The tumor microenvironment consists of a heterogenous population of cells which includes tumor cells and tumor-associated stroma cells (TASCs). The TASCs promote tumor angiogenesis, proliferation, invasion and metastasis. Because stroma cells are found in both healthy and cancerous tissue, targeting the tumor stroma has been difficult due to the lack of targets with high tumor specificity. TEM8 (also known as ANTXR1) is a cell surface tumor endothelial marker that is most highly expressed in human tumor-associated stroma of pancreatic, breast, colon, lung, esophageal, bladder, and ovarian cancers. While low levels of expression are seen in healthy kidney, lung, and brain tissue, preliminary toxicity studies suggest limited, if any, toxic effects in these tissues. This differential expression makes TEM8 an attractive potential target for ADC development due to the ability to selectively target TASCs in many different tumor types.
Researchers at the National Cancer Institute (NCI) have developed fully human monoclonal antibodies and antibody-drug conjugates (ADCs) that target TEM8. The antibodies and ADCs have been tested both in vitro and in vivo and have shown promising data. Monomethyl auristatin E (MMAE)-conjugated TEM8 ADCs led to the eradication of large established tumors and metastases and improved long-term overall survival in mouse models. In addition, the ADC was evaluated in preliminary toxicology studies where it showed limited off-target toxicity.
- Antibody-drug conjugates (ADCs) for the treatment of cancer
- CAR-T cell therapy
- Diagnostic agent for detecting and monitoring TEM8-expressing malignancies.
- A component of multi-specific antibody therapies
- Possible to simultaneously target both tumor cells and tumor stroma;
- Potentially superior adverse events profile than existing agents due to the differential expression of TEM8 on tumor and normal stroma;
- Fully human antibodies are less likely to be recognized and cleared by the immune system upon repeated administration;
- Relevance to a wide range of cancers – representing several major market opportunities;
- High cellular internalization;
- Cross-reactive with mouse and monkey TEM8 making preclinical studies easier and more informative.
Dimiter Dimitrov Ph.D., Brad St. Croix Ph.D. (NCI), Zhongyu Zhu Ph.D. (NCI), Enrique Z. Ubani Ph.D., Michelle Zhan, Saurabh Saha, Gary Decrescenzo, Dean Welsch
C. Szot et al. Tumor stroma-targeted antibody-drug conjugate triggers localized anticancer drug release. [PMID]
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