PET Theranostics for Molecular Imaging and Radioimmunotherapy of Pancreatic Cancer

Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of pancreatic cancer tumours. Panitumumab is an antibody that targets EGFR and can be radiolabeled for molecular imaging and radioimmunotherapy (RIT). This thesis aimed to develop a “theranostic” agent that could be used for both imaging and treatment of pancreatic tumours. The first study demonstrated the ability of 64Cu-panitumumab F(ab′)2 fragments to visualize patient-derived orthotopic pancreatic cancer xenograft mouse models with PET/CT imaging and showed the superiority of panitumumab F(abʹ)2 over IgG or Fab fragments. Next, studies were performed involving metal-chelating polymers (MCPs) to allow antibodies to carry up to 20-fold more chelation sites compared to antibodies directly derivatized with chelators for 64Cu-radiolabeling, thereby amplifying radiation delivered per antibody. This work demonstrated that the presence of pendant PEG chains on MCPs resulted in longer blood circulation times compared to MCPs without pendant PEG chains. The next study demonstrated that 64Cu-panitumumab F(ab′)2 was useful in RIT when combined with radiosensitizing agents in pancreatic cancer xenograft mouse models. Tumour regression was not achieved so the final investigation compared 64Cu and 177Lu-panitumumab F(abʹ)2, which have similar β-emission energies but 177Lu has double the abundance of β-emissions compared to 64Cu. 64Cu-RIT and 177Lu-RIT were compared to external γ-irradiation to determine their relative biological effectiveness (RBE) in four pancreatic cancer cell lines, with different EGFR overexpression and proliferation rates. This work demonstrated that the degree of EGFR overexpression did not predict responsiveness of cells to RIT with 64Cu- or 177Lu-RIT. Also, fast growing cells responded very well to 64Cu-RIT while slow growing cells responded extremely poorly, while proliferation rate did not correlate with response to 177Lu-RIT. In conclusion, 64Cu-panitumumab F(ab′)2 fragments can be useful in PET imaging of pancreatic cancer tumours and that 177Lu-panitumumab F(ab′)2 fragments are more appropriate for RIT.Ph.D