Targeting and therapy of human glioma xenografts in vivo using radiolabeled antibodies

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. ¹¹¹In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (uCi) of tumor activity per gram per 100 uCi injected activity compared to 4.5 uCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. Tumor dose found in normal organs is less than 20% of the tumor dose, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibodies QC1054 and ZME018, which define a tumor-associated and a second melanoma-associated antigen, respectively, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of ⁹⁰Y-radiolabeled P96.5, QCI054, and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Average absorbed doses of 3770 ± 445 (mean ± SEM), 2043 ± 134, and 645 ± 48 cGy in tumor, 353 ± 41, 243 ± 22, and 222 ± 13 cGy in a contralateral control intramuscular site, 980 ± 127, 815 ± 41, and 651 ± 63 cGy in liver, and 275 ± 14, 263 ± 11, and 256 ± 18 cGy in total body were observed 7 days following administration of I00 uCi ⁹⁰Y-radiolabeled P96.5, QCI054, and ZME018, respectively. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or ⁹⁰Y-radiolabeled P96.5, QCI054, or ZME018. Striking tumor regression and prolonged survival were measured following administration of ⁹⁰Y-labeled P96.5. Average maximal decreases in tumor volume were 42.7 ± 11.9 and 94.2 ± 3.3 percent 28 and 58 days following 100 and 200 uCi⁹⁰Y-radiolabeled P96.5 administration, respectively. The time required to achieve four times the initial tumor volume was 6.1 ± 0.9 days for buffer; 43 12 and 63 ± 10 days for 50 and 100 uCi ⁹⁰Y-radiolabeled P96.5; 7 ± 2, 20 ± 1, and 53 ± 4 for 50, 100, and 200 uCi ⁹⁰Y-radiolabeled QCI054; and 9 ± 1, 13 ± 1, and 29 ± 3 days for 50, 100, and 200 uCi ⁹⁰Y-radiolabeled ZME0I8, respectively. Average tumor regrowth failed to occur 180 days following administration of 200 uCi ⁹⁰Y-labeled P96.5. Targeting specificity via shared neuroectodermal antigens provides a basis for human glioma radioimmunotherapy.