The Preston Robert Tisch Brain Tumor Center at Duke

Basic and Clinical Research Program | Summary of Research Activities

New Radiolabeling Technology and Isotopes (211At and 177Lu) for Peptides and Monoclonal Antibodies

Dr. Zalutsky has continued to investigate the relationship between the nature of the labeling site on a biomolecule and its degradation in both the intracellular and extracellular environments. This work has formed the basis for radiohalogenation strategies for proteins and peptides that are rapidly internalized by tumor cells after binding to cell surface receptors.

Approaches that have been successfully applied in animal models of human malignancies include prosthetic groups composed of positively-charged D-amino acids as well as guanidine-substituted benzoates. Compared with conventional labeling approaches, these reagents increased tumor retention of an anti-EGFRvIII mAb by a factor of 4.

A second area of research in the oncologic radiopharmaceutical chemistry group is the use of alpha-particle emitting radionuclides for cancer therapy. Alpha particles are high linear energy transfer radiation with a range of only a few cell diameters, making them ideal for application in tandem with cell-specific targeting molecules under development in the Cancer Immunobiology Program. Ongoing studies utilize the -emitting radiohalogen 211At, taking advantage of the fact that the Duke University Medical Center cyclotron is one of only a few accelerators in the country that can produce this promising radionuclide.

Ongoing research in the astatine project that has direct implications for translational and clinical objectives includes high-level cyclotron targetry, radioastatination chemistry, high-LET radiobiology, radiolytic effects, and evaluations of the acute normal organ toxicity of -emitting therapeutics in animal models. In addition, new methods for microdosimetry have been developed and implemented that utilize histological images to evaluate radiation effects on a cellular and subcellular level. A consequence of these dosimetry investigations is the emergence of tumor blood vessels as an excellent target for the development of -particle emitting targeted radiotherapeutics.

Based on these studies, Drs. Zalutsky and Bigner obtained an IND from the FDA to evaluate the administration of 211At-labeled chimeric 81C6 mAb into surgically created glioma resection cavities. This is the first clinical investigation of a radiotherapeutic agent labeled with 211At in the world, and in the 17 patients treated to date, minimal toxicity and encouraging survival has been observed. The experience gleaned with this 211At-labeled mAb should greatly facilitate the initiation of clinical trials with other targeting vectors under development in the Cancer Center, with those directed at lymphoma, leukemia and tumor vasculature being of first priority.

Printer Friendly Page Send this Story to a Friend