Transfer of copper from a chelated ⁶⁷Cu-antibody conjugate to ceruloplasmin in lymphoma patients

The Lym-1 monoclonal antibody was conjugated with the bifunctional chelating agent 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT), using 2IT as a linker, and radiolabeled with ⁶⁷Cu to make the radiopharmaceutical, ⁶⁷Cu-2IT-BAT-Lym-1. Ten patients received a total of 18 doses of ⁶⁷Cu-2IT-BAT-Lym-1 as targeted, systemic radiotherapy. The beta phase of blood clearance, when corrected for ⁶⁷Cu decay, was positive or flat, a phenomenon not observed in similar patients treated with ¹³¹I-Lym-1. The flat beta phase of blood clearance suggested recycling of ⁶⁷Cu from ⁶⁷Cu-2IT-BAT-Lym-1 to another plasma protein. Therefore, the amount of ⁶⁷Cu transferred from the radiopharmaceutical to CP, Alb, and TF was measured using affinity-purified polyclonal antibodies. The fraction of plasma ⁶⁷Cu precipitated by anti-human CP increased daily; most blood radioactivity was ⁶⁷Cu-CP after a median of 4 days (range 2-7 days). The transfer of ⁶⁷Cu to CP was observed in all patients and was consistent from dose to dose within the same patient. An average of 2.8 ± 1.5% (range 0.8-7.8%) of the ⁶⁷Cu dose (%ID) was transferred to CP. The release rate of ⁶⁷Cu-CP from the liver into the blood was 0.9 ± 0.4 %ID/day for the first 3 days. The ⁶⁷Cu-CP effective clearance half-life was 3.7 ± 0.7 days. Subtraction of the ⁶⁷Cu-CP activity from the total blood radioactivity yielded a biphasic blood clearance similar to that obtained for patients given ¹³¹I-Lym-1. Cu-67-CP increased the AUC for whole blood by 24 ± 10%. The %ID of ⁶⁷Cu recycled correlated with GGT, ALT, and alkaline phosphatase levels; r = 0.958 (p < 0.001), 0.857 (p < 0.01), and 0.822 (p < 0.01), respectively. Albumin levels correlated negatively with recycled copper (r = -0.745, p < 0.05). The data suggest that the liver metabolizes ⁶⁷Cu-2IT-BAT-Lym-1 and recycles a small fraction of the ⁶⁷Cu, transferring it to CP. Copyright (C) 1999 Elsevier Science Inc.