of a humanized anti-FGFR3 IgG1 monoclonal antibody, a cleavable GGFG linker, and the payload DXD. The antibody was engineered in 293 cells and conjugated via thiol-based chemistry, achieving a drug-to-antibody ratio (DAR) of eight. Comprehensive preclinical assessments, including in vitro and in vivo studies using BCa cells, organoids, cellderived xenograft and patient-derived xenograft (PDX) models, were conducted to evaluate efficacy, targeting ability, mechanism, safety and tissue distribution. LZU-WZLYFG001 demonstrated high purity, targeting specificity and low endotoxin levels, and it significantly inhibited BCa cell proliferation, migration and invasion at nanomolar concentrations, with efficacy strongly associated with FGFR3 expression levels. Mechanistic studies showed binding to FGFR3, internalization and lysosomal release of LZU-WZLYFG001. In organoid and xenograft models, LZU-WZLYFG001 exhibited superior efficacy compared with the gemcitabine + cisplatin (GC) regimen, particularly in GC-resistant PDX tumors, while also showing robust 3D penetration, a bystander effect, and no significant short-term toxicity. Collectively, these findings demonstrate that LZU-WZLYFG001 exhibits excellent preclinical efficacy and safety, and its superiority over GC, together with its activity in resistant tumors, highlights its potential as a novel therapeutic option for BCa.

Keywords

Antibody-drug conjugate / Bladder cancer / Fibroblast growth factor receptor 3 / DXD

Conflicts of interest

All authors declare they have no conflicts of interests.

Acknowledgments

This work is supported by the Major Science and Technology Special Project of Gansu Province (24ZDFA002), the National Natural Science Foundation of China (82060459), the Key Research and Development Program of Gansu Province (23YFFA0007), the Joint Research Fund of Gansu Province (23JRRA1511). Native language support: Home for Researchers (www.home-for-researchers.com).

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