Abstract 231: Conformation-specific monoclonal antibodies against Notch1 target aberrant Notch1 signaling in cancer stem cells.

Abstract

Abstract Notch signaling pathway plays a key role in regulating various cell fates including those of stem cells, throughout the mammalian development and adult homeostasis. Here we report characterization of anti-Notch1 monoclonal antibodies (mAb's) with potential therapeutic applications. Antibodies against various domains of human-Notch1 receptor were generated and characterized, mAb's generated against primary ligand-binding domain (EGF like repeats 11-12) and activation domain NRR (Negative Regulatory region) showed most prominent therapeutic potential. The Notch1 specific mAb 602.101 against ligand-binding domain (EGF like repeats 11-12) prevents binding of Jagged and Delta-like ligands and subsequent Notch1 receptor activation in breast cancer stem cells. Further, antibody treatment leads to apoptosis, inhibition of epithelial to mesenchymal transitions as well as irreversible depletion of cancer stem cells. The conformation specific mAb's against Notch1 NRR can specifically distinguish between the mutant and the wild type human Notch1 receptor present on cancer cells. Anti-NRR mAb's 604.107 (mutant specific) and 604.132 (wild type specific) specifically inhibited Notch1 signaling in leukemic and breast cancer stem cells. These mAbs can serve as a potential tool to irreversibly combat therapy resistant cancer stem cell subpopulations and to inhibit the epithelial to mesenchymal transitions in various types of cancers. Citation Format: Ankur Sharma, Annapoorni Rangarajan, Rajan R. Dighe. Conformation-specific monoclonal antibodies against Notch1 target aberrant Notch1 signaling in cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 231. doi:10.1158/1538-7445.AM2013-231