Immunospecific saturable clearance mechanisms for indium-111-labeled anti-melanoma monoclonal antibody 96.5 in humans.

Liver uptake of 111In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an 111In-labeled anti-melanoma antibody 96.5 (111In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of 111In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to 111In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of 111In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to 111In-96.5 infusion demonstrated a significant drop [P less than 0.001] in the liver/heart ratio of radioactivity [2.81 +/- 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 +/- 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (Vd) and the plasma t1/2 both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration X time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P less than 0.05). Although tissue distribution of 111In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.

Radioimaging of melanoma using 99mTc-labeled Fab fragment reactive with a high molecular weight melanoma antigen.

Twenty patients with metastatic malignant melanoma were studied with 99mTc-labeled monoclonal antibody (MoAb) Fab fragment (NR-Ml-05) reactive with a high molecular weight (Mr 240,000) melanoma associated antigen. Patients received 40 mg unlabeled irrelevant MoAb (NR-2AD-IgG) and 7.5 mg unlabeled NR-Ml-05 (whole IgG) prior to infusion of 10 mg 99mTc-labeled (10-25 mCi) NR-Ml-05 Fab. Unlabeled MoAb were given to block nonspecific and specific binding sites. Gamma camera scans and single photon emission computed tomography were performed at 8 and 24 h postadministration. Of 172 preexisting lesions, 136 were imaged for a sensitivity of detection of 79%. Imaging was site and size dependent with the greatest sensitivity for liver lesions (100%) and the least for bowel (0%). Six sites (2 skin, 1 lung, 3 liver) were detected by single photon emission computed tomography that were missed on routine planar images. Forty-one additional unconfirmed sites were seen. Of these, 7 (17%) have been confirmed as tumor after a median follow-up time of 6 months. False positive scans included scar tissue, areas of chronic inflammation, an infected femoral aneurysm, and septic emboli. Nonspecific uptake of radioactivity occurred in kidney, gallbladder, bowel, thyroid, and myocardium. Human anti-mouse antibodies were detected in up to 69% of patients. In summary, radioimaging with 99mTc-NR-Ml-05 is a sensitive test, especially for detecting liver lesions. It is safe, simple to administer, and convenient for the patient. Biodistribution and imaging sensitivity differ significantly from studies in which 111In-labeled anti-melanoma MoAb have been used.

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.

Clinical parameters related to optimal tumor localization of indium-111-labeled mouse antimelanoma monoclonal antibody ZME-018.

Radioimmunolocalization of an 111In-labeled mouse antimelanoma monoclonal antibody (MoAb), ZME-018, was examined in 21 patients with metastatic malignant melanoma. Each patient received a single. i.v. infusion of MoAb at concentrations ranging from 1 mg to 20 mg, coupled to 5 mCi 111In by the chelating agent DPTA. No toxicity was observed in any patient. Total-body and regions of interest scans performed at 4, 24, and 72 hr following MoAb administration revealed uptake in 63 out of 105 previously diagnosed metastases for an overall sensitivity of 60%. Uptake was consistently observed in liver/spleen, and less frequently in bowel, testes, axillae and bone. Sensitivity of detection increased significantly at doses of MoAb above 2.5 mg, with 74% of lesions imaging at 20 mg/5 mCi compared with 29% at 2.5 mg/5 mCi (p less than 0.005). A significant correlation was observed between tumor uptake of 111In-MoAb conjugate and increasing tumor size. Soft-tissue lesions such as skin and lymph node metastases were imaged to a greater extent (76%) than visceral metastases (19%). In five of six patients, biopsies obtained from 3 days to 14 days after MoAb administration showed antibody present on tumor cells as demonstrated by flow cytometry and/or radioimmunoassay. Human anti-murine immunoglobulin responses were observed in seven of 17 patients studied. Mean plasma clearance of ZME-018 was prolonged with a T1/2 of 24.7 hr and increased slightly with increasing MoAb dose. Urinary excretion of 111In averaged 12.4% of the injected dose over 48 hours. Radioimmunolocalization of melanoma with 111In-labeled ZME-018 appears feasible. The sensitivity of the technique was related to dose, tumor size, and disease site.

Radioimmunoimaging in malignant melanoma patients with the use of indium-111-labeled antimelanoma monoclonal antibody (ZME-018) to high-molecular-weight antigen.

Radioimmunolocalization of an 111In-labeled, mouse antimelanoma monoclonal antibody (MAb), ZME-018, was examined in 30 patients with metastatic malignant melanoma. Each patient received a single iv infusion of MAb at concentrations ranging from 0.6 to 40 mg, coupled to 5 mCi 111In by the chelating agent pentetic acid. No toxicity was observed in any patient. Total-body and region of interest scans performed at 4, 24, and 72 hours following MAb administration revealed uptake in 110 of 171 previously diagnosed metastases for a sensitivity of 64%. Nonspecific uptake of radioactivity was consistently observed in the liver and spleen, and less frequently in the bowel, testes, axillae, and bone. Sensitivity of detection increased significantly at doses of MAb above 2.5 mg, with 74% of the lesions imaging at 20 mg/5 mCi compared with 29% at 2.5 mg/5 mCi (P less than .005). Sensitivity actually decreased slightly at the 40-mg dose. There was a significant correlation between tumor uptake of MAb-111In-conjugate and increasing tumor size. Soft tissue lesions, such as skin and lymph node metastases, were imaged to a greater extent (77%) than were visceral metastases (40%). Mean plasma clearance of ZME-018 was prolonged with a half-life of 33.6 hours in patients receiving 40 mg, compared with 17.8 hours in patients given 2.5 mg (P less than .01). Urinary excretion of the isotope averaged 11.4% of the injected dose over 48 hours. Hence radioimmunolocalization of melanoma with 111In-ZME-018 appeared feasible. The sensitivity of the technique varies with MAb dose, specific activity of 111In-MAb conjugate, tumor size, and disease site.