GDF15单抗筛选及其联合卡铂逆转卵巢癌铂耐药的研究OA
Screening of anti-GDF15 monoclonal antibodies and their combination with carboplatin to reverse platinum resistance in ovarian cancer
目的 探讨生长分化因子15(growth differentiation factor 15,GDF15)单克隆抗体在逆转卵巢癌铂耐药中的作用,并筛选疗效最佳的候选抗体,同时阐明其潜在分子机制.方法 于2025年4月至2026年1月在中国医学科学院化学研究所和中国医学科学院北京协和医院肿瘤医院构建SK-OV-3-R铂耐药细胞系及患者来源异种移植(patient-derived xenograft,PDX)模型.体内外平行筛选5种GDF15单克隆抗体以确定最优候选.采用二苯基四氮唑溴盐(MTT)法检测细胞活力,异硫氰酸荧光素标记的膜联蛋白V/碘化丙啶(Annexin V-FITC/PI)双染结合流式细胞术评估细胞凋亡;通过γ-H2AX流式检测评估DNA损伤水平;采用蛋白激酶B(AKT)激动剂和抑制剂干预验证相关信号通路.PDX模型中监测肿瘤体积并计算肿瘤生长抑制率(tumor growth inhibition,TGI).结果 筛选确定CTL-002为最优GDF15单克隆抗体.在SK-OV-3-R细胞中,CTL-002联合卡铂可显著增强抗肿瘤效应,半数抑制浓度(IC50)由29.47 μmol/L降低至13.60 μmol/L,凋亡率升高至(26.85±1.6)％.同时,联合治疗能显著提高γ-H2AX平均荧光强度,提示DNA损伤水平增加.机制研究表明,AKT抑制剂可模拟CTL-002的增敏作用,而AKT激动剂可部分逆转其效应.在PDX模型中,联合治疗组终点肿瘤体积为(170.37±17.72)mm3,肿瘤体积抑制率(TGI)达66.3％,显著优于卡铂单药组(47.9％).结论 GDF15单克隆抗体CTL-002可显著增强卡铂对铂耐药卵巢癌的体外抑制效应并提高体内抑瘤效果,提示GDF15单克隆抗体具有逆转卵巢癌铂耐药的潜在应用价值.
Objective To investigate the role of Growth Differentiation Factor 15(GDF15)monoclonal antibodies in reversing platinum resistance in ovarian cancer,to identify the most effective candidate antibody,and to explore the underlying molecular mechanisms.Methods This study was carried out from April 2025 to January 2026 at the Institute of Chemistry,Chinese Academy of Sciences,and the Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College.A platinum-resistant ovarian cancer cell line(SK-OV-3-R)and a patient-derived xenograft(PDX)model were established.Five GDF15 monoclonal antibodies were screened in parallel in vitro and in vivo to determine the optimal candidate.Cell viability was assessed by MTT assay,and apoptosis was evaluated using Annexin V-FITC/PI staining followed by flow cytometry.DNA damage was measured by γ-H2AX flow cytometry.AKT activator and inhibitor were applied to investigate the involvement of the PI3K/AKT signaling pathway.Tumor volume and tumor growth inhibition(TGI)were assessed in the PDX model.Results CTL-002 was identified as the most effective GDF15 monoclonal antibody.In SK-OV-3-R cells,CTL-002 combined with carboplatin significantly enhanced antitumor activity,reducing the IC50 from 29.47 μmol/L to 13.60 μmol/L and increasing the apoptosis rate to(26.85±1.6)％.Meanwhile,the combination treatment markedly increased γ-H2AX mean fluorescence intensity,indicating elevated DNA damage.Mechanistically,AKT inhibition mimicked the sensitizing effect of CTL-002,whereas AKT activatior partially reversed it.In the PDX model,the combination therapy significantly suppressed tumor growth,with a final tumor volume of(170.37±17.72)mm3 and a TGI of 66.3％,which was superior to carboplatin monotherapy(47.9％).Conclusion The anti-GDF15 monoclonal antibody CTL-002 can significantly enhance the in vitro inhibitory effect of carboplatin against platinum-resistant ovarian cancer and improve its antitumor efficacy in vivo,suggesting that anti-GDF15 monoclonal antibodies have potential clinical value for reversing platinum resistance in ovarian cancer.
李泓瑶;孙怡;徐梦珂;赵丹
国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院,北京 100021国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院,北京 100021国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院,北京 100021国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院,北京 100021
医药卫生
卵巢癌GDF15单克隆抗体卡铂
ovarian cancerGDF15monoclonal antibodycarboplatin
《中国实用妇科与产科杂志》 2026 (5)
560-564,5
北京市自然科学基金(7252116) Beijing Natural Science Foundation(7252116)
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