作者: Chen, Dongni ; Wu, Qingde ; Hu, Yuling ; Cao, Bihui ; Shen, Yan ; Lian, Hui ; Liu, Manting ; Leidner, Rom ; Zhao, Ming ; Yang, Lili ; Hu, Hong ; He, Jinping ; Li, Junping ; Yang, Shuo ; He, Bingjia ; Ye, Xiaodie ; Zhang, Zhenfeng ; Fan, Weijun ; Zhi, Chen ; Xu, Linfeng

Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.

2023-06-01·Clinical cancer research : an official journal of the American Association for Cancer Research

Preclinical Efficacy of the Antibody–Drug Conjugate CLDN6–23-ADC for the Treatment of CLDN6-Positive Solid Tumors

Article

作者: Chau, Kevin ; Panayiotou, Richard ; Liang, Min ; Xie, Bin ; O'Brien, Neil A ; Hoffstrom, Benjamin ; Brugge, Joan S ; Hong, Jenny J ; Handly-Santana, Abram ; Presta, Leonard ; Lu, Ming ; McDermott, Martina S J ; Slamon, Dennis J ; Jia, Weiping ; Glaspy, John ; Zhang, Jun ; Press, Michael F ; Gong, KeWei ; Luo, Tong ; Davenport, Simon

Abstract:

Purpose::

Claudin-6 (CLDN6) is expressed at elevated levels in multiple human cancers including ovarian and endometrial malignancies, with little or no detectable expression in normal adult tissue. This expression profile makes CLDN6 an ideal target for development of a potential therapeutic antibody–drug conjugate (ADC). This study describes the generation and preclinical characterization of CLDN6–23-ADC, an ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker.

Experimental Design::

A fully humanized anti-CLDN6 antibody was conjugated to MMAE resulting in the potential therapeutic ADC, CLDN6–23-ADC. The antitumor efficacy of CLDN6–23-ADC was assessed for antitumor efficacy in CLDN6-positive (CLDN6+) and -negative (CLDN6−) xenografts and patient-derived xenograft (PDX) models of human cancers.

Results::

CLDN6–23-ADC selectively binds to CLDN6, versus other CLDN family members, inhibits the proliferation of CLDN6+ cancer cells in vitro, and is rapidly internalized in CLDN6+ cells. Robust tumor regressions were observed in multiple CLDN6+ xenograft models and tumor inhibition led to markedly enhanced survival of CLDN6+ PDX tumors following treatment with CLDN6–23-ADC. IHC assessment of cancer tissue microarrays demonstrate elevated levels of CLDN6 in 29% of ovarian epithelial carcinomas. Approximately 45% of high-grade serous ovarian carcinomas and 11% of endometrial carcinomas are positive for the target.

Conclusions::

We report the development of a novel ADC, CLDN6–23-ADC, that selectively targets CLDN6, a potential onco-fetal-antigen which is highly expressed in ovarian and endometrial cancers. CLDN6–23-ADC exhibits robust tumor regressions in mouse models of human ovarian and endometrial cancers and is currently undergoing phase I study.

100 项与 GB-7008-01-vcMMAE 相关的药物交易

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