双抗肿瘤抗体药PD-L1/TGF-β对小鼠脑原位人脑胶质瘤模型的抑制作用研究  

Inhibitory effects of dual anti-tumor antibody drug PD-L1/TGF-βon orthotopic implantation model of brain glioma in mice

作　　者：党明安 赵云霞 王园园 江魁 DANG Ming-an;ZHAO Yun-xia;WANG Yuan-yuan;JIANG Kui(Henan Provincial Center for Drug Evaluation and Inspection,Zhengzhou 450008,China;Henan Biomedical Industry Research Institute,Xinxiang 453200,China;International Joint Laboratory of Genetic Engineering Drugs in Henan Province,Xinxiang 453200,China;Henan Provincial Key Laboratory of Recombinant Protein Drugs,Xinxiang 453200,China)

机构地区：[1]河南省药品审评查验中心,河南郑州450008 [2]河南省生物医药产业研究院,河南新乡453200 [3]河南省基因工程药物国际联合实验室,河南新乡453200 [4]河南省重组蛋白药物重点实验室,河南新乡453200

出　　处：《药学学报》2025年第3期739-746,共8页Acta Pharmaceutica Sinica

摘　　要：本研究主要探究程序性死亡配体1/转化生长因子β(PD-L1/TGF-β)双抗药物在huHSC-NCG小鼠脑原位移植人脑胶质瘤细胞U251-luciferase荷瘤模型中的抗肿瘤作用[本实验所有动物实验均获得集萃药康实验动物伦理委员会批准,伦理审查编号:GPTAP20230706-3]。体外采用流式细胞术检测PD-L1/TGF-β双抗药物与U251细胞表面PD-L1靶点的抗体抗原结合活性。通过人源化免疫系统的小鼠脑胶质瘤原位模型评价PD-L1/TGF-β双抗药物体内药效。小动物活体成像和脑组织重量(含肿瘤组织)结果表明,PD-L1/TGF-β双抗药对原位脑胶质瘤的生长有抑制作用。脑组织中药物含量(ELISA法)和药物分布(免疫组化法)结果表明,PD-L1/TGF-β双抗药物能够进入脑胶质瘤内部发挥免疫检查点的功能,从而对脑胶质瘤发挥抑制作用。小鼠脑组织的免疫荧光染色结果表明,药物激活了免疫系统,与免疫系统存在协同抗肿瘤效应。本研究结果表明,PD-L1/TGF-β双抗药物在小鼠脑原位人脑胶质瘤模型中透过血肿瘤屏障(BTB),因此表现出较强抑瘤作用。综上所述,PD-L1/TGF-β双抗药物对人脑胶质瘤的抑制作用为人脑胶质瘤的治疗提供新策略。This study mainly explored the anti-tumor effects of programmed death ligand 1/transforming growth factor-β(PD-L1/TGF-β)bispecific antibody drugs in the huHSC-NCG mouse brain orthotopic transplantation model of human glioma cell U251-luciferase(all animal experiments in this study were approved by the Experimental Animal Ethics Committee of GemPharmatech,and the ethics review number is GPTAP20230706-3).The antibody-antigen binding activity of the PD-L1/TGF-βbispecific antibody drugs to PD-L1 target on U251 cells was detected by flow cytometry in vitro.The antitumor activity of PD-L1/TGF-βbispecific antibody drugs was evaluated using a brain glioma in orthotopic implantation model with humanized immune system.Live animal imaging and brain tissue(including tumor tissue)weight results showed that the PD-L1/TGF-βdual antibody drug had an inhibitory effect on the growth of glioma in situ.The results of drug content(ELISA assay)and drug distribution(immunohistochemistry assay)in brain tissue showed that PD-L1/TGF-βdual antibody could enter the brain glioma and play the function of immune checkpoint,thus playing an inhibitory role in brain glioma.Immunofluorescence staining of mouse brain tissue showed that the drug activated the immune system and had synergistic anti-tumor effect with the immune system.These results showed that the PD-L1/TGF-βbispecific antibody drugs have broken through the blood-tumor barrier in orthotopic implantation model of mouse brain glioma and demonstrated a strong anti-tumor effect.In conclusion,the inhibitory effects of PD-L1/TGF-βbispecific antibody drugs on human brain glioma provides a new strategy for the treatment of human brain glioma.

关 键 词：双抗药物 huHSC-NCG小鼠 原位接种 脑胶质瘤 药效 血肿瘤屏障 

分 类 号：R966[医药卫生—药理学]