抗体偶联药物(antibody drug conjugates, ADC)作为抗肿瘤治疗的前沿技术,近年来取得了显著进展。ADC通过连接子将高活性小分子毒素与高特异性抗体进行偶联,不仅能够实现对肿瘤细胞的精准打击,同时降低了药物的全身毒性,进而扩大了治疗...抗体偶联药物(antibody drug conjugates, ADC)作为抗肿瘤治疗的前沿技术,近年来取得了显著进展。ADC通过连接子将高活性小分子毒素与高特异性抗体进行偶联,不仅能够实现对肿瘤细胞的精准打击,同时降低了药物的全身毒性,进而扩大了治疗的有效性和安全性窗口。然而,由于ADC分子设计的复杂性,其疗效和安全性受多种因素影响。模型引导的药物开发(model informed drug development, MIDD)是一种通过数学和统计模型进行建模和模拟,对药物研发进行定量分析和决策指导的方法。这种方法为新药研发提供强大的工具支持。通过MIDD整合ADC相关的多方面数据和信息,有助于理解ADC的复杂机制、药代动力学和药效学等作用特征,为优化ADC研发流程和临床转化决策提供独特见解。本文将介绍MIDD和ADC的基本概念,并浅析MIDD在ADC研发不同阶段的应用案例,旨在为ADC的发展提供有益参考。展开更多
AIM:To investigate protective effects of a novel recombinant decoy receptor drug RC28-E on retinal damage in early diabetic rats.METHODS:The streptozotocin(STZ)-induced diabetic rats were randomly divided into 6 group...AIM:To investigate protective effects of a novel recombinant decoy receptor drug RC28-E on retinal damage in early diabetic rats.METHODS:The streptozotocin(STZ)-induced diabetic rats were randomly divided into 6 groups:diabetes mellitus(DM)group(saline,3μL/eye);RC28-E at low(0.33μg/μL,3μL),medium(1μg/μL,3μL),and high(3μg/μL,3μL)dose groups;vascular endothelial growth factor(VEGF)Trap group(1μg/μL,3μL);fibroblast growth factor(FGF)Trap group(1μg/μL,3μL).Normal control group was included.At week 1 and 4 following diabetic induction,the rats were intravitreally injected with the corresponding solutions.At week 6 following the induction,apoptosis in retinal vessels was detected by TUNEL staining.Glial fibrillary acidic protein(GFAP)expression was examined by immunofluorescence.Blood-retinal barrier(BRB)breakdown was assessed by Evans blue assay.Ultrastructural changes in choroidal and retinal vessels were analyzed by transmission electron microscopy(TEM).Content of VEGF and FGF proteins in retina was measured by enzyme linked immunosorbent assay(ELISA).The retinal expression of intercellular cell adhesion molecule-1(ICAM-1),tumor necrosis factor-α(TNF-α),VEGF and FGF genes was examined by quantitative polymerase chain reaction(qPCR).RESULTS:TUNEL staining showed that the aberrantly increased apoptotic cells death in diabetic retinal vascular network was significantly reduced by treatments of medium and high dose RC28-E,VEGF Trap,and FGF Trap(all P〈0.05),the effects of medium and high dose RC28-E or FGF Trap were greater than VEGF Trap(P〈0.01).GFAP staining suggested that reactive gliosis was substantially inhibited in all RC28-E and VEGF Trap groups,but the inhibition in FGF Trap group was not as prominent.Evans blue assay demonstrated that only high dose RC28-E could significantly reduce vascular leakage in early diabetic retina(P〈0.01).TEM revealed that the ultrastructures in choroidal and retinal vessels were damaged in early diabetic retina,which was ameliorated to differential extents by each drug.The expression of VEGF and FGF2 proteins was significantly upregulated in early diabetic retina,and normalized by RC28-E at all dosages and by the corresponding Traps.The upregulation of ICAM-1 and TNF-αin diabetic retina was substantially suppressed by RC28-E and positive control drugs.CONCLUSION:Dual blockade of VEGF and FGF2 by RC28-E generates remarkable protective effects,including anti-apoptosis,anti-gliosis,anti-leakage,and improving ultrastructures and proinflammatory microenvironment,in early diabetic retina,thereby supporting further development of RC28-E into a novel and effective drug to diabetic retinopathy(DR).展开更多
Despite significant advances in targeted therapies and immunotherapies,non-small cell lung cancer(NSCLC)continues to present a global health challenge,with a modest five-year survival rate of 28%,largely due to the em...Despite significant advances in targeted therapies and immunotherapies,non-small cell lung cancer(NSCLC)continues to present a global health challenge,with a modest five-year survival rate of 28%,largely due to the emergence of treatment-resistant and metastatic tumors.In response,we synthesized a novel bioactive compound,ethyl 6-chlorocoumarin-3-carboxylyl L-theanine(TClC),which significantly inhibited NSCLC growth,epithelial mesenchymal transition(EMT),migration,and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity.TClC disrupts autocrine loops that promote tumor progression,particularly in stem-like CD133-positive NSCLC(CD133+LC)cells,which are pivotal in tumor metastasis.Through targeted molecular assays,we identified direct binding targets of TClC,including Akt,NF-κB,β-catenin,EZH2,and PD-L1.This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter,underscoring the compound’s poly-pharmacological potential.These results position TClC as a promising candidate for NSCLC treatment,signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.展开更多
Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive local...Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.展开更多
