Pharmacokinetics of 111ln-labeled Anti-p97 Monoclonal Antibody in Patients with Metastatic Malignant Melanoma

James L. Murray, Thomas P. Haynie, Evan M Hersh, Howard J. Glenn, Monroe F. Jahns, Robert S. Benjamin, James M. Frincke, Dennis J. Carlo

Research output: Contribution to journalArticle

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Abstract

Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at closes between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111ln by the bifunctional chelating agent diethyltriamine-pentaacetic acid. Clearance of 111ln from plasma closely fit an open, one-compartment mathematical model (r2 > 0.90). The overall half-life of 111ln in plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111ln label approximated the total blood volume (7.8 ± 0.7 liters) at the 1-mg dose and decreased to 3.0 ± 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody Hi plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111ln-labeled antibody pharmacokinetics. This suggests that the 111ln radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111ln label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111ln-labeled chelate complex unattached to antibody. Analysis of the 111ln label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. These studies show that murine monoclonal antibodies are cleared slowly from the circulation in humans and that early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.

Original languageEnglish (US)
Pages (from-to)2382-2386
Number of pages5
JournalCancer Research
Volume45
Issue number5
StatePublished - May 1 1985
Externally publishedYes

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Melanoma
Pharmacokinetics
Monoclonal Antibodies
Antibodies
Liver
Theoretical Models
Chelating Agents
Blood Volume
Radioisotopes
Half-Life
Spleen
Enzyme-Linked Immunosorbent Assay
Binding Sites
Kidney
Acids
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Murray, J. L., Haynie, T. P., Hersh, E. M., Glenn, H. J., Jahns, M. F., Benjamin, R. S., ... Carlo, D. J. (1985). Pharmacokinetics of 111ln-labeled Anti-p97 Monoclonal Antibody in Patients with Metastatic Malignant Melanoma. Cancer Research, 45(5), 2382-2386.

Pharmacokinetics of 111ln-labeled Anti-p97 Monoclonal Antibody in Patients with Metastatic Malignant Melanoma. / Murray, James L.; Haynie, Thomas P.; Hersh, Evan M; Glenn, Howard J.; Jahns, Monroe F.; Benjamin, Robert S.; Frincke, James M.; Carlo, Dennis J.

In: Cancer Research, Vol. 45, No. 5, 01.05.1985, p. 2382-2386.

Research output: Contribution to journalArticle

Murray, JL, Haynie, TP, Hersh, EM, Glenn, HJ, Jahns, MF, Benjamin, RS, Frincke, JM & Carlo, DJ 1985, 'Pharmacokinetics of 111ln-labeled Anti-p97 Monoclonal Antibody in Patients with Metastatic Malignant Melanoma', Cancer Research, vol. 45, no. 5, pp. 2382-2386.
Murray JL, Haynie TP, Hersh EM, Glenn HJ, Jahns MF, Benjamin RS et al. Pharmacokinetics of 111ln-labeled Anti-p97 Monoclonal Antibody in Patients with Metastatic Malignant Melanoma. Cancer Research. 1985 May 1;45(5):2382-2386.
Murray, James L. ; Haynie, Thomas P. ; Hersh, Evan M ; Glenn, Howard J. ; Jahns, Monroe F. ; Benjamin, Robert S. ; Frincke, James M. ; Carlo, Dennis J. / Pharmacokinetics of 111ln-labeled Anti-p97 Monoclonal Antibody in Patients with Metastatic Malignant Melanoma. In: Cancer Research. 1985 ; Vol. 45, No. 5. pp. 2382-2386.
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abstract = "Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at closes between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111ln by the bifunctional chelating agent diethyltriamine-pentaacetic acid. Clearance of 111ln from plasma closely fit an open, one-compartment mathematical model (r2 > 0.90). The overall half-life of 111ln in plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111ln label approximated the total blood volume (7.8 ± 0.7 liters) at the 1-mg dose and decreased to 3.0 ± 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody Hi plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111ln-labeled antibody pharmacokinetics. This suggests that the 111ln radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111ln label over 48 h was between 12 and 23{\%} of the total administered dose and is assumed to represent 111ln-labeled chelate complex unattached to antibody. Analysis of the 111ln label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. These studies show that murine monoclonal antibodies are cleared slowly from the circulation in humans and that early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.",
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