The primary objective of this study is to determine the clinical effectiveness of radiolabeled monoclonal antibodies (MAbs) to unique intracellular antigens as a means of selectively targeting human cancers which contain abnormally permeable, degenerating cells. Previous studies have shown that a high proportion of malignant tumors undergo degeneration and cell death with the formation of necrosis. In addition, the inadequate blood supply and impaired phagocytic responses within the tumor favor the accumulation of degenerating cells adjacent to viable areas of the tumor. In contrast, normal tissues have a relatively low rate of cell death and are charterized by a rapid and orderly removal of necrotic elements. Based upon these observations it was hypothesized that MAbs to abundant intracellular antigens which are structural components of the cell and are therefore retained by degenerating cells, maybe used to target a wide range of human malignancies. To test this hypothesis, three major studies using selected antinuclear MAbs generated were performed. The first demonstrated conclusively that these MAbs can image human tumor transplants in nude mice with no apparent uptake by normal tissues. The second showed that when labeled with I-131, these MAbs can be used as an effective treatment modality in a human cervical carcinoma-nude mouse model and the third, verified the ability of these MAbs to penetrate and bind selectively to early and late necrotic regions in the center of tumors. In this application the intention is to extend these studies by using a syngeneic mouse tumor to obtain additional data using established metastatic tumor models of the mouse. In particular, two key issues will be addressed, namely, can this approach (designated Tumor Necrosis Treatment, TNT) be used to monitor conventional cytoreductive therapy by imaging techniques, and secondly, can TNT be used as an adjuvant to standard cytoreductive therapy. To answer these questions, tumor-bearing mice will be treated with chemotherapeutic agents and at various time intervals after treatment receive therapeutic doses of radiolabeled TNT antibodies. Sequential imaging and biodistribution studies will be used to determine the optimal time after cytoreductive therapy to administer the radiolabled antibodies. Autoradiography and vascular leakage studies will be performed in paralled to identify important factors involved in antibody localization. The relative merits of several candidate MAbs, the use of whole MAb versus fragments, and the testing of different radionuclides and conjugation methods will be explored to optimize the effectiveness of this novel approach.
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