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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 2

m825 specifically binds mouse and human TEM8.

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m825 specifically binds mouse and human TEM8.
(A) Uptake of m825 or m825...
(A) Uptake of m825 or m825-MMAE (TEM8-ADC, green) was evaluated in CHO-TEM8 cells after shifting cells from 4oC to 37oC for 60 minutes. Cell membranes were counterstained with CellMask Orange. Scale bar: 10 μm. (B) m825 IP of proteins from CHO cells stably expressing human CMG2 or TEM8, or 293 cells stably expressing mCMG2, mTEM8, mANTXRL, or hANTXRL. Immunoprecipitated proteins were immunoblotted (IB) with anti-TEM8 mAb (αTEM8) (rabbit c37), anti-CMG2 mAb (clone 1H8), and anti-FLAG mAb. GAPDH was used as a loading control. (C) Flow cytometry was used to evaluate m825-MMAE reactivity in CHO cells stably expressing hCMG2 or hTEM8, or 293 cells expressing mCMG2, mTEM8, mANTXRL, or hANTXRL. As a positive control, PA-FITC was used to bind both CMG2 and TEM8, and anti-FLAG antibodies were used to detect mouse and human FLAG-tagged ANTXRL proteins. (D) RT-PCR was used to evaluate mouse Antxrl mRNA expression in various adult organs and E7, E11, E15, and E17 whole embryos. (E) RT-PCR was used to evaluate human ANTXRL mRNA expression in various adult organs. (F) Chemical structure of m825-MMAE linker and warhead. The maleimidocaproyl attachment group (green), p-aminobenzylcarbamate (PABC) spacer (blue), and the cathepsin B–cleavable valine-citrulline dipeptide (red) are indicated. The gray cloud highlights the amide group susceptible to cleavage by carboxylesterase 1C in mouse serum. (G) Cell viability assays were used to measure the activity of m825 naked Ab or m825-MMAE (T8-ADC) against 293 or 293 cells overexpressing human TEM8 (293-T8). Data represent the mean ± SD. M, molecular weight marker.

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