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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National Cancer Institute (NCI)
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Diagnostic Radiology Study Section (RNM)
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University of Massachusetts Medical School Worcester
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Hnatowich, D J; Fritz, B; Virzi, F et al. (1993) Improved tumor localization with (strept)avidin and labeled biotin as a substitute for antibody. Nucl Med Biol 20:189-95
Hnatowich, D J; Mardirossian, G; Rusckowski, M et al. (1993) Directly and indirectly technetium-99m-labeled antibodies--a comparison of in vitro and animal in vivo properties. J Nucl Med 34:109-19
Mardirossian, G; Wu, C; Hnatowich, D J (1993) The stability in liver homogenates of indium-111 and yttrium-90 attached to antibody via two popular chelators. Nucl Med Biol 20:65-74
Hnatowich, D J; Mardirossian, G; Rusckowski, M et al. (1993) Pharmacokinetics of the FO23C5 anti-CEA antibody fragment labelled with 99Tcm and 111In: a comparison in patients. Nucl Med Commun 14:52-63
Wu, C; Virzi, F; Hnatowich, D J (1992) Investigations of N-linked macrocycles for 111In and 90Y labeling of proteins. Int J Rad Appl Instrum B 19:239-44
Hnatowich, D J; Rusckowski, M; Siebecker, D A et al. (1992) Pharmacokinetics of indium-111 labeled 10-3D2 antibreast-tumor antibody in patients. J Nucl Biol Med 36:7-13
Aas, M; Mardirossian, G; Griffin, T W et al. (1992) Long-term biodistribution in tumored mice of murine and chimeric B72.3-IgG antibody radiolabeled with 114mIn via both DTPA and a macrocyclic chelator. J Nucl Biol Med 36:33-40
Mardirossian, G; Wu, C; Rusckowski, M et al. (1992) The stability of 99Tcm directly labelled to an Fab' antibody via stannous ion and mercaptoethanol reduction. Nucl Med Commun 13:503-12
Rusckowski, M; Fritz, B; Hnatowich, D J (1992) Localization of infection using streptavidin and biotin: an alternative to nonspecific polyclonal immunoglobulin. J Nucl Med 33:1810-5
Virzi, F; Fritz, B; Rusckowski, M et al. (1991) New indium-111 labeled biotin derivatives for improved immunotargeting. Int J Rad Appl Instrum B 18:719-26

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