Evaluation of TAK-264, an Antibody-Drug Conjugate in Pancreatic Cancer Cell Lines and Patient-Derived Xenograft Models

  • Clin Cancer Drugs. 2018;5(1):42-49. doi: 10.2174/2212697X05666180516120907.
Anna R Schreiber  1 ,  Anna Nguyen  1 ,  Stacey M Bagby  1 ,  John J Arcaroli  1  2 ,  Betelehem W Yacob  1 ,  Kevin Quackenbush  1 ,  Joe L Guy  3 ,  Thomas Crowell  4 ,  Bradley Stringer  4 ,  Hadi Danaee  4 ,  Thea Kalebic  4 ,  Wells A Messersmith  1  2 ,  Todd M Pitts  1  2
Affiliations
  • 1. Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, CO, USA.
  • 2. University of Colorado Cancer Center, Aurora, CO, USA.
  • 3. Univeristy of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
  • 4. Takeda, Cambridge, MA, USA.
PMID: 30631747 DOI: 10.2174/2212697X05666180516120907
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.

Keywords
GCC; PDX models; TAK-264; antibody-drug conjugate; p-histone H3; pancreatic cancer.
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