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首页> 外文期刊>Neoplasia: an international journal for oncology research >Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models
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Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models

机译：Mirvetuximab Soravtansine（IMGN853），一种叶酸受体靶向抗体-药物结合物，可增强卵巢癌模型中标准治疗药物的活性

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Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC. Combinations of IMGN853 with carboplatin or doxorubicin resulted in synergistic antiproliferative effects in the IGROV-1 ovarian cancer cell line in vitro. IMGN853 potentiated the cytotoxic activity of carboplatin via growth arrest and augmented DNA damage; cell cycle perturbations were also observed in cells treated with the IMGN853/doxorubicin combination. These benefits translated into improved antitumor activity in patient-derived xenograft models in vivo in both the platinum-sensitive (IMGN853/carboplatin) and platinum-resistant (IMGN853/pegylated liposomal doxorubicin) settings. IMGN853 co-treatment also improved the in vivo efficacy of bevacizumab in platinum-resistant EOC models, with combination regimens causing significant regressions and complete responses in the majority of tumor-bearing mice. Histological analysis of OV-90 ovarian xenograft tumors revealed that concurrent administration of IMGN853 and bevacizumab caused rapid disruption of tumor microvasculature and extensive necrosis, underscoring the superior bioactivity profile of the combination regimen. Overall, these demonstrations of combinatorial benefit conferred by the addition of the first FRα-targeting ADC to established therapies provide a compelling framework for the potential application of IMGN853 in the treatment of patients with advanced ovarian cancer.
机译：叶酸受体α（FRα）的表达升高是上皮性卵巢癌（EOC）的特征，因此将该受体确立为开发治疗该疾病的新疗法的候选靶标。 Mirvetuximab soravtansine（IMGN853）是一种抗体-药物偶联物（ADC），其靶向FRα用于肿瘤定向递送的美登木素生物素DM4，这是一种通过抑制微管动力学诱导有丝分裂停滞的有效药物。在这里，在EOC的临床前模型中评估了IMGN853与批准的治疗药物的组合。 IMGN853与卡铂或阿霉素的组合在体外对IGROV-1卵巢癌细胞系产生协同抗增殖作用。 IMGN853通过阻止生长和增加DNA损伤来增强卡铂的细胞毒活性;在用IMGN853 /阿霉素组合治疗的细胞中也观察到细胞周期的扰动。这些益处转化为在患者敏感的异种移植模型中，在对铂敏感的（IMGN853 /卡铂）和对铂耐药的（IMGN853 /聚乙二醇脂质体阿霉素）的体内，提高了抗肿瘤活性。 IMGN853联合治疗还改善了贝伐单抗在铂耐药性EOC模型中的体内疗效，在大多数荷瘤小鼠中，联合用药方案可导致明显的消退和完全反应。 OV-90卵巢异种移植肿瘤的组织学分析显示，同时施用IMGN853和贝伐单抗可导致肿瘤微脉管系统快速破坏和广泛坏死，从而强调了联合治疗方案的出色生物活性。总体而言，通过将第一个靶向FRα的ADC加入已确立的疗法中，所产生的组合益处的这些证明为IMGN853在晚期卵巢癌患者的治疗中的潜在应用提供了令人信服的框架。

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