RESUMO
BACKGROUND: J591 is a monoclonal antibody that targets the external domain of the prostate-specific membrane antigen (PSMA). Besides prostate cancer cells, it also targets the neovasculature of non-prostate solid tumors. We provide an analysis of the antibody mass-dose dependency of lesion uptake and normal tissue retention, together with an assessment of lesion detectability using (111)In-J591 imaging, compared with conventional imaging in patients with a variety of solid tumors. METHODS: Twenty patients in six cohorts received fixed amounts (5, 10, 20, 40, 60, and 100 mg) of J591 in a phase I trial. A maximum of four administrations per patient was given, with each administration separated by 3 weeks. All antibody administrations included 370 MBq (10 mCi) of (111)In labeled to 2 mg of J591 via the chelating agent DOTA. Three whole body (WB) gamma camera scans with at least one SPECT scan, along with multiple WB count-rate measurements and blood samples, were obtained for all patients. The effect of escalating antibody mass on lesion uptake and normal tissue retention was evaluated using lesion, liver, serum, and WB residence times and ratios thereof for each treatment cycle. Lesion detectability using (111)In-J591 imaging was compared to the standard imaging on a lesion-by-lesion basis. RESULTS: A total of 170 lesions in 20 patients were detected by standard or (111)In-J591 imaging. (111)In-J591 targeted both skeletal and soft tissue diseases in all tumor types. (111)In-J591 imaging identified 74% (20/27) of skeletal lesions, 53% (18/34) of nodes, and 64% (70/109) of other soft tissue/organ lesions. There was increasing (111)In-J591 uptake in lesions with increasing antibody mass-dose, coupled with decreasing retention in the liver for increments up to 20 mg, and no significant change at higher antibody mass. CONCLUSIONS: Radiolabeled J591 antibody has potential as a targeting agent for solid tumor vasculature and lesion detection. Bone and soft tissue lesions arising from tumors of diverse origin were targeted by the anti-PSMA antibody J591. For the detection of lesions in these tumors by J591 antibody scans, an antibody mass of 20 mg is adequate. The optimal time of imaging is 5 to 7 days post-injection.
RESUMO
UNLABELLED: J591, a monoclonal antibody that targets the external domain of the prostate-specific membrane antigen, has potential as an agent for radioimmunotherapy. A pilot trial was performed in patients with prostate cancer using repetitive administrations of escalating masses of J591. An analysis was performed to assess lesion detectability by (111)In-J591 gamma-camera imaging compared with standard imaging methods and the effect of increasing antibody mass on lesion detectability, biodistribution, and dosimetry. METHODS: Fourteen patients with metastatic prostate cancer received escalating amounts (10, 25, 50, and 100 mg) of J591 in a series of administrations each separated by 3 wk. All antibody administrations included a fixed amount of the radiolabeled antibody (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-J591 ((111)In-DOTA-J591) (2 mg of J591 labeled with 185 MBq [5 mCi] of (111)In via the chelating agent DOTA). Three whole-body gamma-camera scans with at least 1 SPECT scan together with multiple whole-body counting-rate measurements and serum activity-concentration measurements were obtained in all patients. Images were analyzed for distribution and lesion targeting. Estimates of clearance rates and liver and lesion uptake were made for each treatment cycle. These estimates were used to generate dosimetric projections for radioimmunotherapy with (90)Y-labeled J591. RESULTS: A total of 80 lesions in 14 patients were detected. Both skeletal and soft-tissue diseases were targeted by the antibody as seen on (111)In-J591 scans. The antibody localized to 93.7% of skeletal lesions detected by conventional imaging. Clearance of radioactivity from the whole body, serum, and liver was dependent on antibody mass. Normalized average values of the ratio of residence times between lesion and liver for 10, 25, 50, and 100 mg of antibody were 1.0, 1.9, 3.2, and 4.0. Dosimetric projections for radioimmunotherapy with (90)Y-labeled J591 suggested similar absorbed doses to lesions for treatment at the maximally tolerated activity (MTA), irrespective of antibody mass. However, absorbed doses to liver at the MTA would be antibody mass-dependent with estimates of 20, 10, 7, and 5 Gy for 10, 25, 50, and 100 mg of J591. CONCLUSION: The proportion of the amount of antibody increased in lesions and decreased in the liver with increasing mass of administered antibody up to a dose of 50 mg. Proportional hepatic uptake continued to decrease with increasing antibody mass up to 100 mg. The optimal antibody mass for radioimmunotherapy would therefore appear to be greater than or equal to 50 mg.
