Pharmacokinetics of indium-111 labeled 10-3D2 antibreast-tumor antibody in patients.

In a program to investigate patient pharmacokinetics of labeled anti-tumor antibodies, a study of the 10-3D2 anti-breast tumor antibody was conducted. The F(ab')2 fragment, coupled with DTPA, was radiolabeled with indium-111 and 1 mg (37 MBq, or 1 mCi) administered to each of 7 patients with documented or suspected breast carcinoma. Abnormal accumulations of radioactivity were observed in only one patient even though 5 had evidence of disease at the time of imaging. Despite the reported absence of circulating antigen to this antibody, sera from one patient showed evidence of a high molecular weight immune complex by size exclusion HPLC. However, this patient had detectable circulating HAMA, which cannot be excluded as the cause of such immune complex. Urine excretion of radioactivity varied greatly from patient to patient (from 2-34% ID within the first day) but the mean value (0.22% ID/hour) was equal to that seen by us in previous studies. The biodistribution of the label was found to be unusual in that kidney levels increased in all patients during the first day and, in particular, liver radioactivity levels decreased in all patients.

Pharmacokinetics in patients of an anti-carcinoembryonic antigen antibody radiolabeled with indium-111 using a novel diethylenetriamine pentaacetic acid chelator.

The pharmacokinetics of the C110 anti-carcinoembryonic antigen antibody radiolabeled with 111In via a novel benzylisothiocyanate derivative of diethylenetriamine pentaacetic acid have been determined in 12 patients. The chelator was attached to the protein via a thiourea bond and in such a way that all 5 carboxymethyl arms were presumably able to participate in chelation. Patients with known or suspected colorectal carcinoma received between 5 and 20 mg of the IgG antibody labeled with 5 mCi of 111In. Individual organ radioactivity levels were quantitated, and serum and urine samples were analyzed, principally by size exclusion high-performance liquid chromatography (HPLC). Total urinary excretion averaged 0.18% of the injected dose/h with large patient to patient variation. At early times postadministration (less than 8 h) the predominant radiolabeled species in urine was free diethylenetriamine pentaacetic acid most probably administered as a small radiocontaminant in the injectate. Thereafter, radioactivity in urine was primarily present as a low molecular weight catabolic product. Analysis of serum by size exclusion HPLC occasionally showed 3 radioactivity peaks, 2 of which are due to circulating immune complexes and labeled antibody. The third peak is of low molecular weight and is due to one or more products of antibody catabolism. Transchelation of 111In to circulating transferrin was observed but at modest levels. Quantitation of organ radioactivity showed that 18 +/- 4 (SD)% of the injected dose was in the liver at 1 day postadministration and 1.4 +/- 1.1 and 1.2 +/- 0.9% was in the spleen and in both kidneys, respectively, at this time. The mean half-life for clearance of total injected radioactivity was fitted to a single exponential and was found to be 34 h (SD, 14 h; N = 13) and that for antibody alone, assessed by size exclusion HPLC analysis of serum samples, was calculated to be 22 h (SD, 8 h; N = 10). Neither of these values nor organ radioactivity levels were affected by antibody-loading dose.

Imaging of tumor in patients with indium-111-labeled biotin and streptavidin-conjugated antibodies: preliminary communication.

Tumor localization in patients has been achieved through the in vivo use of streptavidin and biotin. In these preliminary studies, the monoclonal antibody HMFG1 was conjugated with streptavidin and 1 mg was administered intravenously to each of 10 patients with documented squamous cell carcinoma of the lung. Two to 3 days later, 111In-labeled biotin was also administered intravenously. No evidence of toxicity was observed. Background radioactivity levels were reduced in liver (1% ID at 24 hr) and kidneys (2%) and in all other normal tissues and blood. Images of lung tumor were obtained in as little as 2 hr following administration of labeled biotin. In eight patients, tumor was detected with labeled biotin alone without the previous administration of streptavidin-conjugated antibody but in three of these patients, the images were improved with the prior administration of conjugated antibody. These results suggest that this approach may improve the tumor-to-normal tissue radioactivity ratios in radioimmunotargeting.

Patient biodistribution of intraperitoneally administered yttrium-90-labeled antibody.

Although 90Y is one of the best radionuclides for radioimmunotherapeutic applications, the lack of gamma rays in its decay complicates the estimation of radiation dose since its biodistribution cannot be accurately determined by external imaging. A limited clinical trial has been conducted with tracer doses (1 mCi) of 90Y in five patients who then received second-look surgery such that tissue samples were obtained for accurate radioactivity quantitation by in vitro counting. The anti-ovarian antibody OC-125 as the F(ab')2 fragment was coupled with diethylenetriaminepentaacetic acid, radiolabeled with 90Y and administered intraperitoneally to patients with suspected or documented ovarian cancer. Size exclusion and ion exchange high performance liquid chromatography analysis of patient ascitic fluid and serum samples showed no evidence of radiolabel instability although a high molecular weight species (presumably immune complex) was observed in three patients. Total urinary excretion of radioactivity prior to surgery averaged 7% of the administered radioactivity while at surgery the mean organ accumulation was 8% of the administered radioactivity in serum, 10% in liver, 7% in bone marrow, and 19% in bone with large patient to patient variation. The mean tumor/normal tissue radioactivity ratio varied between 3 and 25. On the assumption that the above radioactivity levels were achieved immediately following administration, that the radioactivity remained in situ until decayed and that the dimensions of tumor were sufficient to completely attenuate the emissions of 90Y, the dose to tumor for a 1-mCi administration would be approximately 50 rad with normal tissues receiving approximately 8 rad.

Pharmacokinetics of 111In-labeled OC-125 antibody in cancer patients compared with the 19-9 antibody.

We recently reported on the pharmacokinetics in 14 cancer patients of the 19-9 antibody radiolabeled with 111In. We have now repeated this investigation in 18 cancer patients using the OC-125 antibody, in part to compare the in vivo behavior of two murine monoclonal antibodies of the same subclass administered as the F(ab')2 fragments, by the same route and at the same dose. As in the earlier investigation, 1 mg of fragments was infused i.v., and organ quantitation was obtained for up to 72 h along with frequent blood and urine samples for chromatographic evaluation. Analysis of urine showed that activity clearance by this route amounted to 0.29%/h and consisted of labeled DTPA only in early samples and metabolic products thereafter. Analysis of serum samples often showed the presence of a high-molecular-weight species appearing within 24 h. This species is probably due to antibody binding to circulating antigen, although the percentage of circulating activity present as this species did not correlate well with circulating antigen levels. As before, organ accumulation was greatest in the liver, although levels were significantly reduced (12% compared to 20% of administered dose at 24 h, P less than 0.01). Plasma clearance was also significantly different: whereas the label in the case of the OC-125 antibody showed one-compartment clearance kinetics and remained in the plasma compartment, in the 19-9 case the label diffused to a second, unidentified compartment.