A Monoclonal Antibody Targeting The Human Urokinase Plasminogen Activator Receptor (Upar) Combined With Bevacizumab Inhibits The Growth Of Colon Cancer Metastases In The Liver: Differential Effects Mediated By Tumor Burden

A65 The urokinase plasminogen activator receptor (uPAR) has been implicated in a number of processes that contribute to tumor progression and metastasis including tumor cell proliferation, invasion, adhesion and angiogenesis. Thus, uPAR represents an attractive therapeutic target for the treatment of cancer. We have developed a novel antibody, ATN-658, that targets uPAR. In contrast to previous therapeutic approaches targeting uPAR, ATN-658 does not inhibit the binding of uPA to uPAR and can bind to uPAR regardless of whether it is occupied by uPA. In addition, ATN-658 can bind to the residual fragment of uPAR frequently observed in tumors that remains attached to the membrane after proteolysis. We have previously demonstrated that ATN-658 significantly inhibited pancreatic cancer growth, invasion and metastasis in an orthotopic xenograft model (Bauer et al., Cancer Res 65:7775-81, 2005). In this study, we extend the results obtained in this pancreatic cancer model to a model of colon cancer metastasis to the liver combining ATN-658 with another biologic agent, bevacizumab, instead of chemotherapy. HCT-116 human colon carcinoma cells, which express uPAR, were injected directly into the livers of nude mice to mimic seeded metastatic lesions. In the first study, cells were allowed to seed and establish tumors for 4 days prior to initiating treatment. ATN-658 (10 mg/kg 2X/ week) and bevacizumab (5 mg/kg 2X/week) were administered intraperitoneally (IP) as monotherapies as well as in combination until 25% of the mice in the vehicle control group became moribund (usually around day 28), at which time all the mice were euthanized and the volume of their liver tumors determined using caliper measurements. Bevacizumab monotherapy inhibited tumor growth by ~85% (p