111In and 225Ac-labeled cixutumumab for imaging and alpha particle radiotherapy of IGF-1R positive triple negative breast cancer

Insulin growth factor receptor (IGF-1R) is overexpressed in many cancers of epithelial origin where it confers enhance proliferation and resistance to therapies targeted at other receptors. Anti-IGF-1R monoclonal antibodies have not demonstrated significant improvements in patient outcomes in clinical trials. Humanized monoclonal antibody cixutumumab (IMC-A12) binds to IGF-1R with low nM affinity. In this study cixutumumab was conjugated with p-SCN-Bn-DOTA and radiolabeled with 111In or 225Ac for imaging or radiotherapy using a triple negative breast cancer (TNBC) model SUM149PT. The antibody conjugate showed low nM affinity to IGF-1R which was not affected by conjugation and radiolabeling procedures. Cixutumumab immunoconjugates was effectively internalized in SUM149PT and was cytotoxic to the cells with an EC50 of 225Ac-cixutumumab (0.02 nM) that was almost 5000-fold less than unlabeled cixutumumab (95.2 nM). MicroSPECT imaging of SUM149PT xenograft showed the highest tumor uptake occurred at 48 h post ...