Trop-2及靶向Trop-2抗体偶联药物在妇科恶性肿瘤中的应用进展

doi:10.12280/gjfckx.20240887

摘要/Abstract

摘要：

宫颈癌、卵巢癌和子宫内膜癌是妇科常见的恶性肿瘤，发病率呈上升趋势且患病群体趋于年轻化，严重威胁女性健康。尽管经过规范治疗部分患者的病情可以得到改善，但仍有很大一部分患者病情恶化，预后不佳，临床上亟待寻找可用于精准治疗及提高预后的新靶点。人滋养细胞表面抗原2（trophoblast cell surface antigen 2，Trop-2）是一种在多种肿瘤组织中高表达的跨膜糖蛋白，通过细胞表面受体信号在宫颈癌、子宫内膜癌、卵巢癌的增殖、侵袭、转移等多个生物学过程中发挥重要作用，使其成为早期诊断的重要潜在标志物，并且可用于评估肿瘤的进展和患者的预后状况。在治疗方面，针对Trop-2的抗体药物偶联物（antibody-drug conjumate，ADC）等靶向治疗策略显示出良好的应用前景。例如，戈沙妥珠单抗（sacituzumab govitecan，SG）作为靶向Trop-2的ADC，在妇科恶性肿瘤的治疗中已取得显著疗效，并被纳入相关临床应用指南。目前，多项针对Trop-2的ADC药物的临床试验正在积极开展，Trop-2有望在妇科恶性肿瘤的早期发现和治疗中发挥越来越重要的作用，为患者带来更大的生存希望。

关键词: 人滋养细胞表面抗原2, 抗体药物偶联物, 宫颈肿瘤, 卵巢肿瘤, 子宫内膜肿瘤, 治疗, 预后

Abstract:

Cervical cancer, ovarian cancer and endometrial cancer are common gynecological malignancies with increasing incidence and younger age groups, which seriously threatens women′s health. Although the conditions of some patients can be improved after standardized treatment, a large proportion of patients still have deteriorating conditions and poor prognosis, and there is an urgent need to find new targets for precise treatment and improved prognosis. Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein that is highly expressed in various tumor tissues, and plays an important role in the proliferation, invasion and metastasis of cervical, endometrial and ovarian cancers through cell surface receptor signaling, making it an important potential marker for early diagnosis, and can be used to access tumor progression and patient prognosis. In the therapeutic aspect, targeted therapeutic strategies such as antibody-drug conjugate (ADC) against Trop-2 have shown promising applications. For example, sacituzumab govitecan (SG), as an ADC targeting Trop-2, has achieved remarkable efficacy in the treatment of gynecological malignancies and has been incorporated into relevant clinical application guidelines. At present, a number of clinical trials of ADC drugs targeting Trop-2 are actively underway, and Trop-2 is expected to play an increasingly important role in the early detection and treatment of gynecological malignant tumors, and bring patients greater hope for survival.

Key words: Trophoblast cell surface antigen 2, Antibody-drug conjugate, Uterine cervical neoplasms, Ovarian neoplasms, Endometrial neoplasms, Therapy, Prognosis

白耀俊, 王思瑶, 令菲菲, 张森淮, 李红丽, 刘畅. Trop-2及靶向Trop-2抗体偶联药物在妇科恶性肿瘤中的应用进展[J]. 国际妇产科学杂志, 2025, 52(1): 1-7.

BAI Yao-jun, WANG Si-yao, LING Fei-fei, ZHANG Sen-huai, LI Hong-li, LIU Chang. Progress of Trop-2 and Targeted Trop-2 Antibody-Coupled Drugs in Gynecological Malignant Tumors[J]. Journal of International Obstetrics and Gynecology, 2025, 52(1): 1-7.

