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.