With the development of novel antibody-drug conjugates(ADC)such as T-DXd(trastuzumab deruxtecan)and HER3-DXd(patritumab deruxtecan),global tumor cell targeting has become possible beyond the human epidermal growth fac...With the development of novel antibody-drug conjugates(ADC)such as T-DXd(trastuzumab deruxtecan)and HER3-DXd(patritumab deruxtecan),global tumor cell targeting has become possible beyond the human epidermal growth factor receptor(HER)2-positive setting[1,2].Both drugs offer promising options for individualized treatment targeting HER2 and HER3 expression,potentially even in tumors which are currently considered“HER2-negative”.展开更多
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
目的对人表皮生长因子受体2(HER-2)低表达乳腺癌的临床特征、抗体偶联药物(antibody drug conjugates,ADCs)在HER-2低表达人群的治疗进展进行总结。方法以“HER-2 low breast cancer、antibody drug conjugates”为英文关键词在PubMed...目的对人表皮生长因子受体2(HER-2)低表达乳腺癌的临床特征、抗体偶联药物(antibody drug conjugates,ADCs)在HER-2低表达人群的治疗进展进行总结。方法以“HER-2 low breast cancer、antibody drug conjugates”为英文关键词在PubMed数据库进行检索,检索时间为自建库至2022年12月。纳入标准:(1)HER-2低表达乳腺癌的生物学和临床特征;(2)ADCs药物的临床前试验和临床试验。排除标准:(1)个案报道;(2)重复的临床试验。最终纳入50篇文献。结果随着ADCs药物临床数据的不断公布,HER-2低表达乳腺癌的概念逐渐被重视。HER-2低表达乳腺癌有望成为一个全新的治疗亚型。以T-Dxd为代表的ADCs药物,包括Trastuzumab-emtansine、Trastuzumab-deruxtecan、Trastuzumab-Duocarmazine、ARX-788、XMT-1522、MEDI4276、A166和MRG002已经在HER-2低表达乳腺癌人群中展示出较好的疗效,相信新型ADCs在不久的未来能够成为HER-2低表达乳腺癌人群的治疗新选择。结论以T-Dxd为代表的新型ADCs的不断问世将成为HER-2低表达乳腺癌人群的治疗新选择,并改善该人群的预后。展开更多
文摘With the development of novel antibody-drug conjugates(ADC)such as T-DXd(trastuzumab deruxtecan)and HER3-DXd(patritumab deruxtecan),global tumor cell targeting has become possible beyond the human epidermal growth factor receptor(HER)2-positive setting[1,2].Both drugs offer promising options for individualized treatment targeting HER2 and HER3 expression,potentially even in tumors which are currently considered“HER2-negative”.
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.
文摘目的对人表皮生长因子受体2(HER-2)低表达乳腺癌的临床特征、抗体偶联药物(antibody drug conjugates,ADCs)在HER-2低表达人群的治疗进展进行总结。方法以“HER-2 low breast cancer、antibody drug conjugates”为英文关键词在PubMed数据库进行检索,检索时间为自建库至2022年12月。纳入标准:(1)HER-2低表达乳腺癌的生物学和临床特征;(2)ADCs药物的临床前试验和临床试验。排除标准:(1)个案报道;(2)重复的临床试验。最终纳入50篇文献。结果随着ADCs药物临床数据的不断公布,HER-2低表达乳腺癌的概念逐渐被重视。HER-2低表达乳腺癌有望成为一个全新的治疗亚型。以T-Dxd为代表的ADCs药物,包括Trastuzumab-emtansine、Trastuzumab-deruxtecan、Trastuzumab-Duocarmazine、ARX-788、XMT-1522、MEDI4276、A166和MRG002已经在HER-2低表达乳腺癌人群中展示出较好的疗效,相信新型ADCs在不久的未来能够成为HER-2低表达乳腺癌人群的治疗新选择。结论以T-Dxd为代表的新型ADCs的不断问世将成为HER-2低表达乳腺癌人群的治疗新选择,并改善该人群的预后。
