Given that tumor endothelial marker 8 (TEM8) is expressed on the stroma of many solid tumors, Szot et al. combined MMAE (a microtubule-disrupting drug) with an anti-TEM8 antibody as an antibody-drug conjugate (ADC). The ADC was endocytosed by TEM8+ stromal cells, where the MMAE was cleaved from the antibody and released into the tumor, leading to bystander killing of primary and metastatic tumors and increased survival in mice. Stromal cells were resistant to MMAE due to high expression of P-glycoprotein, which exported the drug from the cells and served as a biomarker for sensitive tumor cells. The ADC was generally well tolerated.
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.
Author Info: (1) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (2) BioMed Valley Discoveries Inc., Kansas City,
Author Info: (1) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (2) BioMed Valley Discoveries Inc., Kansas City, Missouri, USA. (3) BioMed Valley Discoveries Inc., Kansas City, Missouri, USA. (4) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, Maryland, USA. (5) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research (FNLCR), Frederick, Maryland, USA. (6) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research (FNLCR), Frederick, Maryland, USA. (7) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (8) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (9) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (10) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (11) Transgenic Core Facility, MCGP, NCI, Frederick, Maryland, USA. (12) Transgenic Core Facility, MCGP, NCI, Frederick, Maryland, USA. (13) Veterinary Pathology Section, Pathology/Histotechnology Laboratory, Leidos Biomedical Research Inc., FNLCR, Frederick, Maryland, USA. (14) Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, Maryland, USA. (15) Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, Maryland, USA. (16) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, Maryland, USA. (17) BioMed Valley Discoveries Inc., Kansas City, Missouri, USA. (18) BioMed Valley Discoveries Inc., Kansas City, Missouri, USA. (19) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (20) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA. (21) Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, Maryland, USA. (22) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, Maryland, USA.
