赛托珠单抗戈维汀（IMMU-132）在子宫和卵巢癌肉瘤中的临床前活性。

Preclinical activity of sacituzumab govitecan (IMMU-132) in uterine and ovarian carcinosarcomas.

作者信息

Lopez Salvatore, Perrone Emanuele, Bellone Stefania, Bonazzoli Elena, Zeybek Burak, Han Chanhee, Tymon-Rosario Joan, Altwerger Gary, Menderes Gulden, Bianchi Anna, Zammataro Luca, Manzano Aranzazu, Manara Paola, Ratner Elena, Silasi Dan-Arin, Huang Gloria S, Azodi Masoud, Schwartz Peter E, Raspagliesi Francesco, Angioli Roberto, Buza Natalia, Hui Pei, Bond Heather M, Santin Alessandro D

机构信息

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.

出版信息

Oncotarget. 2020 Feb 4;11(5):560-570. doi: 10.18632/oncotarget.27342.

BACKGROUND

Uterine and ovarian carcinosarcomas (CS) are rare cancers with poor prognosis. Sacituzumab-govitecan (SG) is a new class of antibody-drug-conjugate (ADC) targeting the human-trophoblast-cell-surface marker (Trop-2) conjugated with the active metabolite of irinotecan (SN-38). We evaluated the efficacy of SG against biologically aggressive CS.

METHODS

Trop-2 expression was evaluated in 10 formalin-fixed-paraffined-embedded (FFPE) CS by immunohistochemistry and 9 primary CS cell-lines by flow-cytometry. One Trop-2 low/negative (SARARK14) and two Trop-2 positive (SARARK4, SARARK9) cell-lines were tested in cell-viability assays . The antitumor activity of SG was tested in xenografts models (ie, SARARK9) with strong Trop-2 expression.

RESULTS

Strong/diffuse staining was seen in 30% (3/10) of FFPE tumors and 33% (3/9) of primary CS cell lines. Trop-2 positive cell-lines (SARARK4, SARARK9) showed higher sensitivity to SG when compared to Trop-2 low/negative (SARARK14) cell lines. In xenografts, twice-weekly intravenous administration of SG for three weeks showed a significant tumor growth inhibition when compared to control, to ADC control and to the naked AB (p=0.004, p=0.007 and p=0.0007, respectively). SG significantly improved overall survival at 90 days when compared to control groups (p<0.0001).

CONCLUSION

SG may represent a novel class of active drugs for carcinosarcomas patients overexpressing Trop-2.

背景

子宫和卵巢癌肉瘤（CS）是预后较差的罕见癌症。赛托珠单抗-戈维汀（SG）是一类新型的抗体药物偶联物（ADC），靶向人滋养层细胞表面标志物（Trop-2），并与伊立替康的活性代谢产物（SN-38）偶联。我们评估了SG对具有生物学侵袭性的CS的疗效。

方法

通过免疫组织化学在10例福尔马林固定石蜡包埋（FFPE）的CS中评估Trop-2表达，并通过流式细胞术在9个原发性CS细胞系中评估。在细胞活力测定中测试了1个Trop-2低表达/阴性（SARARK14）细胞系和2个Trop-2阳性（SARARK4、SARARK9）细胞系。在具有强Trop-2表达的异种移植模型（即SARARK9）中测试了SG的抗肿瘤活性。

结果

在30%（3/10）的FFPE肿瘤和33%（3/9）的原发性CS细胞系中观察到强/弥漫性染色。与Trop-2低表达/阴性（SARARK14）细胞系相比，Trop-2阳性细胞系（SARARK4、SARARK9）对SG表现出更高的敏感性。在异种移植中，与对照组、ADC对照组和裸抗体相比，每周两次静脉注射SG三周显示出显著的肿瘤生长抑制（分别为p=0.004、p=0.007和p=0.0007）。与对照组相比，SG在90天时显著改善了总生存期（p<0.0001）。