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 l...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,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.展开更多
基金supported by the Major Science and Technology Special Project of Gansu Province(24ZDFA002)the National Natural Science Foundation of China(82060459)+1 种基金the Key Research and Development Program of Gansu Province(23YFFA0007)the Joint Research Fund of Gansu Province(23JRRA1511)。
文摘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,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.
