Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody.

Sixteen patients with non-Hodgkin's lymphoma were infused with 6.2 to 58.2 mCi (0.2 to 3.9 mg) doses of radioactive iodine (131I)-labeled LL2 immunoglobulin G (IgG) or F(ab')2, in order to study antibody distribution, pharmacokinetics, dosimetry, toxicity, tumor targeting, and therapy. LL2 is a murine IgG2a monoclonal antibody (MAb) reactive with B cells and non-Hodgkin's B-cell lymphoma. In a series of five assessable therapy patients, doses as small as 30 mCi 131I-LL2 IgG or F(ab')2 resulted in tumor responses (two partial remissions, two mixed and minor responses, and one no response), while one patient receiving diagnostic doses as low as 6.2 mCi showed a partial remission for 1 year and a complete remission after a second low radiation dose. No acute toxicities were noted, and only myelotoxicity accompanied therapeutic doses, with grade IV marrow toxicity seen in three of seven patients receiving total doses of about 50 mCi. Dosimetry calculations showed spleen and tumor dose rules of about 4.6 cGy/mCi, which was three to four times the dose to other organs. Despite the administration of relatively low doses of LL2 (0.2 to 3.9 mg), 82% of 60 known extrasplenic lymphoma sites were imaged. Serum clearance showed an average distribution half-life (T1/2) of 2.1 hours and an elimination T1/2 of 32.0 hours. The average total-body clearance T1/2 was 43 to 45 hours. LL2's antigenic target does not appear to be shed in high amounts into the circulation. Three of eight patients having at least two injections showed a human antimouse antibody response. These patients may have been presensitized to animal protein. An interesting observation in this study was the marked drop in circulating B lymphocytes after the administration of radioiodinated LL2 or anticarcinoembryonic antigen MAbs, suggesting that this is a nonspecific radiation effect and not necessarily related to the binding of MAb to normal B cells.

Clinical evaluation of tumor targeting with a high-affinity, anticarcinoembryonic-antigen-specific, murine monoclonal antibody, MN-14.

BACKGROUND: The authors previously reported that an anticarcinoembryonic antigen antibody against a carcinoembryonic antigen (CEA)-specific epitope is preferred for clinical investigations. They developed a second generation, CEA-specific murine monoclonal antibody (MoAb), MN-14 (IMMU-14), that has a tenfold higher affinity. This report summarizes the initial clinical experience with the new MoAb. METHODS: MN-14 immunoglobulin G (IgG) (0.5-6.0 mg) was labeled with radioactive iodine (I131) (5-80 mCi) and injected into 22 patients with cancer. External scintigraphy was used to determine targeting in patients with low and highly elevated plasma CEA. Quantitative external scintigraphy methods were used to determine organ and tumor clearance rates and absorbed radiation doses. Targeting data were correlated with several factors, including MoAb protein dose, plasma CEA, and relative tumor burden. RESULTS: Despite more than 80% complexation with plasma CEA of more than 500 ng/ml, all known tumor sites were disclosed by external scintigraphy. The overall sensitivity of tumor targeting on a lesion basis was 89%. The residence time in the blood was predicted by body weight (P = 0.05) and the log of plasma CEA (P = 0.043). The absorbed dose to the red marrow and total body could be predicted by the body weight of the patient, but no other factor contributed significantly to the clearance rate or absorbed dose to the organs. Individual tumors received an average dose of 9.3 +/- 6.4 cGy/mCi. The absorbed dose to the tumors was negatively correlated to the weight of the tumor, and the percent uptake in the tumor was positively correlated to the estimated total tumor burden. Patients injected with approximately 5 mg of MN-14 IgG were more likely to have anti-mouse antibodies (HAMA) develop than were patients who were injected with less MoAb. CONCLUSIONS: These results suggest that MN-14 targets tumors effectively, even in the presence of elevated circulating CEA. Additional studies are necessary to determine if an advantage for the higher affinity MN-14 MoAb, compared with the lower affinity NP-4 MoAb, can be appreciated clinically.