PRETARGETING STRATEGIES FOR CENTRAL NERVOUS MALIGNANCY RADIOIMMUNOTHERAPY

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The overall objective of this proposal is to improve the clinical utility of radiolabeled monoclonal antibodies (MAbs) for the treatment of CNS tumors. Our hypothesis is that the efficacy of radioimmunotherapy is critically dependent on the type of nuclide and MAb labeling method that are used. During the past few years, we have developed novel strategies for labeling MAbs with the radioimmunotherapy and emits beta-particles with a maximum range in tissue of 102 mm. Astatine-211 decays by the emission of alpha-particles, which have a range of only a few cell diameters and a higher relative biological effectiveness than beta-particles. This nuclide might be ideal for the treatment of neoplastic maningitis. Fluorine-18 sis a positron emitter, and MAbs labeled with 18F offer the attractive possibility of using positron emission tomography (PET) to quantitate the distribution of labeled MAbs. PET imaging could provide more accurate dosimetry for both tumor and normal tissues and greatly facilitate radioimmunotherapy planning. The goal of this work is to be able to transfer our radiohalogenation technologies to the clinical domain as expeditiously as possible. These studies will be performed using chimeric Mel-14 and its fragments. This MAb was selected because of its potential utility for the treatment of gliomas and melanomas, particularly via intratumoral and intrathecal delivery. In addition, the selection of chimeric Mel-14 is supported by the encouraging results obtained in extensive preclinical work and clinical pilot studies that we have performed with murine Mel-14 F(ab')2. The specific aims of this project are: a) to label intact chimeric Mel-14 IgG and its fragments with 131I, 211At, and 18F using N-succinimidyl [131I] iodobenzoate, [211At] astatobenzoate, and [18F] fluorobenzoate, respectively, without compromising immunoreactivity; b) to determine the pharmacokinetics of radiohalogenated intact chimeric Mel-14 and its fragments in subcutaneous, intracranial, and neoplastic meningitis human tumor xenograft models; c) to investigate the in vitro radiotoxicity of 131I- and 211At-labeled intact chimeric mel-14 and its fragments in human tumor 2 cell lines; d) to evaluate the toxicity of 131I- and 211At-labeled intact chimeric Mel-14 and its fragments in normal and athymic mice; and e) to determine the therapeutic potential of intact chimeric Mel-14 and its fragments labeled with equitoxic doses of 131I and 211At in subcutaneous, intracranial, and neoplastic meningitis human tumor xenograft models.