Pharmacokinetics of 111In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma.

Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111In 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 111In 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 in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111In-labeled antibody pharmacokinetics. This suggests that the 111In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111In-labeled chelate complex unattached to antibody. Analysis of the 111In 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.

Radioimmunoimaging in malignant melanoma with 111In-labeled monoclonal antibody 96.5.

A radiolabeled monoclonal antibody (96.5) reactive with an Mr 97,000 antigen found on over 80% of melanoma cell lines and tissue extracts was examined for its ability to detect malignant melanoma metastases in vivo. For imaging purposes, it was conjugated with diethyltriaminepentaacetic acid and subsequently labeled with 111In by chelation. Thirty-one patients with metastatic melanoma received single injections of monoclonal antibody 96.5 at concentrations ranging from 0.5 to 20 mg and at specific activities of 111In ranging from 0.125 to 4 mCi/mg. Total-body scans were performed at various time intervals following administration. No serious side effects were observed. Of a total of 100 previously documented metastatic sites, 50 imaged for a specificity of 50%. The number of sites imaged increased significantly as the amount of antibody administered increased relative to the average radiation dose. Considerable background uptake of isotope was observed in blood pool and other organs with gradual acquisition of label in tumor sites by 48 to 72 h. Hence, tumor imaging of melanoma using 111In-labeled monoclonal antibody 96.5 appeared feasible, especially at antibody doses above 2 mg.

Detection of metastatic adrenal carcinoma using 131I-6-beta-iodomethyl-19-norcholesterol total body scans.

Adrenal and total body scintigraphs with 131I-6-beta-iodomethyl-19-norcholesterol were obtained in 5 patients who had had prior resection of adrenal cortical carcinoma. The results were compared with roentgenographic findings and liver, bone, and total body gallium-67 citrate scintigraphs. Metastatic lesions were detected with radiolabeled cholesterol in 4 of 5 patients, including 3 liver metastases, 2 bone metastases, and 1 lung metastasis. These lesions were also demonstrated by one or more of the other diagnostic modalities. All initial findings were negative in a fifth patient, who developed brain metastases within two months. The 6-methyl-analog of iodocholesterol makes it possible to detect metastatic adrenocortical carcinoma with total body scans. Whether or not this agent is "tumor specific" and will be of significant clinical utility will have to be determined more fully in a larger series of patients.

Sealed sources in synthetic absorbable suture: a new method for permanent interstitial implantation.

Inactive gold grains are embedded at 1-cm intervals along a synthetic, absorbable surgical suture, then subjected to neutron irradiation in a nuclear reactor, forming a new material for permanent interstitial implant therapy. Assembling and activating the sealed sources in an absorbable carrier, the physical properties of the irradiated suture, its behavior in tissue, and the methods and results of implantation in the dog are described.