Malignant gliomas and CNS metastases from solid tumors such as malignant melanoma respond poorly to present therapy. The hypothesis in this proposal is that radiolabeled monoclonal antibodies (MCA) may improve diagnosis and therapy of primary and metastatic brain tumors. Monoclonal antibodies which are cross-reactive with gliomas and melanoma have been developed, and these antibodies demonstrate no reactivity with normal nervous system tissue. These antibodies have been radiolabeled, demonstrate specific localization in human glioma xenografts in athymic mice, and mediate radioimmunotherapeutic effects in human gliomas growing in athymic mice. The long-term objective is to develop specific radiolabeled monoclonal antibodies for radioimmunotherapy of malignant glioma and metastatic melanoma to the CNS.
Specific aims i nclude the evaluation of the clinical potential of radiolabeled monoclonal antibodies or their fragments for imaging and therapy in patients. The pharmacokinetics and biodistribution of selected MCA will be determined in non-human primates to calculate radiation absorbed doses to normal tissues and to demonstrate lack of toxicity by clinical and histopathologic criteria. The pharmacokinetics and biodistribution of the MCA will be studied in patients with malignant glioma or metastatic melanoma to the brain to calculate radiation absorbed doses to normal tissue and the brain tumor. Combinations of antibodies will also be investigated. The efficacy of radioimmunotherapy will be evaluated in patients with malignant gliomas or metastases of melanoma to the brain with the individual or combinations of radiolabeled MCA with which radiation dose calculations demonstrate that 8,000 to 12,000 rads can be delivered to the brain tumors.
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