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
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).
