Loss of label in vivo and uptake of radioactivity by normal tissues confound the clinical application of radiolabeled monoclonal antibodies (MAbs). The central hypothesis of this proposal is that optimized MAb labeling methodology would lead to greater retention of activity in tumor and more favorable tumor-to-normal-tissue dose ratios. Our goal is to improve the clinical utility of MAb imaging and therapy by developing better methods for labeling MAbs and their fragments with radioiodine nuclides and 211At. Iodine-131, the most frequently used nuclide for radioimmunotherapy, emits beta-particles with a maximum range in tissue of 1-2 mm, but its usefulness for labeling MAbs is compromised by in vivo dehalogenation. More effective approaches for MAb radioiodination would also facilitate the use of 1231 and SPECT imaging, an approach that might be valuable not only for lesion detection, but also for dosimetry estimation prior to therapy. Astatine-21 1 emits alpha-particles that have a higher radiobiological effectiveness and shorter range than beta- particles and, for certain therapeutic applications, it may be better matched to the geometry of the tumor. This continuation application focuses on experiments with MAbs directed against tenascin, an extra-cellular matrix antigen found in brain tumors and other malignancies including breast carcinoma. The improved labeling methods developed for use with these MAbs also could offer advantages for labeling other MAbs, including those directed against breast, ovarian, colon, lung and prostate cancer.
Our specific aims are: 1) To label anti-tenascin MAbs chimeric 81C6 and ECM 119 and their F(ab')2 fragments with radioiodine nuclides and 211At using N-succinimidyl 3-iodobenzoate and N-succinimidyl 3-[211At] astatobenzoate and to evaluate their potential for diagnostic and therapeutic applications; the proposed studies include characterization of immunoreactivity and affinity; evaluation of tissue distribution in normal mice and athymic rodents with subcutaneous, intracerebral, and neoplastic meningitis xenografts; determination of in vitro radiotoxicity; and assessment of therapeutic efficacy in athymic rodent xenograft models; 2) To investigate other labeling strategies in order to define the optimal template for labeling both intact MAbs and F(ab')2 fragments with radioiodine and 211At. These approaches include N-succinimidyl halopyridine-carboxylates and substituted benzoates as well as the use of D-amino acid spacers. Promising methods will be evaluated as outlined in Specific Aim 1; and 3) To determine labeled MAb and fragment catabolites in normal tissue and tumor.
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