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.
Mirick
G R
GR
University of California at Davis Medical Center, Sacramento, USA.
O'Donnell
R T
RT
DeNardo
S J
SJ
Shen
S
S
Meares
C F
CF
DeNardo
G L
GL
D000328:Adult; D000368:Aged; D000906:Antibodies; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002570:Ceruloplasmin / Q000276:immunology / Q000378:metabolism*; D002614:Chelating Agents / Q000378:metabolism / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006571:Heterocyclic Compounds / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D000922:Immunotoxins / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008228:Lymphoma, Non-Hodgkin / Q000097:blood* / Q000201:enzymology / Q000378:metabolism / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009942:Organometallic Compounds / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011233:Precipitin Tests; D019275:Radiopharmaceuticals / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000906:Antibodies; D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D000922:Immunotoxins; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C113624:copper(II)-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; C097568:copper-67-2IT-BAT-Lym-1; D002570:Ceruloplasmin