Abstract C181: Preclinical efficacy and pharmacodynamics of SCH 900105 (AV-299) an anti-HGF antibody in an intracranial glioblastoma model

Abstract

Abstract Hepatocyte growth factor (HGF) is a pluripotent growth factor produced predominantly by mesenchymal or stromal cells, and binds to the well-characterized tyrosine kinase receptor, c-Met. The HGF/c-Met pathway is frequently deregulated in different types of human cancers and is thought to play an important role in regulating tumor growth, invasion, metastasis and drug resistance. HGF/c-Met autocrine and paracrine loops have been reported in a number of human cancers including breast, lung, bladder, gastric, head and neck, glioma, multiple myeloma, leukemias, and certain sarcomas. SCH 900105, formerly known as AV-299, is a potent, humanized anti-HGF antibody. It is currently in phase 1 clinical trials that demonstrated good safety and tolerability. It has been shown to neutralize HGF binding to c-Met and inhibits its biological function in vitro, such as cell signaling, growth, motility, invasion and drug resistance. SCH 900105 was also shown to have potent anti-tumor activity in autocrine and paracrine GBM, NSCLC, pancreatic and multiple myeloma xenograft models both as monotherapy and in combinations with chemotherapeutics or targeted agents. In vivo efficacy of systemically administered SCH 900105 was evaluated in an intracranial autocrine U87MG model. In these studies, SCH 900105 treatment resulted in significant survival benefit over an IgG treated control group. Immunohistochemistry staining for SCH 900105 in the intracranial tumor tissue suggested adequate tumor penetration of the antibody. Treatment also led to significantly decreased tumor phospho-c-Met, increased cleaved caspase-3, as well as decreased Ki67 and CD31 staining. Greater survival benefit was also seen when SCH 900105 was combined with temozolomide in U87 intracranial model. These findings suggest evaluating SCH 900105 in GBM is warranted. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C181.