CD70 antibody-drug conjugate as a potential therapeutic agent for uterine leiomyosarcoma,American Journal of Obstetrics and Gynecology

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CD70 antibody-drug conjugate as a potential therapeutic agent for uterine leiomyosarcoma
American Journal of Obstetrics and Gynecology ( IF 8.7 ) Pub Date : 2020-08-19 , DOI: 10.1016/j.ajog.2020.08.028
Ruriko Nakae ₁ , Shinya Matsuzaki ₂ , Satoshi Serada ₃ , Koji Matsuo ₄ , Mayu Shiomi ₅ , Kazuaki Sato ₆ , Yoshikazu Nagase ₅ , Satoko Matsuzaki ₇ , Satoshi Nakagawa ₅ , Kosuke Hiramatsu ₅ , Akiko Okazawa ₅ , Toshihiro Kimura ₅ , Tomomi Egawa-Takata ₈ , Eiji Kobayashi ₅ , Yutaka Ueda ₅ , Kiyoshi Yoshino ₉ , Tetsuji Naka ₃ , Tadashi Kimura ₅

Affiliation

Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan; Department of Obstetrics and Gynecology, Sumitomo Hospital, Osaka, Japan.
Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA.
Center for Intractable Immune Disease, Kochi Medical School, Kochi University, Kochi, Japan.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan.
Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA; Department of Obstetrics and Gynecology, Otemae Hospital, Osaka, Japan.
Department of Obstetrics and Gynecology, Osaka Police Hospital, Osaka, Japan; Department of Obstetrics and Gynecology, Kansai Rosai Hospital, Amagasaki, Japan.
Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan; Department of Obstetrics and Gynecology, University of Occupational and Environmental Health, Fukuoka, Japan.

Background

Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy originating in the myometrium of the uterine corpus that tends to recur even after complete surgical excision. Current therapeutic agents have only modest effects on uterine leiomyosarcoma. Although antibodies and antibody-drug conjugates have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma.

Objective

This study aimed to examine the activity of tumoral CD70 in uterine leiomyosarcoma and assess the antitumor activity of CD70–antibody-drug conjugate treatment in uterine leiomyosarcoma.

Study Design

Target membrane proteins were screened by profiling and comparing membrane protein expression in 3 uterine leiomyosarcoma cell lines (SK-UT-1, SK-LMS-1, and SKN) and normal uterine myometrium cells using the isobaric tags for relative and absolute quantitation labeling method. Western blotting, fluorescence-activated cell sorting analyses, and immunohistochemistry were used to examine CD70 expression in the membrane proteins in uterine leiomyosarcoma cell lines and clinical samples. We developed an antibody-drug conjugate with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F and investigated its antitumor effects against uterine leiomyosarcoma (in vitro, in vivo, and in patient-derived xenograft models).

Results

CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the 3 uterine leiomyosarcoma cell lines, CD70 expression was confirmed in SK-LMS-1 cells by western blotting and fluorescence-activated cell sorting analysis. CD70 overexpression was observed in 19 of 21 (90.5%) tumor specimens from women with uterine leiomyosarcoma. To generate CD70–antibody-drug conjugate, anti-CD70 monoclonal antibody was conjugated with a novel derivative of monomethyl auristatin F. CD70–antibody-drug conjugate showed significant antitumor effects on SK-LMS-1 cells (half maximal inhibitory concentration, 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70–antibody-drug conjugate significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume, 129.8 vs 285.5 mm³; relative reduction, 54.5%; P<.001) and patient-derived xenograft mouse model (tumor volume, 128.1 vs 837.7 mm³; relative reduction, 84.7%; P<.001).

Conclusion

Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70–antibody-drug conjugate may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma.

中文翻译：

CD70抗体-药物偶联物作为子宫平滑肌肉瘤的潜在治疗剂

背景

子宫平滑肌肉瘤是一种罕见且具有侵略性的妇科恶性肿瘤，起源于子宫体的子宫肌层，即使在完全手术切除后也倾向于复发。当前的治疗剂对子宫平滑肌肉瘤只有中等程度的作用。尽管抗体和抗体-药物偶联物已被公认为可用于其他癌症的靶向治疗，但尚无研究评估这种方法对子宫平滑肌肉瘤的作用。

目的

这项研究的目的是检查子宫平滑肌肉瘤中肿瘤CD70的活性，并评估子宫平滑肌肉瘤中CD70-抗体-药物结合治疗的抗肿瘤活性。

学习规划

通过对3种子宫平滑肌肉瘤细胞系（SK-UT-1，SK-LMS-1和SKN）和正常子宫肌层细胞中的膜蛋白表达进行分析并比较膜蛋白的表达，并使用等压标记进行相对定量和绝对定量标记。Western印迹，荧光激活的细胞分选分析和免疫组化被用来检查子宫平滑肌肉瘤细胞系和临床样品中膜蛋白CD70的表达。我们开发了一种与目标膜蛋白的单克隆抗体（与单甲基澳瑞他汀F连接）的抗体-药物偶联物，并研究了其对子宫平滑肌肉瘤的抗肿瘤作用（在体外，体内以及在患者来源的异种移植模型中）。

结果

CD70被鉴定为在子宫平滑肌肉瘤细胞系中高表达的特异性抗原。在3种子宫平滑肌肉瘤细胞系中，通过western印迹和荧光激活细胞分选分析证实了SK-LMS-1细胞中的CD70表达。在患有子宫平滑肌肉瘤的妇女的21例肿瘤标本中，有19例（90.5％）观察到CD70过表达。为了产生CD70-抗体-药物偶联物，将抗CD70单克隆抗体与新型单甲基澳瑞他汀F衍生物偶联。CD70-抗体-药物偶联物对SK-LMS-1细胞显示出显着的抗肿瘤作用（半数最大抑制浓度为0.120 nM ），并且对CD70阴性子宫平滑肌肉瘤细胞没有抗肿瘤作用。CD70-抗体-药物偶联物在SK-LMS-1异种移植小鼠模型中显着抑制了肿瘤的生长（肿瘤体积，分别为129.8和285.5 mm³；相对减少54.5％；P <.001）和患者来源的异种移植小鼠模型（肿瘤体积，分别为128.1和837.7 mm ³ ;相对减少，为84.7％; P <.001）。