Abstract 5471: Notch-antibody drug conjugates have a different mechanism of action than Notch signaling inhibitors and induce tumor regression.

Abstract

Abstract There are four different Notch receptors in mammalian cells that have overlapping patterns of expression in embryonic and adult tissues, but fulfill non-redundant roles during hematopoietic stem cell specification, T cell development, intestinal crypt cell specification and vascular development. Notch receptors are over-expressed or amplified in certain human tumors and regulate cell proliferation, differentiation, and survival through an intracellular domain that functions as a transcriptional activator. Several strategies are in development to block Notch signaling for therapeutic purposes in cancer, including gamma-secretase inhibitors that block all Notch signaling and antibody-based targeting of individual receptors. However, blocking pathway activation with inhibitory antibodies has proven to be less efficacious than originally anticipated. Therefore, we have targeted Notch with antibody-drug conjugates (ADCs) that combine the specificity of high affinity anti-Notch antibodies with the cytotoxicity of microtubule inhibitors. These ADCs enhance efficacy and also allow targeting in tumors that overexpress Notch but are not driven by its signaling. Notch antibodies were conjugated though cleavable and non-cleavable linkers to novel tubulin inhibitor-based payloads. Notch-ADCs inhibited the in vitro growth of lung, breast and ovarian cancer cell lines in the low ng/ml range and in vivo regressed the growth of established human tumor xenografts. Our data demonstrate that Notch-ADCs are more potent than small molecule inhibitors and unconjugated antibodies, and induce sustained tumor regression in pre-clinical models. Citation Format: Kenneth G. Geles, Yijie Gao, Latha Sridharan, Andreas Giannakou, Ting-Ting Yamin, Jonathan Golas, Manoj Charati, Kiran Khandke, Judy Lucas, Andreas Maderna, Christopher J. O'Donnell, Lioudmila Tchistiakova, Hans-Peter Gerber, Puja Sapra. Notch-antibody drug conjugates have a different mechanism of action than Notch signaling inhibitors and induce tumor regression. [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 5471. doi:10.1158/1538-7445.AM2013-5471