图/表 1

参考文献 38

[1]	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660.
[2]	Tymon-Rosario J, Gorman M, Richardson DL, et al. Advances in antibody-drug conjugates for gynecologic malignancies[J]. Curr Opin Obstet Gynecol, 2023, 35(1):6-14. doi: 10.1097/GCO.0000000000000838.
[3]	Perrone E, Manara P, Lopez S, et al. Sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo[J]. Mol Oncol, 2020, 14(3):645-656. doi: 10.1002/1878-0261.12627.
[4]	Tymon-Rosario J, Zeybek B, Santin AD. Novel antibody-drug conjugates: current and future roles in gynecologic oncology[J]. Curr Opin Obstet Gynecol, 2021, 33(1):26-33. doi: 10.1097/GCO.0000000000000642.
[5]	Koltai T, Fliegel L. The Relationship between Trop-2, Chemotherapeutic Drugs, and Chemoresistance[J]. Int J Mol Sci, 2023, 25(1):87. doi: 10.3390/ijms25010087.
[6]	孙丽平, 苗庆芳. 以TROP2为靶点的抗体偶联药物相关研究进展[J]. 中国医药生物技术, 2023, 18(5):428-434. doi: 10.3969/j.issn.1673-713X.2023.05.006.
[7]	Corti C, Boscolo Bielo L, Schianca AC, et al. Future potential targets of antibody-drug conjugates in breast cancer[J]. Breast, 2023, 69:312-322. doi: 10.1016/j.breast.2023.03.007. pmid: 36996620
[8]	Qiu S, Zhang J, Wang Z, et al. Targeting Trop-2 in cancer: Recent research progress and clinical application[J]. Biochim Biophys Acta Rev Cancer, 2023, 1878(4): 188902. doi: 10.1016/j.bbcan.2023.188902.
[9]	Sakach E, Sacks R, Kalinsky K. Trop-2 as a Therapeutic Target in Breast Cancer[J]. Cancers(Basel), 2022, 14(23):5936. doi: 10.3390/cancers14235936.
[10]	Revathidevi S, Murugan AK, Nakaoka H, et al. APOBEC: A molecular driver in cervical cancer pathogenesis[J]. Cancer Lett, 2021, 496:104-116. doi: 10.1016/j.canlet.2020.10.004. pmid: 33038491
[11]	Zeybek B, Manzano A, Bianchi A, et al. Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan[J]. Sci Rep, 2020, 10(1):973. doi: 10.1038/s41598-020-58009-3.
[12]	冯倩倩, 卢丹. TROP2在宫颈病变中的表达及临床研究[J]. 实用妇科内分泌电子杂志, 2020, 7(28):53,57.
[13]	龙腾飞, 闫芸芳, 彭广兰, 等. 人滋养细胞表面抗原在宫颈病变中表达的研究[J]. 安徽医科大学学报, 2013, 48(10):1240-1242.
[14]	杨旭峰, 雷龙春, 成争艳. 宫颈鳞癌组织TROP2蛋白的表达特点及其与预后的相关性[J]. 临床与病理杂志, 2018, 38(11):2371-2377. doi: 10.3978/j.issn.2095-6959.2018.11.013.
[15]	杨黎娜, 姚雪静. 以Trop-2为靶标的抗肿瘤研究进展[J]. 中外医学研究, 2021, 19(2):189-191. doi: 10.14033/j.cnki.cfmr.2021.02.074.
[16]	Bignotti E, Todeschini P, Calza S, et al. Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients[J]. Eur J Cancer, 2010, 46(5):944-953. doi: 10.1016/j.ejca.2009.12.019. pmid: 20060709
[17]	马水根, 杨进, 廖革望, 等. TROP2在卵巢浆液性囊腺癌中的表达及其与预后的关系[J]. 现代生物医学进展, 2015, 15(18):3530-3533,3543. doi: 10.13241/j.cnki.pmb.2015.18.033.
[18]	吴彬. TROP2在浆液性卵巢癌组织中的表达及对其生物学行为的影响[D]. 济南: 山东大学, 2019.
[19]	Wen Y, Ouyang D, Zou Q, et al. A literature review of the promising future of TROP2: a potential drug therapy target[J]. Ann Transl Med, 2022, 10(24):1403. doi: 10.21037/atm-22-5976.
[20]	龙腾飞, 程玲慧, 王彦, 等. 人滋养细胞表面抗原(Trop-2)在病变子宫内膜中表达的研究[J]. 现代生物医学进展, 2020, 20(24):4793-4796. doi: 10.13241/j.cnki.pmb.2020.24.044.
[21]	Shen Y, Shi R, Zhao R, et al. Clinical application of liquid biopsy in endometrial carcinoma[J]. Med Oncol, 2023, 40(3):92. doi: 10.1007/s12032-023-01956-4. pmid: 36757457
[22]	Bignotti E, Zanotti L, Calza S, et al. Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma[J]. BMC Clin Pathol, 2012,12:22. doi: 10.1186/1472-6890-12-22.
[23]	Vranic S, Gatalica Z. Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers[J]. Bosn J Basic Med Sci, 2022, 22(1):14-21. doi: 10.17305/bjbms.2021.6100.
[24]	Tarantino P, Carmagnani Pestana R, Corti C, et al. Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies[J]. CA Cancer J Clin, 2022, 72(2):165-182. doi: 10.3322/caac.21705.
[25]	Lombardi P, Filetti M, Falcone R, et al. Overview of Trop-2 in Cancer: From Pre-Clinical Studies to Future Directions in Clinical Settings[J]. Cancers(Basel), 2023, 15(6):1744. doi: 10.3390/cancers15061744.
[26]	王浩, 黄佳, 钟薇, 等. 靶向Trop-2的抗体偶联药物:戈沙妥珠单抗[J]. 中国新药与临床杂志, 2023, 42(8):498-502. doi: 10.14109/j.cnki.xyylc.2023.08.04.
[27]	Guerra E, Alberti S. The anti-Trop-2 antibody-drug conjugate Sacituzumab Govitecan-effectiveness, pitfalls and promises[J]. Ann Transl Med, 2022, 10(9):501. doi: 10.21037/atm-22-621. pmid: 35928735
[28]	中国抗癌协会宫颈癌专业委员会, 周晖, 张丙忠, 等. 妇科恶性肿瘤抗体偶联药物临床应用指南(2024年版)[J]. 中国实用妇科与产科杂志, 2024, 40(5):516-525. doi: 10.19538/j.fk2024050111.
[29]	Tymon-Rosario JR, Gorman M, Santin AD. Targeted Therapies in the Treatment of Uterine Serous Carcinoma[J]. Curr Treat Options Oncol, 2022, 23(12):1804-1817. doi: 10.1007/s11864-022-01030-7.
[30]	杨琦, 李翠翠, 邱永康, 等. Trop2靶向的肿瘤分子影像及治疗研究进展[J]. 中国医学影像学杂志, 2022, 30(9):970-973,978. doi: 10.3969/j.issn.1005-5185.2022.09.021.
[31]	Varughese J, Cocco E, Bellone S, et al. High-grade, chemotherapy-resistant primary ovarian carcinoma cell lines overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibody[J]. Gynecol Oncol, 2011, 122(1):171-177. doi: 10.1016/j.ygyno.2011.03.002. pmid: 21453957
[32]	Han C, Perrone E, Zeybek B, et al. In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma[J]. Gynecol Oncol, 2020, 156(2):430-438. doi: 10.1016/j.ygyno.2019.11.018.
[33]	Perrone E, Lopez S, Zeybek B, et al. Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer[J]. Front Oncol, 2020,10:118. doi: 10.3389/fonc.2020.00118.
[34]	姚雪, 刘金荣, 殷郑娜, 等. 抗Trop-2 IgG抗体联合顺铂对卵巢癌细胞特性的影响[J]. 临床和实验医学杂志, 2022, 21(18):1949-1953. doi: 10.3969/j.issn.1671-4695.2022.18.013.
[35]	褚楚, 刘金荣, 张慧林, 等. 人源抗Trop-2 Fab对宫颈癌细胞生物学特性的影响[J]. 南京医科大学学报(自然科学版), 2015, 35(3):320-325. doi: 10.7655/NYDXBNS20150305.
[36]	Chiba Y, Kojima Y, Yazaki S, et al. Trop-2 expression and the tumor immune microenvironment in cervical cancer[J]. Gynecol Oncol, 2024, 187:51-57. doi: 10.1016/j.ygyno.2024.04.022. pmid: 38723340
[37]	Furlanetto J, Marmé F, Loibl S. Sacituzumab govitecan: past, present and future of a new antibody-drug conjugate and future horizon[J]. Future Oncol, 2022, 18(28):3199-3215. doi: 10.2217/fon-2022-0407. pmid: 36069628
[38]	Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial[J]. Ann Oncol, 2021, 32(6):746-756. doi: 10.1016/j.annonc.2021.03.005. pmid: 33741442

