Systemic Delivery of Anti-HGF Monoclonal Antibody Inhibits Glioma Growth Through Downstream Oncogenic Signaling Molecules

Hepatocyte growth factor (HGF) and its transmembranous receptor tyrosine kinase, c-Met, contribute to the malignant phenotype of glioblastomas and to poor patient prognosis. HGF binding to c-Met leads to the activation/phosphorylation of downstream oncogenic signaling molecules. We proposed that L2G7, a neutralizing anti-HGF monoclonal antibody, will inhibit c-Met dependent downstream signaling molecules in HGF expressing tumors. We used semi-quantitative dual infrared immunofluorescence imaging to determine the effects of L2G7 on intracranial glioma growth and activation of downstream signaling molecules. We also used immunohistochemistry to examine tumor cell apoptosis (anti-cleaved caspase 3), cell proliferation (anti-MIB1), and angiogenesis (anti-laminin). Systemic L2G7 inhibited tumor growth and prolonged animal survival. The activation of oncogenic signaling molecules was inhibited in response to L2G7 when compared to control animals. From this, it can be concluded that anti-HGF inhibits the growth of HGF-dependent glioma and oncogenic signaling, enhances apoptosis, and inhibits tumor cell proliferation and angiogenesis. This response is due to the inhibition of downstream oncogenic signaling molecules. Since most tumors express multiple receptor tyrosine kinase systems besides HGF and c-Met, we plan to determine if combining L2G7 with other receptor tyrosine kinase inhibitors improve anti-tumor responses.