1. Abstract 1692: Antibody-drug conjugates to target cell surface TACE-cleaved amphiregulin in breast cancer
- Author
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Paraic A. Kenny, Kelly S. Levano, Edmund C. Jenkins, Eric H. Jung, and Matthew Levy
- Subjects
Cancer Research ,biology ,business.industry ,Cancer ,Estrogen receptor ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,Oncology ,Monomethyl auristatin E ,chemistry ,Amphiregulin ,Tumor progression ,Immunology ,medicine ,Cancer research ,biology.protein ,Epidermal growth factor receptor ,skin and connective tissue diseases ,business ,Tamoxifen ,medicine.drug - Abstract
Approximately 70% of breast cancer cases are Estrogen Receptor (ER) positive. In many cases, these patients are well-served by endocrine therapies such as tamoxifen and aromatase inhibitors, however the emergence of endocrine-resistant disease in up to 40% of these patients is a major clinical concern. This necessitates treatment with more toxic chemotherapies which are often successful at delaying tumor progression, but are not curative. Recent work from our group and others has demonstrated that Amphiregulin, an Epidermal Growth Factor Receptor (EGFR) ligand, is a critical effector of ER signaling in both normal development and breast cancer pathogenesis, and is expressed in both endocrine-sensitive and endocrine-resistant breast cancer. Like other EGFR ligands, Amphiregulin is proteolytically processed at the cell surface to release a soluble EGFR-binding signaling domain and a residual cell-associated stalk. In this project, we are developing antibodies that selectively recognize the residual transmembrane Amphiregulin cleavage product with the goal of developing antibody-drug conjugates with which to selectively target tumor cells with high levels of Amphiregulin shedding. We have generated six humanized antibodies that recognize the cell-associated neo-epitope revealed following the TACE-mediated proteolytic release of Amphiregulin. Using both flow Cytometry and immunofluorescence, we demonstrate that these antibodies selectively recognize cleaved over full-length Amphiregulin in estrogen receptor positive breast cancer cells. Conjugation of these antibodies with a pH-sensitive dye, pHrodo, demonstrates robust and rapid antibody internalization in live cells. Conjugation of these antibodies with monomethyl auristatin E results in the disruption of the microtubule network of breast cancer cells followed by cell death. We propose that these agents may have utility in the treatment of breast and other cancers in which Amphiregulin expression and processing play a prominent role. This study is supported by the Department of Defense Breast Cancer Research Program (W81XWH-14-1-0294). Citation Format: Edmund C. Jenkins, Kelly S. Levano, Eric H. Jung, Matthew Levy, Paraic A. Kenny. Antibody-drug conjugates to target cell surface TACE-cleaved amphiregulin in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2015-1692
- Published
- 2015