Background:Current treatment options for human epidermal growth factor receptor 2(HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit.Further,there is no specific treatment for HER2 i...Background:Current treatment options for human epidermal growth factor receptor 2(HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit.Further,there is no specific treatment for HER2 immunohistochemistry(IHC)2+and fluorescence in-situ hybridization-negative patients.Here,we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer.Methods:Patients with HER2-overexpressing(IHC 2+or 3+),locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC482.5 mg/kg alone every 2 weeks.The primary endpoint was the objective response rate(ORR)assessed by an independent review committee.Secondary endpoints included progressionfree survival(PFS),overall survival(OS),duration of response,time to progression,disease control rate,and safety.Results:Of 179 patients screened,125 were eligible and received RC48 treatment.The ORR was 24.8%(95%confidence interval[CI]:17.5%-33.3%).The median PFS and OS were 4.1 months(95%CI:3.7-4.9 months)and 7.9 months(95%CI:6.7-9.9 months),respectively.The most frequently reported adverse events were decreased white blood cell count(53.6%),asthenia(53.6%),hair loss(53.6%),decreased neutrophil count(52.0%),anemia(49.6%),and increased aspartate aminotransferase level(43.2%).Serious adverse events(SAEs)occurred in 45(36.0%)patients,and RC48-related SAEs were mainly decreased neutrophil count(3.2%).Seven patients had adverse events that led to death were not RC48-related.Conclusions:RC48 showed promising activity with manageable safety,suggesting potential application in patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.展开更多
文摘抗体偶联药物(antibody drug conjugates, ADC)作为抗肿瘤治疗的前沿技术,近年来取得了显著进展。ADC通过连接子将高活性小分子毒素与高特异性抗体进行偶联,不仅能够实现对肿瘤细胞的精准打击,同时降低了药物的全身毒性,进而扩大了治疗的有效性和安全性窗口。然而,由于ADC分子设计的复杂性,其疗效和安全性受多种因素影响。模型引导的药物开发(model informed drug development, MIDD)是一种通过数学和统计模型进行建模和模拟,对药物研发进行定量分析和决策指导的方法。这种方法为新药研发提供强大的工具支持。通过MIDD整合ADC相关的多方面数据和信息,有助于理解ADC的复杂机制、药代动力学和药效学等作用特征,为优化ADC研发流程和临床转化决策提供独特见解。本文将介绍MIDD和ADC的基本概念,并浅析MIDD在ADC研发不同阶段的应用案例,旨在为ADC的发展提供有益参考。
文摘AIM:To investigate protective effects of a novel recombinant decoy receptor drug RC28-E on retinal damage in early diabetic rats.METHODS:The streptozotocin(STZ)-induced diabetic rats were randomly divided into 6 groups:diabetes mellitus(DM)group(saline,3μL/eye);RC28-E at low(0.33μg/μL,3μL),medium(1μg/μL,3μL),and high(3μg/μL,3μL)dose groups;vascular endothelial growth factor(VEGF)Trap group(1μg/μL,3μL);fibroblast growth factor(FGF)Trap group(1μg/μL,3μL).Normal control group was included.At week 1 and 4 following diabetic induction,the rats were intravitreally injected with the corresponding solutions.At week 6 following the induction,apoptosis in retinal vessels was detected by TUNEL staining.Glial fibrillary acidic protein(GFAP)expression was examined by immunofluorescence.Blood-retinal barrier(BRB)breakdown was assessed by Evans blue assay.Ultrastructural changes in choroidal and retinal vessels were analyzed by transmission electron microscopy(TEM).Content of VEGF and FGF proteins in retina was measured by enzyme linked immunosorbent assay(ELISA).The retinal expression of intercellular cell adhesion molecule-1(ICAM-1),tumor necrosis factor-α(TNF-α),VEGF and FGF genes was examined by quantitative polymerase chain reaction(qPCR).RESULTS:TUNEL staining showed that the aberrantly increased apoptotic cells death in diabetic retinal vascular network was significantly reduced by treatments of medium and high dose RC28-E,VEGF Trap,and FGF Trap(all P〈0.05),the effects of medium and high dose RC28-E or FGF Trap were greater than VEGF Trap(P〈0.01).GFAP staining suggested that reactive gliosis was substantially inhibited in all RC28-E and VEGF Trap groups,but the inhibition in FGF Trap group was not as prominent.Evans blue assay demonstrated that only high dose RC28-E could significantly reduce vascular leakage in early diabetic retina(P〈0.01).TEM revealed that the ultrastructures in choroidal and retinal vessels were damaged in early diabetic retina,which was ameliorated to differential extents by each drug.The expression of VEGF and FGF2 proteins was significantly upregulated in early diabetic retina,and normalized by RC28-E at all dosages and by the corresponding Traps.The upregulation of ICAM-1 and TNF-αin diabetic retina was substantially suppressed by RC28-E and positive control drugs.CONCLUSION:Dual blockade of VEGF and FGF2 by RC28-E generates remarkable protective effects,including anti-apoptosis,anti-gliosis,anti-leakage,and improving ultrastructures and proinflammatory microenvironment,in early diabetic retina,thereby supporting further development of RC28-E into a novel and effective drug to diabetic retinopathy(DR).
