Monoclonal antibodies for copper-64 PET dosimetry and radioimmunotherapy

Background: We previously described a two-antibody model of Cu-64 radioimmunotherapy to evaluate low-dose, solid-tumor response. This model was designed to test the hypothesis that cellular internalization is critical in causing tumor cell death by mechanisms in addition to radiation damage. The purpose of the present study was to estimate radiation dosimetry for both antibodies (mAbs) using positron emission tomography (PE T) imaging and evaluate the effect of internalization on tumor growth. Results: Dosimetry was similar between therapy groups. Median time to tumor progression to 1 g ranged from 7-12 days for control groups and was 32 days for both treatment groups (p < 0.0001). No statistically significant difference existed between any control group or between the treatment groups. Material and Methods: In female nude mice bearing LS174T colon carcinoma xenografts, tumor dosimetry was calculated using serial PE T images of three mice in each group of either internalizing Cu-64-labeled DOTA-cBR96 (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or non-internalizing Cu-64-labeled DOTA-cT84.66 from 3 to 48 h. For the therapy study, controls (n = 10) received saline, DOTA-cBR96 or DOTA-cT84.66. Treatment animals (n = 9) received 0.890 mCi of Cu-64-labeled DOTA-cBR96 or 0.710 mCi of 64Cu-labeled DOTA-cT84.66. Tumors were measured daily. Conclusions: PET imaging allows the use of Cu-64 for pre-therapy calculation of tumor dosimetry. In spite of highly similar tumor dosimetry, an internalizing antibody did not improve the outcome of Cu-64 radioimmunotherapy. Radio-resistance of this tumor cell line and copper efflux may have confounded the study. Further investigations of the therapeutic efficacy of Cu-64-labeled mAbs will focus on interaction between Cu-64 and tumor suppressor genes and copper chaperones.