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

Gary R. Mirick, Robert T O'Donnell, Sally J. Denardo, Sui Shen, Claude F. Meares, Gerald L Denardo

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)841-845
Number of pages5
JournalNuclear Medicine and Biology
Volume26
Issue number7
DOIs
StatePublished - Oct 1999

Fingerprint

Ceruloplasmin
Copper
Lymphoma
Antibodies
Radiopharmaceuticals
Radioactivity
Liver
Recycling
Chelating Agents
Area Under Curve
Alkaline Phosphatase
Half-Life
Blood Proteins
Albumins
Radiotherapy
copper-67-2IT-BAT-Lym-1

Keywords

  • Ceruloplasmin
  • Copper
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Transfer of copper from a chelated 67Cu-antibody conjugate to ceruloplasmin in lymphoma patients. / Mirick, Gary R.; O'Donnell, Robert T; Denardo, Sally J.; Shen, Sui; Meares, Claude F.; Denardo, Gerald L.

In: Nuclear Medicine and Biology, Vol. 26, No. 7, 10.1999, p. 841-845.

Research output: Contribution to journalArticle

Mirick, Gary R. ; O'Donnell, Robert T ; Denardo, Sally J. ; Shen, Sui ; Meares, Claude F. ; Denardo, Gerald L. / Transfer of copper from a chelated 67Cu-antibody conjugate to ceruloplasmin in lymphoma patients. In: Nuclear Medicine and Biology. 1999 ; Vol. 26, No. 7. pp. 841-845.
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title = "Transfer of copper from a chelated 67Cu-antibody conjugate to ceruloplasmin in lymphoma patients",
abstract = "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.",
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AU - Mirick, Gary R.

AU - O'Donnell, Robert T

AU - Denardo, Sally J.

AU - Shen, Sui

AU - Meares, Claude F.

AU - Denardo, Gerald L

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N2 - 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.

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