Targeted α-therapy using 227Th-APOMAB and cross-fire antitumour effects

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.