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Tumor stroma–targeted antibody-drug conjugate triggers localized anticancer drug release
Christopher Szot, … , Dimiter S. Dimitrov, Brad St. Croix
Christopher Szot, … , Dimiter S. Dimitrov, Brad St. Croix
Published June 4, 2018
Citation Information: J Clin Invest. 2018;128(7):2927-2943. https://doi.org/10.1172/JCI120481.
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Research Article Angiogenesis

Tumor stroma–targeted antibody-drug conjugate triggers localized anticancer drug release

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Abstract

Although nonmalignant stromal cells facilitate tumor growth and can occupy up to 90% of a solid tumor mass, better strategies to exploit these cells for improved cancer therapy are needed. Here, we describe a potent MMAE-linked antibody-drug conjugate (ADC) targeting tumor endothelial marker 8 (TEM8, also known as ANTXR1), a highly conserved transmembrane receptor broadly overexpressed on cancer-associated fibroblasts, endothelium, and pericytes. Anti-TEM8 ADC elicited potent anticancer activity through an unexpected killing mechanism we term DAaRTS (drug activation and release through stroma), whereby the tumor microenvironment localizes active drug at the tumor site. Following capture of ADC prodrug from the circulation, tumor-associated stromal cells release active MMAE free drug, killing nearby proliferating tumor cells in a target-independent manner. In preclinical studies, ADC treatment was well tolerated and induced regression and often eradication of multiple solid tumor types, blocked metastatic growth, and prolonged overall survival. By exploiting TEM8+ tumor stroma for targeted drug activation, these studies reveal a drug delivery strategy with potential to augment therapies against multiple cancer types.

Authors

Christopher Szot, Saurabh Saha, Xiaoyan M. Zhang, Zhongyu Zhu, Mary Beth Hilton, Karen Morris, Steven Seaman, James M. Dunleavey, Kuo-Sheng Hsu, Guo-Jun Yu, Holly Morris, Deborah A. Swing, Diana C. Haines, Yanping Wang, Jennifer Hwang, Yang Feng, Dean Welsch, Gary DeCrescenzo, Amit Chaudhary, Enrique Zudaire, Dimiter S. Dimitrov, Brad St. Croix

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Figure 6

m825-MMAE activation by TSCs drives bystander killing.

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m825-MMAE activation by TSCs drives bystander killing.
(A) In vitro CM t...
(A) In vitro CM transfer assay. (B) Flow cytometric analysis of TEM8 expression on HT29 tumor cells and TSCs using m825. (C) HT29 viability following treatment with CM from ADC-treated TSCs. CM were generated by exposing TSCs to m825-MMAE for 24 hours, 48 hours, or 72 hours. Additional controls included HT29 tumor cells or TSCs treated with nonconditioned m825-MMAE. Data represent the mean ± SEM. (D) Impact of MMAE on the viability of HT29 and HT29/P-gp tumor cells in the presence of P-gp inhibitors 50 nM tariquidar (Tar) or 900 nM valspodar (Val). Data represent the mean ± SEM. (E) Impact of TSC T8-ADC CM and 50 nM tariquidar on HT29 and HT29/Pg-p tumor cell viability. Nonconditioned m825-MMAE was tested against HT29 tumor cells as a negative control. Data represent the mean ± SEM. (F) HT29 cell viability following treatment with TSC TEM8-ADC CM prepared in the presence of 20 μM CA074, an extracellular cathepsin B inhibitor, or 20 μM Z-FA-FMK (ZFA), an intracellular cathepsin B inhibitor. As a control, 20 μM ZFA was also added to HT29 cells with TSC-CM after m825-MMAE activation. Data represent the mean ± SEM. (G) Growth of s.c. HT29/P-gp tumors. Treatments with vehicle or m825-MMAE (T8-ADC) (green arrows) were initiated when tumors reached approximately 100 mm3. n = 15/group. Data represent the mean ± SEM. (H) RT-PCR was used to evaluate ABCB1 mRNA expression in all reported cell lines. EIF4H was used as a loading control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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