We will expand our on-going investigations into the coupling and labeling of proteins using the cyclic anhydride of DTPA and into the in vitro and in vivo behavior of the proteins and the attached labels. Specifically, we will study several attractive anti-tumor antibodies, labeled with indium-111, in cancer patients to further establish the pharmacokinetic and stability of the label and to assess this imaging modelity for the detection of cancer. These studies will be modeled after our previous clinical investigation although we will include two additional studies. We will co-administer with the indium-111 labeled antibody, the same antibody labeled at tracer levels with iodine-125. Thereby we will compare, in the same patient and for the same antibody, the behavior of both labels. In addition, we will use normal and tumor tissue obtained from these patients at surgery in the in vitro antibody binding assay developed in our laboratory to assess its value in predicting antibody localization in patients. We will also apply the cyclic anhydride labeling methodology to the labeling of tissue plasminogen activator with indium-111. Our initial investigations of this labeled protein in vitro and in animals suggest that it may be useful for the detection of forming clots. It is possible that this study may proceed quickly to clinical trials. Other radionuclides besides indium-111 have attractive properties. We will continue to improve upon the labeling of antibodies with yttrium-90 towards the eventual goal of preparing a product suitable for use in patients for therapy. Similarly, we will investigate gadolinium-153-labeled proteins to establish whether label stability in serum is sufficient for NMR contrast use. We will also continue our studies into the labeling of proteins with technetium-99m. Besides labeling antibodies with this radionuclide, we will label tissue plasminogen activator because of its rapid clot localization and blood clearance. Finally, we plan a number of in vitro investigations. For example, we will continue to use liver homogenates to determine the fate of indium and iodine labeled antibodies. We will investigate liver localization of antibody modified in the carbohydrate region and we will investigate aspects of protein chemistry such as the measurement of the immunoreactive fraction after alterations in coupling procedure.
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