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.
View: Text | PDF
Research Article Angiogenesis Therapeutics

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

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

×

Figure 5

TEM8 expression in stromal cells is required for TEM8-ADC tumor cell killing in vivo.

Options: View larger image (or click on image) Download as PowerPoint
TEM8 expression in stromal cells is required for TEM8-ADC tumor cell kil...
(A) Growth of s.c. human colon HT29 tumor xenografts in Tem8 WT and Tem8-KO mice. Treatments with vehicle or 10 mg/kg m825-MMAE (TEM8-ADC) were initiated when tumors reached an average size of 150 mm3 (green arrows). (B) Co-IF staining was used to monitor the localization of m825-MMAE (red) in HT29 tumors 24 hours after i.v. injection. The i.v. injected m825-MMAE was detected in post-staining tissue sections with Texas red–labeled anti-human secondary antibodies. Total TEM8 in tumors was detected by staining with rabbit anti-TEM8 mAb (green). Bottom panel shows m825 colocalization with CD31+ endothelium (green). Arrowheads highlight regions of colocalization (yellow in the merged image). Scale bar: 20 μm. (C) IF staining was used to detect TUNEL+ apoptotic cells (red) 48 hours after treatment of orthotopic HPAC-T8–/– tumors with vehicle or 50 mg/kg TEM8-ADC. Tumor epithelial cells were labeled with human-specific anti-EpCAM antibodies (green; top), and CAFs were labeled with α-SMA antibodies (green; bottom). White and yellow arrowheads (insets) indicate double-positive tumor cells and CAFs, respectively. Scale bars: 50 μm; original magnification, ×40 (insets). (D) Quantification of TUNEL+EpCAM+ HPAC tumor cells and TUNEL+α-SMA+ CAFs 48 hours after treatment with 0, 10, and 50 mg/kg TEM8-ADC. Data represent the mean ± SD. *P = 0.0005 and **P < 0.0001, by Student’s t test. (E) Quantification of TUNEL+EpCAM+ HT29 tumor cells 24 to 94 hours after treatment with 50 mg/kg TEM8-ADC. Data represent the mean ± SD. The P value in E was determined by Student’s t test.