Abstract #1246: Preclinical efficacy and pharmacodynamics of SCH 900105 (AV-299), an anti-HGF antibody

Hepatocyte growth factor (HGF) is the soluble ligand for the c-Met receptor tyrosine kinase. The study of human and animal tumor models has provided compelling evidence that signaling through the HGF/c-Met pathway mediates a plethora of cellular activities that are involved in cancer cell dysregulation, tumorigenesis, and metastasis including proliferation, survival, angiogenesis, migration, and invasion. Tumor cell 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, also known as AV-299, is a humanized IgG1 antibody with high affinity to HGF and neutralizes its biological functions with sub-nM potency. In vivo efficacy of SCH 900105 was explored in both autocrine and paracrine xenograft models. In these studies, SCH 900105 treatment resulted in significant tumor regression at doses as low as 0.1 mg/kg in one model. SCH 900105 treatment also demonstrated dose-dependent efficacy in paracrine models of the HGF-dependent xenograft lines in SCID mice engineered to produce human HGF. In these models, SCH 900105 treatment resulted in dose-dependent increases in complexed SCH 900105/HGF in serum. Treatment also led to significant decreases in tumor phospho-c-Met levels, phospho-Akt, increased cleaved caspase-3, as well as decrease in Ki67 staining. To explore the effects of dosing schedule on tumor growth inhibition, xenograft studies were performed with various dosing frequencies. All schedules resulted in initial tumor regression; however, SCH 900105 was most efficacious in causing tumor regression and delaying ultimate tumor escape when administered twice weekly compared to weekly or bi-weekly treatment. Several combination studies were also performed with other target therapeutics, chemotherapies and anti-angiogenic agents in subcutaneous and orthotopic models. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1246.