AVEO Pharmaceuticals, Inc. (NASDAQ: AVEO), a biopharmaceutical company focused on discovering, developing and commercializing cancer therapeutics, today announced preclinical data which demonstrate that its Notch1-specific monoclonal antibody is a highly potent inhibitor of Notch1 function in both in vitro and in vivo models. These data were presented today at the American Association for Cancer Research (AACR) 101st Annual Meeting 2010 in Washington, D.C.
“We believe that the Notch pathway plays a critical role in the maintenance of tumors. The activity of our Notch1 targeted monoclonal antibody seen in preclinical data to date highlights the potential utility of this therapy.”
Effective blockade of Notch signaling has been demonstrated to effectively inhibit tumor angiogenesis, supporting the development of AVEO's Notch1 antibody as an anti-angiogenic agent. Recent data have also suggested an important role for Notch signaling in cancer stem cell maintenance. In the AVEO studies, the expression of Notch pathway-related genes was correlated with Notch pathway dependence in human cancer cell lines to identify tumors that are dependent upon tumor autonomous Notch signaling. Expression of a single Notch target gene, HeyL, was correlated with sensitivity of human cancer cell lines to inhibition of ligand-dependent Notch signal, confirming its role as a predictive biomarker of Notch-dependent tumors. Moreover, elevated HeyL expression identified a significant subset of tumors driven by the mutant Kras oncogene that may be dependent upon Notch signaling. Importantly, the lack of toxicity observed with AVEO's anti-Notch1 antibody in mouse models suggests that the antibody may be combinable with other targeted therapies to enhance anti-angiogenesis effects in the treatment of cancer.
"We believe that the progress we've made in the development of a robust monoclonal antibody pipeline is significant. These data follow on the heels of advances in our partnered antibody programs achieved last year, with our anti-HGF antibody AV-299 and anti-ErbB3 antibody AV-203, and are indicative of the continued potential we envision for our biology-driven oncology antibody pipeline focused on novel targets including RON, Notch and FGFR," said Tuan Ha-Ngoc, president and chief executive officer of AVEO Pharmaceuticals. "We believe that the Notch pathway plays a critical role in the maintenance of tumors. The activity of our Notch1 targeted monoclonal antibody seen in preclinical data to date highlights the potential utility of this therapy."
The Notch receptors are a family of four receptors on the surface of cells, Notch 1-4, whose activity has been shown to play important roles in normal stem cell function and in multiple aspects of tumor biology. Recent data also demonstrated a key role for Notch signaling in tumor angiogenesis.
AVEO generated monoclonal antibodies that inhibit various Notch receptors to assess the therapeutic potential of targeting the Notch pathway in cancer. Biochemical studies demonstrated that the antibody bound to the Notch1 ligand binding domain with high affinity, prevented ligand mediated activation of the receptor, and specifically repressed Notch1-dependent signaling with high potency. Specific inhibition of Notch1 by the antibody did not result in the dose-limiting gut toxicity observed with pan-Notch inhibitors, yet inhibition of functional angiogenesis was observed upon antibody treatment in both in vitro and in vivo models. The lack of toxicity seen with the antibody in mouse models suggests that inhibition of Notch1 could effectively be combined with other therapies to enhance treatment, or to overcome resistances to VEGF/VEGFR inhibition.
Also presented during the course of the meeting were chimeric mouse and Human-in-Mouse (HIM) models in support of AVEO's lead candidate tivozanib, a highly potent and selective inhibitor of VEGF receptors 1, 2 and 3, as well as preclinical data highlighting new targets in cancer, such as Furin.