Abstract 4358: Monoclonal antibodies to Notch receptors may enable targeting of tumor autonomous and tumor micro-environmental processes
Authors: O'Hagan Rónán C. , Okamura Heidi , Kreuter Kelly , Bell Alisa , Perino Samantha , Keane David , Monti Anthony , Rideout William , Winston William , Meetze Kristan , Gyuris Jeno 
Published: June 2012

AVEO has developed a series of inducible mouse models of cancer which, through the preservation of critical tumor/stromal interactions, facilitate identification of cell-surface and secreted proteins that represent viable targets for therapeutic antibodies and other biologics. Functional genetic screens performed in vivo in these models identified the Notch pathway as a critical regulator of tumor maintenance. This finding is consistent with emerging evidence that activation of Notch signaling via receptor point mutation, receptor amplification, and elevated receptor and ligand expression, plays a key role in various human cancers. Moreover, the Notch pathway controls diverse aspects of tumorigenesis and tumor maintenance, regulating tumor autonomous processes and interactions with the microenvironment, including angiogenesis. To further understand the role of the Notch pathway in tumor maintenance, and to assess the therapeutic potential of targeting the Notch pathway in cancer, we have generated monoclonal antibodies that inhibit various Notch receptors.

Characterization of monoclonal antibodies targeting Notch1 or Notch3 through cell-based and biochemical studies demonstrated that these antibodies bound with high affinity and high specificity to the ligand binding domains of the Notch receptors, prevented ligand mediated activation of the target receptor, and specifically repressed Notch-dependent signaling with high potency. Effective inhibition of functional angiogenesis was observed upon anti-Notch1 antibody treatment in both in vitro and in vivo models. Significantly, specific inhibition of Notch1 by this antibody did not result in the dose-limiting gut toxicity observed with pan-Notch inhibitors such as gamma-secretase inhibitors. Humanized versions of the Notch1 monoclonal antibodies have been generated and characterized.

Inhibition of tumor growth by the Notch3 monoclonal antibody was effected through tumor cell autonomous mechanisms. To identify tumors that are dependent upon tumor autonomous Notch signaling, gene expression profiles were correlated with Notch pathway dependence in human cancer cell lines. Expression of specific downstream targets was highly correlated with sensitivity of human cancer cell lines to inhibition of ligand-dependent Notch signal. This biomarker of Notch pathway dependence successfully predicted that a subset of Kras mutant pancreatic and colon cancer cell lines would be highly sensitive to Notch pathway inhibition. Moreover, identification of Notch1 and Notch3-specific target genes further enables selection of tumors that will respond to monoclonal antibodies specifically targeting one or other, or both of these receptors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4358. doi:10.1158/1538-7445.AM2011-4358