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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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

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Figure 4

m825-MMAE blocks orthotopic pancreatic tumor growth as well as established colon and breast cancer metastases.

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m825-MMAE blocks orthotopic pancreatic tumor growth as well as establish...
(A) BLI of tumors following orthotopic injection of HPAC-luc pancreatic cancer cells into the pancreas. At 19 dpi, the mice were sorted into 2 groups of equal average tumor burden, and treatments with PBS (vehicle) or 10 mg/kg m825-MMAE (TEM8-ADC) were given twice weekly for 3 weeks. (B) Quantification of tumor burden from the HPAC study shown in A. Data represent the mean ± SEM. (C) Kaplan-Meier survival analysis of the HPAC study shown in A. P < 0.001, for m825-MMAE versus vehicle, by log-rank analysis. n = 16/group. (D) BLI was used to monitor orthotopic MiaPaCa-luc pancreatic tumor burden. In this study, mice were randomized and treatments initiated 27 dpi (10 mg/kg TEM8-ADC; twice weekly for 3 weeks). P = 0.003, by Student’s t test, for m825-MMAE versus vehicle 65 dpi. n = 12/group. (E) Kaplan-Meier survival analysis of the MiaPaCa study shown in D. P < 0.001 m825-MMAE versus vehicle, by log-rank analysis. n = 11/group. (F) BLI was used to monitor orthotopic HPAC-luc pancreatic tumor burden following treatment with 3 mg/kg TEM8-ADC (twice weekly for 3 weeks), 30 mg/kg gemcitabine (thrice weekly for 2 weeks), or a combination of both agents. (G) BLI was used to monitor HCT-116-luc colon tumor liver metastases in mice following intrasplenic injection of tumor cells. BLI was used 7 dpi to randomize mice into vehicle or 10 mg/kg TEM8-ADC treatment groups. (H) Kaplan-Meier survival analysis of the HCT-116 study shown in G. P < 0.001, for m825-MMAE versus vehicle, by log-rank analysis. n = 19 or 20/group. Arrows in B–H indicate the day of treatment initiation. (I) BLI was used to monitor MDA-MB-231-luc breast tumor lung metastases in mice following i.v. injection of tumor cells. Mice were randomized into vehicle or 3 mg/kg or 10 mg/kg TEM8-ADC treatment groups 7 dpi. Data represent the mean ± SEM. P = 0.03, by Student’s t test, for 10 mg/kg versus 3 mg/kg m825-MMAE 32 dpi. n = 14/group.