ABSTRACT
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [177Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [225Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225. RESULTS: Cell binding and internalisation of [225Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [225Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [225Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [225Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [225Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations. CONCLUSION: [225Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.
ABSTRACT
Resistance to conventional cancer treatments is a major problem associated with solid tumours. Tumour hypoxia is associated with a poor prognosis and with poor treatment outcomes; therefore, there is a need for treatments that can kill hypoxic tumour cells. One potential option is targeted α-radioimmunotherapy, as α-particles can directly kill hypoxic tumour cells. The murine monoclonal antibody DAB4 (APOMAB), which binds dead tumour cells after DNA-damaging treatment, was conjugated and radiolabelled with the α-particle-emitting radionuclide thorium-227 (Th). Mice bearing Lewis lung tumours were administered Th-DAB4 alone or after chemotherapy and the tissue biodistribution of the radioimmunoconjugate was examined, as was the effect of these treatments on tumour growth and survival. Th-DAB4 accumulated in the tumour particularly after chemotherapy, whereas the distribution in healthy tissues did not change. Th-DAB4 as a monotherapy increased survival, with more pronounced responses observed when given after chemotherapy. We have shown that targeted α-therapy of necrotic tumour cells with Th-DAB4 had significant and surprising antitumour activity as it would occur only through a cross-fire effect.