Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRα as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors (P < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FRα, induced twofold increase in median survival (P < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRα 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment. Mol Cancer Ther; 17(5); 1003–11. ©2018 AACR.

中文翻译：

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IMGN853（一种靶向与 DM4 相关的叶酸受体 Alpha 的抗体-药物偶联物）在生物学侵袭性子宫内膜癌中的体外和体内活性

3 级子宫内膜样癌和子宫浆液性癌 (USC) 占子宫内膜癌死亡的绝大多数。本研究的目的是确定这些生物侵袭性（II 型）子宫内膜癌中叶酸受体 α (FRα) 的表达，并评估 FRα 作为 IMGN853（mirvetuximab soravtansine）的可靶向受体。通过免疫组织化学 (IHC) 和流式细胞术在 90 个子宫内膜样和 USC 样本中评估 FRα 的表达。在表达不同水平 FRα 的原代子宫癌细胞系中研究了体外细胞毒活性和旁观者效应。在异种移植物/患者来源的异种移植物 (PDX) 模型中评估了 IMGN853 的体内抗肿瘤功效。半定量 IHC 分析表明，41% 的 USC 患者过度表达 FRα。此外，FRα的过度表达（即，2+) 通过流式细胞术在 22% (2/9) 的原代子宫内膜样细胞和 27% (3/11) 的原代 USC 细胞系中检测到。在表达 2+ 的子宫肿瘤细胞系中，与对照相比，IMGN853 治疗观察到细胞毒性增加。相比之下，当暴露于 IMGN853 与对照时，具有低 FRα 的肿瘤细胞系没有显示出差异。IMGN853 诱导旁观者杀死 FRα = 0 肿瘤细胞。在子宫内膜样异种移植模型 (END(K)265) 中，携带 2+ FRα，IMGN853 治疗显示肿瘤完全消退（P < 0.001）。在 USC PDX 模型 (BIO(K)1) 中用 IMGN853 治疗，表达 2+ FRα，导致中位生存期增加两倍 (P < 0.001)。IMGN853 在生物侵袭性 FRα 2+ 子宫癌中显示出令人印象深刻的抗肿瘤活性。这些临床前数据表明，过度表达 FRα 的化疗耐药/复发性子宫内膜癌患者可能受益于这种治疗。摩尔癌症治疗; 17(5); 1003-11。©2018 AACR。