Anti-Tumor Activities Of Antibodies Targeting The Ron Receptor And A Biomarker Of Response

RON is a receptor tyrosine kinase of the MET family. Stimulation by its ligand, Macrophage Stimulating Protein (MSP), activates a signaling cascade leading to cell growth, migration, invasion and resistance to apoptosis. In animal models, RON overexpression in breast and lung results in tumor growth and metastasis. RON receptor activation in animal models also play a role in tumor-host interactions such as osteolytic bone destruction and tumor associated macrophage infiltration. RON overexpression has been demonstrated in several solid tumors including pancreatic, breast, ovarian and colon. RON overexpression is correlated with disease progression and shorter survival in ovarian and colon cancer. Several isoforms of RON have been reported, including a potentially oncogenic form, RON Δ160 in CRC. Given the strong evidence for the involvement of RON in numerous aspects of tumor biology, investigating an anti-RON antibody as cancer therapy is warranted. We have identified and characterized a panel of antagonistic murine anti-human RON antibodies. Humanization of two antibodies resulted in Superhumanized™ anti-RON antibodies that are capable of inhibiting MSP dependent RON downstream signaling, cell migration and invasion in vitro. The anti-RON antibodies have subnanomolar binding affinity to wildtype RON and RON Δ160 receptors. The lead antibody is capable of internalizing and degrading the receptor in vitro and in vivo. The antibodies are capable of inhibiting growth of engineered murine models that are driven by wildtype or RON Δ160 receptor, as well as traditional human cancer xenografts. Given the complex role of RON in tumor biology, identification of response biomarkers is crucial for identifying the patient populations most likely to benefit from treatment. A multi-gene biomarker potentially predictive of tumor response to RON antibody, the RON pathway index, was tested and validated using a panel of human cancer cell line xenografts. Current results demonstrate a statistically significant correlation between the degree of tumor growth inhibition by anti-RON antibody treatment and RON pathway index value. Thus, we have identified a biomarker of tumor response to anti-RON antibody that can potentially help us identify tumor types or tumor subtypes of interest in the clinic. 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 644. doi:10.1158/1538-7445.AM2011-644