基金supported by the National Key Research and Development Program of China(2017YFB0702600,2017YFB0702602,2017YFB0702602-2)the Shandong Provincial Natural Science Foundation(ZR2019MH076,ZR2022MH291)+3 种基金the Ministry of Science and Technology of the People’s Republic of China(“863 grant”,2012AA020206)the Department of Science and Technology of Shan-dong Province(20092009GG10002087)the National Natural Science Foundation of China(81603024,30973553)the NIH grant R01 CA186100,Wenzhou Institute University of Chinese Academy of Sciences,and Corbett Estate Fund for the Cancer Research(62285-531021-41800,62285-531021-51800,62285-531021-61800,62285-531021-71800).
文摘Despite significant advances in targeted therapies and immunotherapies,non-small cell lung cancer(NSCLC)continues to present a global health challenge,with a modest five-year survival rate of 28%,largely due to the emergence of treatment-resistant and metastatic tumors.In response,we synthesized a novel bioactive compound,ethyl 6-chlorocoumarin-3-carboxylyl L-theanine(TClC),which significantly inhibited NSCLC growth,epithelial mesenchymal transition(EMT),migration,and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity.TClC disrupts autocrine loops that promote tumor progression,particularly in stem-like CD133-positive NSCLC(CD133+LC)cells,which are pivotal in tumor metastasis.Through targeted molecular assays,we identified direct binding targets of TClC,including Akt,NF-κB,β-catenin,EZH2,and PD-L1.This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter,underscoring the compound’s poly-pharmacological potential.These results position TClC as a promising candidate for NSCLC treatment,signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.
基金supported by National Key Research and Development Plan(grant number:2022YFC2409902).
文摘Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.
基金This study was funded by RemeGen Co.,Ltd.This work was also supported by the National Natural Science Foundation of China(No.91959205)the Ministry of Science and Technology of China(No.2017YFC1308900,No.2018ZX09201-015)Beijing Municipal Health Commission(No.2020-1-1022)。
文摘Background:Current treatment options for human epidermal growth factor receptor 2(HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit.Further,there is no specific treatment for HER2 immunohistochemistry(IHC)2+and fluorescence in-situ hybridization-negative patients.Here,we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer.Methods:Patients with HER2-overexpressing(IHC 2+or 3+),locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC482.5 mg/kg alone every 2 weeks.The primary endpoint was the objective response rate(ORR)assessed by an independent review committee.Secondary endpoints included progressionfree survival(PFS),overall survival(OS),duration of response,time to progression,disease control rate,and safety.Results:Of 179 patients screened,125 were eligible and received RC48 treatment.The ORR was 24.8%(95%confidence interval[CI]:17.5%-33.3%).The median PFS and OS were 4.1 months(95%CI:3.7-4.9 months)and 7.9 months(95%CI:6.7-9.9 months),respectively.The most frequently reported adverse events were decreased white blood cell count(53.6%),asthenia(53.6%),hair loss(53.6%),decreased neutrophil count(52.0%),anemia(49.6%),and increased aspartate aminotransferase level(43.2%).Serious adverse events(SAEs)occurred in 45(36.0%)patients,and RC48-related SAEs were mainly decreased neutrophil count(3.2%).Seven patients had adverse events that led to death were not RC48-related.Conclusions:RC48 showed promising activity with manageable safety,suggesting potential application in patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.
