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Tumor necrosis treatment of ME-180 human cervical carcinoma model with 131I-labeled TNT-1 monoclonal antibody.

In contrast to normal tissues, many malignant tumors contain a high proportion of dead and dying cells. The loss of membrane integrity that accompanies cellular degeneration permits macromolecules, including antibodies, to freely enter the cell cytoplasm. Based upon these observations, it was hypothesized that monoclonal antibodies to intracellular antigens, which are integral structural components and are retained by degenerating cells, may be used to target a wide range of human malignancies. Previous studies by our laboratory utilizing these principles have demonstrated the feasibility of imaging four different histological types of human cancer in a nude mouse model, using monoclonal antibodies directed against insoluble intranuclear antigens. The present study describes the application of this approach, designated tumor necrosis treatment, for the radioimmunotherapy of transplantable ME-180 human cervical carcinomas in the nude mouse. Groups of tumor-bearing nude mice received three weekly treatments of 150 or 300 microCi of 131I-labeled experimental (TNT-1) or control (Lym-1) monoclonal antibodies. Detailed biodistribution data, dosimetric evaluations, and therapeutic results are presented to demonstrate the effective and preferential targeting of 131I-labeled TNT-1 monoclonal antibody within the tumor. In the experimental groups, the dose delivered to the tumor was sufficient to induce clinical regressions in 88% of treated animals, without evidence of toxicity to normal tissues. Complete regressions were obtained in 25% of the mice treated with high dose TNT-1. Microscopic examination of the implantation sites of these mice demonstrated the presence of acute radiation damage and residual keratin-positive tumor cells showing marked evidence of degeneration. Dosimetric data obtained over the 3-week treatment period showed that, unlike control treated mice, which received approximately 500 cGy each week, the experimental animals received increasing doses of radiolabeled antibody with each treatment (averages for weeks 1, 2, and 3: 1066, 2046, and 2476 cGy, respectively). In accordance with these data, enhanced imaging and therapeutic responses were observed with each therapeutic dose in the TNT-1-treated groups, compared with controls. These results indicate that TNT-1 therapy produces an ever expanding population of TNT-1-positive targets in the tumor as a result of the centrifugal killing of adjacent viable tumor cells. To help illustrate these results, a four-compartment model of the dose distribution kinetics of TNT-1 is presented for discussion with respect to the possible application of this method for the imaging and treatment of cancer in