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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 July 2, 2018; First published June 4, 2018
Citation Information: J Clin Invest. 2018;128(7):2927-2943. https://doi.org/10.1172/JCI120481.
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Categories: Research Article Angiogenesis Therapeutics

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 1

TEM8 is overexpressed in human tumors.

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TEM8 is overexpressed in human tumors.
(A) Rabbit anti-human TEM8 mAb wa...
(A) Rabbit anti-human TEM8 mAb was used to stain TEM8 in FFPE sections of HT29 tumors grown in Tem8 WT and Tem8-KO mice. Scale bar: 100 μm. (B) IHC was used to evaluate TEM8 expression in multiple human tumors or corresponding normal organs. Scale bar: 100 μm. (C) Co-IF staining of human colorectal tumors for FAP, PDGFRβ, or α-SMA (red) and TEM8 (green). Scale bars: 20 μm. (D) Co-IF staining of human colorectal tumor for CD146 (red) and TEM8 (green). A double-positive endothelial cell is highlighted (arrowheads). Scale bar: 20 μm; original magnification, ×40 (insets in D).
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ISSN: 0021-9738 (print), 1558-8238 (online)

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