药物名称	试验编号	临床阶段	入组人群	估计完成日期
SG（IMMU-132）	NCT04251416	Ⅱ期	复发性子宫内膜癌	2026年2月
	NCT05838521	Ⅱ期	复发性宫颈癌	正在招募
	NCT06028932	Ⅱ期	铂耐药复发性卵巢癌	2027年11月
	NCT06040970	Ⅰ期	铂敏感复发性卵巢癌、子宫内膜癌（SG+顺铂）	未招募
	NCT03964727	Ⅱ期	转移性实体瘤，包括子宫内膜癌	2026年6月
	NCT05119907	Ⅱ期	局部晚期或转移性实体瘤，包括宫颈癌队列	2025年12月
	NCT04826341	Ⅰ/Ⅱ期	HRD阳性肿瘤：+Berzosertib（选择性ATR激酶抑制剂）	2027年3月
SKB-264	NCT04152499	Ⅰ/Ⅱ期	晚期实体瘤，包括EOC、子宫内膜癌	2026年7月
Dato-DXd	NCT05489211	Ⅱ期	晚期/转移性实体瘤，包括子宫内膜癌、卵巢癌	2026年8月
AZD5305	NCT04644068	Ⅰ/Ⅱ期	晚期实体瘤，包括卵巢癌	2026年12月

药物名称	试验编号	临床阶段	入组人群	估计完成日期
SG（IMMU-132）	NCT04251416	Ⅱ期	复发性子宫内膜癌	2026年2月
	NCT05838521	Ⅱ期	复发性宫颈癌	正在招募
	NCT06028932	Ⅱ期	铂耐药复发性卵巢癌	2027年11月
	NCT06040970	Ⅰ期	铂敏感复发性卵巢癌、子宫内膜癌（SG+顺铂）	未招募
	NCT03964727	Ⅱ期	转移性实体瘤，包括子宫内膜癌	2026年6月
	NCT05119907	Ⅱ期	局部晚期或转移性实体瘤，包括宫颈癌队列	2025年12月
	NCT04826341	Ⅰ/Ⅱ期	HRD阳性肿瘤：+Berzosertib（选择性ATR激酶抑制剂）	2027年3月
SKB-264	NCT04152499	Ⅰ/Ⅱ期	晚期实体瘤，包括EOC、子宫内膜癌	2026年7月
Dato-DXd	NCT05489211	Ⅱ期	晚期/转移性实体瘤，包括子宫内膜癌、卵巢癌	2026年8月
AZD5305	NCT04644068	Ⅰ/Ⅱ期	晚期实体瘤，包括卵巢癌	2026年12月