PDF(Pubmed)
Abstract：
Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.
摘要：
抗体-药物缀合物（ADC）代表了一种新型的靶向癌症疗法，将单克隆抗体的特异性与常规化疗的细胞毒性相结合。最近,ADC已在各种实体癌症中表现出改变实践的功效。抗NECTIN-4ADCenfortumabvedotin（EV）刚刚被批准用于尿路上皮癌患者，目前正在对去势抵抗前列腺癌患者进行研究（CRPC，例如II期ENCORE试验）。我们的目的是评估EV在已建立的前列腺癌（PCa）细胞系中的功效，并检查原发性肿瘤（PRIM）和远处转移（MET）中膜性NECTIN-4的表达。NECTIN-4在PCa细胞系组中异质表达。EV导致表达NECTIN-4的PCa细胞（22Rv1和LNCaP）的生长抑制，而NECTIN-4阴性PC-3细胞对EV的反应明显减弱，强调EV反应对其目标表达的依赖性。免疫组织化学染色显示NECTIN-4仅在患有肺和腹膜MET的CRPC患者的一个小亚组中中等膜性表达[n=3/22，H评分≥100，中位H评分140（IQR130-150）]，而100%的PRIM(n=48/48)和86.4%的普通MET站点(n=19/22)，包括淋巴结,骨骼和肝脏MET，NECTIN-4阴性。总之,EV可能对NECTIN-4阳性PCa有效。然而,我们的研究结果表明，肿瘤NECTIN-4表达在转移性PCa中主要较低，这表明EV可能仅在生物标志物分层的亚组中有效。
