Monoclonal antibodies have been developed and characterized that are reactive with antigens present on human gliomas, medulloblastomas and tumors that metastasize to the central nervous system. The hypothesis of this project is that these antibodies, when combined with the appropriate nuclide, could be used to deliver therapeutic levels of radiation more selectively to these tumors. Because they offer different advantages, both the beta emitter iodine-131 and the alpha emitter astatine-211 will be investigated. The beta particles of I-131 have a range in tissue of 1-2 mm, facilitating the irradiation of proximal antigen negative or poorly perfused tumor cells. The alpha particles of At-211 have a greater radio-biological effectiveness and a range of only a few cell diameters, minimizing the dose to neighboring normal brain or spinal tissues. These antibodies will be labeled with these nuclides using the ATE procedure, a method which we developed which decreases the loss of label from the antibody due to dehalogenation in vivo.
The specific aims of this project are: a) to label these monoclonal antibodies with I-131 and At-211 using the ATE method without adversely affecting the immunoreactivity and affinity constant of the antibody; b) to determine the pharmacokinetics of I-131 and At-211 labeled anti-glioma and medulloblastoma monoclonal and antibody fragments in subcutaneous and intracranial human tumor xenograft models; c) to measure the radiotoxicity in vitro of I- 131 and At-211 labeled antibodies in both antigen-positive and control human tumor cell lines; and d) to determine the therapeutic potential of I-131 and At-211 labeled anti-glioma and medulloblastoma antibodies and fragments in athymic mice and rats bearing subcutaneous and intracranial human tumor xenografts. Combinations of labeled antibodies and multiple dose regimens will also be investigated. These studies will hopefully provide the basis for clinical radiotherapeutic trials in patients with gliomas, medulloblastomas and carcinomatosis.
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