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Therapeutic activity of neutralizing monoclonal antibodies targeting hepatoma-derived growth factor in cancer xenograft models.

2517 Background: Hepatoma-derived growth factor (HDGF) is a mitogen for endothelial cells, vessel smooth muscle cells, fibroblasts, as well as some epithelial cells. It is overexpressed in a number of human cancers and its overexpression in tumors strongly correlates with tumor progression, recurrence, and metastasis. We recently showed that down-regulation of HDGF in lung cancer cells reduces tumorigenecity in both in vitro cell and in vivo animal models suggesting HDGF may be of a therapeutic target for cancer.


METHODS
Recombinant HDGF was used to develop a panel of monoclonal antibodies specifically bind to HDGF. Four antibodies were tested for their therapeutic activity in lung and pancreatic cancer xenograft models. The monoclonal antibodies were administered 250μg/animal (5 mice per group) every 3 days IP when the subcutaneous tumors reached approximately 50 mm3.


RESULTS
Two antibodies (C1 and H3) exhibited significant therapeutic activity in A549 lung cancer model whereas H3 also showed a therapeutic effect in MiaPaca-2 pancreatic cancer model. No sign of toxicity in the living animals and histology of major organs were observed in the antibody treated animals. In the A549 model, the mean tumor burden was 960 mm3 for control-IgG treated mice 22 days after tumor inoculation, whereas the mean tumor burdens were 224 mm3 for C1 and 266 mm3 for H3 treated mice (P < 0.05) respectively. In the MiaPaca-2, the mean tumor burden was 994 mm3 for control-IgG treated mice 21 days after tumor inoculation in contrast to 345 mm3 for H3 treated mice (P < 0.05). Consistent with known biologic functions of HDGF, our early morphologic and biomarker analyses suggest that H3 may neutralize tumor cell released HDGF resulting in disruption of tumor stroma and extracellular matrix structures.


CONCLUSIONS
HDGF is a novel therapeutic target for multiple human cancers and neutralizing monoclonal antibodies targeting HDGF are effective in treating lung and pancreatic cancers in animal models. (Supported by DoD grant DAMD17-01-1-01689-1) No significant financial relationships to disclose.