Abstract
BACKGROUND: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload via a peptide linker. METHODS: The antiproliferative effects of TAK-264 assessed in a panel of eleven pancreatic cancer cell lines. Additionally, ten unique pancreatic ductal adenocarcinoma cancer patient-derived xenograft models were treated with TAK-264 and the efficacy was determined. Baseline levels of GCC were analyzed on PDX models and cell lines. Immunoblotting was performed to evaluate the effects of TAK-264 on downstream effectors. RESULTS: GCC protein expression was analyzed by immunoblotting in both normal and tumor tissue; marked increase in GCC expression was observed in tumor tissue. The in vitro experiments demonstrated a range of responses to TAK-264. Eight of the ten PDAC PDX models treated with TAK-264 demonstrated a statistically significant tumor growth inhibition. Immunoblotting demonstrated an increase in phosphorylated-HistoneH3 in both responsive and less responsive cell lines and PDAC PDX models treated with TAK-264. There was no correlation between baseline levels of GCC and response in either PDX or cell line models. CONCLUSION: TAK-264 has shown suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support further investigation of ADC targeting GCC.