Metabolite production in patients with lymphoma after radiometal-labeled antibody administration

Gerald L Denardo, S. J. DeNardo, D. L. Kukis, Robert T O'Donnell, S. Shen, G. R. Mirick, C. F. Meares

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Abstract

Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111ln- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]1,4,7,10- tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-Lym-1 (111ln/90Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111ln- and 90Y-2IT-BAD-Lym-1; 111ln was used as a surrogate tracer for 90Y, which emits no γ-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111ln in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received 111n-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111ln in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111n-2IT-BAD-m170, 91% and 94% of 111ln in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111ln-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111ln/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of 111ln/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111ln/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

Original languageEnglish (US)
Pages (from-to)1324-1333
Number of pages10
JournalJournal of Nuclear Medicine
Volume42
Issue number9
StatePublished - 2001

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Lymphoma
Antibodies
Non-Hodgkin's Lymphoma
Area Under Curve
Immunoconjugates
Immunologic Techniques
Neoplasm Antibodies
Radioimmunotherapy
2IT-BAD-Lym-1 monoclonal antibody
Photons
Volunteers
Hepatocytes
Neoplasms
Prostatic Neoplasms
Cell Culture Techniques
High Pressure Liquid Chromatography
Monoclonal Antibodies
Breast Neoplasms
Acids

Keywords

  • Antibodies
  • Antibody conjugates
  • Cancer
  • Lym-1
  • Lymphoma
  • Metabolism
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Metabolite production in patients with lymphoma after radiometal-labeled antibody administration. / Denardo, Gerald L; DeNardo, S. J.; Kukis, D. L.; O'Donnell, Robert T; Shen, S.; Mirick, G. R.; Meares, C. F.

In: Journal of Nuclear Medicine, Vol. 42, No. 9, 2001, p. 1324-1333.

Research output: Contribution to journalArticle

Denardo, GL, DeNardo, SJ, Kukis, DL, O'Donnell, RT, Shen, S, Mirick, GR & Meares, CF 2001, 'Metabolite production in patients with lymphoma after radiometal-labeled antibody administration', Journal of Nuclear Medicine, vol. 42, no. 9, pp. 1324-1333.
Denardo, Gerald L ; DeNardo, S. J. ; Kukis, D. L. ; O'Donnell, Robert T ; Shen, S. ; Mirick, G. R. ; Meares, C. F. / Metabolite production in patients with lymphoma after radiometal-labeled antibody administration. In: Journal of Nuclear Medicine. 2001 ; Vol. 42, No. 9. pp. 1324-1333.
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title = "Metabolite production in patients with lymphoma after radiometal-labeled antibody administration",
abstract = "Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111ln- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]1,4,7,10- tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-Lym-1 (111ln/90Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111ln- and 90Y-2IT-BAD-Lym-1; 111ln was used as a surrogate tracer for 90Y, which emits no γ-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111ln in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received 111n-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111ln in the patients' plasma in monomeric, metabolite, and complexed forms were 54{\%}, 36{\%}, and 10{\%}, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111n-2IT-BAD-m170, 91{\%} and 94{\%} of 111ln in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111ln-2IT-BAD-Lym-1 contributed a mean 10{\%} of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111ln/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of 111ln/90Y-2IT-BAD-Lym-1 accounted for 10{\%} of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111ln/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.",
keywords = "Antibodies, Antibody conjugates, Cancer, Lym-1, Lymphoma, Metabolism, Radioimmunotherapy",
author = "Denardo, {Gerald L} and DeNardo, {S. J.} and Kukis, {D. L.} and O'Donnell, {Robert T} and S. Shen and Mirick, {G. R.} and Meares, {C. F.}",
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volume = "42",
pages = "1324--1333",
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TY - JOUR

T1 - Metabolite production in patients with lymphoma after radiometal-labeled antibody administration

AU - Denardo, Gerald L

AU - DeNardo, S. J.

AU - Kukis, D. L.

AU - O'Donnell, Robert T

AU - Shen, S.

AU - Mirick, G. R.

AU - Meares, C. F.

PY - 2001

Y1 - 2001

N2 - Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111ln- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]1,4,7,10- tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-Lym-1 (111ln/90Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111ln- and 90Y-2IT-BAD-Lym-1; 111ln was used as a surrogate tracer for 90Y, which emits no γ-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111ln in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received 111n-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111ln in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111n-2IT-BAD-m170, 91% and 94% of 111ln in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111ln-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111ln/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of 111ln/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111ln/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

AB - Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111ln- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]1,4,7,10- tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-Lym-1 (111ln/90Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111ln- and 90Y-2IT-BAD-Lym-1; 111ln was used as a surrogate tracer for 90Y, which emits no γ-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111ln in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received 111n-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111ln in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111n-2IT-BAD-m170, 91% and 94% of 111ln in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111ln-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111ln/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of 111ln/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111ln/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

KW - Antibodies

KW - Antibody conjugates

KW - Cancer

KW - Lym-1

KW - Lymphoma

KW - Metabolism

KW - Radioimmunotherapy

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M3 - Article

VL - 42

SP - 1324

EP - 1333

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

SN - 0161-5505

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