MET抗体偶联药物SHR-A1403在胃癌中的作用初探

MET-antibody drug conjugate SHR-A1403 for gastric cancer

目的探索MET抗体偶联药物SHR-A1403在胃癌中的抗肿瘤作用及潜在作用机制。方法 MET表达水平不同的5株胃癌细胞系MKN45、MGC803、HGC27、MKN28及NCI-N87,经不同浓度的SHR-A1403和裸抗(MET-mAb)处理后,细胞计数试剂盒检测细胞增殖活性;10例人源化胃癌移植瘤(patient-derived xenograft,PDX)模型接受SHR-A1403治疗,明确抑瘤情况。用免疫组织化学(immunohistochemistry,IHC)方法检测肿瘤组织的增殖细胞比例和凋亡情况。结果 SHR-A1403抑制体外胃癌细胞增殖呈剂量和时间依赖性,其抗增殖能力与细胞中MET蛋白表达呈正相关。在10例PDX模型中,SHR-A1403在3例PDX模型中具有较高的抑瘤作用,抑瘤率分别为73%、88%、88%,其中2例PDX组织MET表达IHC 3+,1例PDX组织MET无表达。SHR-A1403通过抑制PDX组织中肿瘤细胞的增殖,并诱导细胞凋亡而发挥抑瘤作用。结论 SHR-A1403在部分胃癌中具有明显的抑瘤作用,但SHR-A1403的明确疗效预测标志物尚需深入探索。

Objective To investigate antitumor activity and underlying mechanisms of MET-antibody drug conjugate(SHR-A1403) in gastric cancer(GC).Method Human MKN45,MGC803,HGC27,MKN28 and NCI-N87 GC cell lines were used to evaluate cell viability using cell counting kit(CCK)-8 assay in vitro.For in vivo studies,ten patient-derived xenografts(PDXs) models were treated with SHR-A1403 to assess its antitumor activity.The proportion of proliferative cells and apoptosis cells in PDX tissues after SHR-A1403 treatment were determined by immunohistochemistry.Result SHR-A1403 inhibited the proliferation of human GC cells in a dose-and time-dependent manner,and the anti-proliferative effect of SHR-A1403 was positively related with MET expression.In vivo,SHR-A1403 exerted strong antitumor activity in 3 out of 10 PDXs models with tumor growth inhibition(TGI) 73%,88% and 88%,respectively.Among these 3 PDXs tissues,2 tissues showed high MET expression(IHC 3 +) and 1 tissue displayed MET negative.SHR-A1403 played its antitumor activity through inhibiting cell proliferation and inducing cell apoptosis.Conclusion SHR-A1403 exerted strong antitumor activity in partial gastric cancers,but the definite predictive biomarkers of SHR-A1403 were needed to be further investigated.