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

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 <i>in vitro</i> and <i>in vivo</i> studies using BCa cells, organoids, cell-derived 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.