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 (ADCs) have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma.
Objective: To examine the activity of tumoral cluster of differentiation 70 (CD70) in uterine leiomyosarcoma and assess the antitumor activity of CD70-ADC treatment in uterine leiomyosarcoma.
Study design: Target membrane proteins were screened by profiling and comparing membrane protein expression in three 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 ADC with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F (MMAF) and investigated its antitumor effects against uterine leiomyosarcoma (in-vitro, in-vivo, and in patient-derived xenograft [PDX] models).
Results: CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the three 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-ADC, anti-CD70 monoclonal antibody was conjugated with a novel derivative of MMAF. CD70-ADC showed significant antitumor effects on SK-LMS-1 cells (IC50 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70-ADC significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume: 129.8 versus 285.5 mm3, 54.5% relative reduction, P<0.001) and PDX mouse model (tumor volume: 128.1 versus 837.7 mm3, 84.7% relative reduction, P<0.001).
Conclusion: Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70-ADC may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma.
Authors: Ruriko Nakae, Shinya Matsuzaki, Satoshi Serada, Koji Matsuo, Mayu Shiomi, Kazuaki Sato, Yoshikazu Nagase, Satoko Matsuzaki, Satoshi Nakagawa, Kosuke Hiramatsu, Akiko Okazawa, Toshihiro Kimura, Tomomi Egawa-Takata, Eiji Kobayashi, Yutaka Ueda, Kiyoshi Yoshino, Tetsuji Naka, Tadashi Kimura
; Full Source: American journal of obstetrics and gynecology 2020 Aug 18;S0002-9378(20)30856-5. doi: 10.1016/j.ajog.2020.08.028.