Monoclonal antibodies (mAbs) are attractive vehicle so far targeting radiation to tumors because of their ability to react specifically with molecular determinants that are either uniquely expressed or over expressed on cancer cells. However, the clinical impact of labeled mAb is hampered by loss of the label from the mAb in vivo and uptake of radioactivity in normal tissues. The goal of this research proposal is to develop more effective approaches for labeling mAbs with radioiodine nuclides and 211At. Iodine-131 is the most frequently used radionuclide in clinical radioimmunotherapy, but its usefulness has been compromised by in vivo dehalogenation of mAbs labeled via conventional methods. Astatine-21 1 emits a-particles that have a higher radiobiological effectiveness and shorter range than P-particles and, for certain therapeutic applications, may be .better matched to the characteristics of the tumor. We have focused our research on mAbs reactive with the epidermal growth factor receptor variant I11 (EGFRvIII) because this mutant receptor is present in high concentrations on glioma, breast carcinomas and other tumors, but is not found on normal tissues including those expressing wild type EGFR. Anti-EGFRvIII mAbs are internalized and processed rapidly, resulting in rapid loss of the label from tumor cells when mAbs are labeled by conventional approaches. Our hypothesis is that optimized labeling methods for internalizing mAbs such as anti-EGFRvIII will enhance tumor retention and tumor-to-noise seal ratios, thereby improving their clinical potential as diagnostic and therapeutic agents. The original specific aim Years 14-18 are: 1) To label anti-EGFRvIII mAbs with radioiodine nuclides and 211Auts ing N-succinimidyl 5-['311]iodo-3- pyridinecarboxylate and N-succinimidyl 5-[211At]astato-3-pyridinecarboxylate and to evaluate their potential as diagnostic and therapeutic radiopharmaceuticals. 2) To investigate other strategies for labeling internalizing mAbs with radioiodine and including the use of alternate positively charged templates, D-amino acid linkers, and new approaches involving oligosaccharide conjugation; and 3)To investigate the nature of the high and low molecular weight labeled catabolites generated in tumor cells in vitro and tumor and normal tissues in vivo and use these data as a guide for developing improved methods for labeling mAbs.
Showing the most recent 10 out of 156 publications
