Abstract 3853: CD70 antibody-drug conjugate: A novel therapeutic agent for platinum-resistant ovarian carcinoma

Abstract

Abstract Objective: The development of therapeutic agents for platinum-resistant ovarian carcinoma remains a significant issue. Currently, the use of antibody-drug conjugates (ADCs) represents an innovative therapeutic approach for various cancers. In this study, we examined the antitumor effect of a CD70-ADC on platinum-resistant serous ovarian carcinoma (SOC). Methods: The CD70 expression was examined in A2780 cells (an SOC cell line) by western blotting and fluorescence activated cell sorting analysis. Cisplatin resistant A2780 cell lines (A2780 CisR cells) were generated, and the IC50 values for the A2780 parent and A2780 CisR cells were determined using modified MTT assays. The A2780 CisR cells were transfected with siRNA to suppress the CD70 expression. The suppression was confirmed by western blotting. Next, the CD70 monoclonal antibodies were generated to investigate their antitumor effect on the A2780 parent and A2780 CisR cells. ADCs, which consisted of CD70 monoclonal antibody linked to monomethyl auristatin F (MMAF, the tubulin polymerization inhibitor), were generated, and their antitumor effect against the A2780 CisR cells was investigated in vitro and in vivo. After the A2780 CisR-xenograft tumors were treated with CD70-ADC, immunohistochemistry (IHC) analysis was performed using antibodies against the mitotic marker, anti-phospho-histone H3. Results: The expression of CD70 was observed in the A2780 CisR cells but not in the A2780 parent cells. CD70 silencing in A2780 CisR cells did not significantly reduce the cisplatin IC50 value nor did it inhibit cell proliferation. The CD70 monoclonal antibodies did not inhibit the proliferation of the A2780 parent and CisR cells. These results suggest that inhibiting the expression of CD70 does not affect the sensitivity of cisplatin and the growth of the tumor. Next, we generated the CD70-ADC. The CD70-ADC did not reach IC50 in the A2780 cells; however, the IC50 value was 0.104 nM for the A2780 CisR cells. CD70-ADC successfully exhibited antitumor effects in the CD70-ADC-treated mice in comparison with the control, i.e., the ADC-treated mice (162.4 vs. 534.2 mm3; p<0.001). IHC staining of the A2780 CisR-xenograft tumors with phosphorylated-histone H3 was performed. The percentage of tumor cells undergoing mitosis was markedly decreased after treatment with CD70-ADC, but not with the control IgG-ADC. These results suggest that MMAF was effectively delivered to the CD70-expressing tumor cells by the anti-CD70 mAb, causing mitotic arrest. Conclusion: Our results revealed that CD70-ADC could be a novel therapeutic agent for platinum-resistant SOC. Citation Format: Mayu Shiomi, Shinya Matsuzaki, Ruriko Nakae, Satoshi Nakagawa, Akiko Okazawa, Eiji Kobayashi, Yutaka Ueda, Satoshi Serada, Tetsuji Naka, Tadashi Kimura. CD70 antibody-drug conjugate: A novel therapeutic agent for platinum-resistant ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3853.