MetMAb, one-Armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival

B16

Pancreatic cancer is a highly lethal disease with a rising incidence. Novel treatment strategies to pancreatic cancer are urgently needed. Hepatocyte growth factor (HGF) and its receptor c-Met are implicated in driving proliferation and metastasis in numerous cancers. In this study, we investigated the efficacy of MetMAb, a novel, monovalent, one-armed antibody against c-Met (OA-5D5) in vitro and in vivo. In vitro, MetMAb inhibited not only phosphorylation of c-Met, Akt, MAP kinase, p70S6 kinase, and Gab-1 but viability of the KP4 pancreatic cancer cells as well. MetMAb was tested in vivo in the orthotopic KP4 pancreatic cancer model. Twelve days after orthotopic injection in nude mice, tumor volumes were measured by high-resolution micro-ultrasound imaging. Mice were separated into two groups and treated with MetMAb (30 mg/kg, twice weekly, i,p.) or vehicle. Two weeks after treatment initiation, ultrasound measurements were repeated. Treatment was continued and survival was monitored for 90 days after cell injection. Pre-treatment tumor volume was not different between the MetMab (8.63 ± 3.61 mm3, n = 20) vs. vehicle group (8.34 ± 3.51 mm3, n = 19). Treatment with MetMAb for 2 weeks abolished tumor growth. Compared to pre-treatment tumor size, tumor volume increased by approximately 92-fold in vehicle-treated animals, while in MetMAb-treated mice tumor volume decreased by 29%. Continuous treatment with MetMAb resulted in a substantial improvement in survival. Day 90 survival was increased by 424% in MetMAb treated mice (55.0%) compared to vehicle controls (10.5%). Logrank (Mantel-Cox) analysis showed significant survival benefit from treatment with MetMAb (p = 0.0004). In orthotopic tumors, MetMAb inhibited c-Met phosphorylation by 81% at 24 hours and 85% at 48 hours. MetMAb also clearly decreased the proliferative index represented by Ki-67-positive nuclei as shown by immunohistochemistry. In addition, to observe the effect of MetMAb on real-time tumor growth and tumor blood vessels, we used the dorsal skin window chamber model containing KP4 tumors. Tumors were observed by light and confocal microscopy, and images recorded pre- and post-treatment with MetMAb or vehicle. MetMAb significantly reduced tumor size within the window but did not significantly alter tumor vascular density. Thus, MetMAb not only inhibited orthotopic KP4 tumor growth but also improved animal survival primarily by inhibiting c-Met phosphorylation, downstream signaling pathway, and cellular responses. The data suggest MetMAb has potential therapeutic value in pancreatic cancer.