The long-term objective of this proposal is to develop more effective methods for the diagnosis and treatment of tumors using radiolabeled monoclonal antibodies (MAb). The hypothesis of this proposal is that improvements in MAb labeling methods can lead to improved tumor to normal tissue radiation dose rations. MAb labeling methods will be developed which maximize a) the in vivo stability of the bond between the radionuclide and the MAb; b) the rate of excretion of the label species created in the catabolism of the labeled MAb; and c) the affinity and immunoreactivity of the MAb for its antigenic target. Our results labeling MAb using N-succinimidyl-3-(tri-n-butylstannyl) benzoate (ATE) suggest the utility of this strategy. Since the optimal nuclide for each application will differ, these labeling methods will be utilized to investigate two approaches for MAb radiotherapy--alpha emitters and beta emitters. Iodine- 131 emits beta particles with a maximum range in tissues of 1-2 nm, facilitating the irradiation of proximal antigen-negative and poorly perfused tumor cells. The alpha particles of At-211 have higher radiobiological effectiveness and shorter range (55-80 um) than beta particles and their cytotoxicity is nearly oxygen-independent. These studies will be performed with 81C6 and Mel-14 and their Fab and F(ab')2 fragments, MAb reactive with a variety of tumors, but not normal tissues, of the central nervous system.
Our specific aims are: a) to optimize methods for labeling MAb with iodine and astatine nuclides; b) to determine the biodistribution of MAb and fragments labeled with I-131 and At-211 via our new methods in athymic mice and rats bearing subcutaneous and intracranial human glioma xenografts; c) to measure the in vitro radiotoxicity of I-131 and At-211 labeled MAb and fragments as well as isotype-matched control MAb in antigen-positive human glioma, medulloblastoma and control cell lines; d) to evaluate the therapeutic potential of MAb and fragments labeled with I-131 and At-211 using our new methods in athymic mice and rats bearing subcutaneous, intracranial and intrathecal human glioma and medulloblastoma xenografts; and e) to determine the pharmacokinetics of labeled MAb and fragments in non-human primates in order to obtain normal tissue radiation dosimetry data as well as to evaluate toxicity by clinical and histopathological criteria.
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