Radioactive Diabodies Halt Breast Cancer

Cancer researchers have used genetically engineered "diabodies,” small dimeric proteins that contain specific antigen-recognition sites, linked to a radioactive isotope to kill human breast tumors that had been transplanted into an immunodefficient mouse model.

Diabodies, which are produced by genetically engineered Escherichia coli, have an average molecular weight of about 55,000 daltons, much smaller than the 180,000 daltons of native IgG. This means that diabodies are rapidly cleared from the blood. However, the high affinity of the diabody for its antigen assures that binding to the tumor will greatly exceed that obtained with monoclonal antibodies targeted to the same cells.

To take advantage of the high avidity of tumor-specific diabodies, investigators at Fox Chase Cancer Center (Philadelphia, PA, USA; www.fccc.edu) attached the beta-emitting radioactive isotope yttrium-90 to diabodies-specific for HER2/neu human tumor-associated antigen. They reported in the September 1, 2004, issue of Cancer Research that a single intravenous dose of C6.5K-A diabodies conjugated with 150 microcuries of yttrium-90 substantially inhibited the growth rates of established MDA-361/DYT2 human breast tumor xenografts in athymic nude mice. On the other hand, double this dosage of radioactive diabodies failed to inhibit growth of SK-OV-3 human ovarian cancer xenografts. The ovarian cancer cells lacked the p53 tumor suppressor gene, which normally would be activated by the damage caused by the radioactive isotope.

"The dimeric C6.5K-A binds to its target antigen 40 times more tenaciously than its individual monomeric components, thus promoting prolonged retention in antigen-laden tumors. At the same time, its small size enables it to efficiently find and penetrate these tumors,” explained first author Dr. Gregory Adams, associate member of the medical science division of the Fox Chase Cancer Center. "The kinetics of the HER2 receptor on the mammary tumor cells are favorable to taking up the diabody. Once the beta-emitter is delivered inside the mammary tumor cells, the radiation causes intracellular damage that probably triggers p53-driven apoptosis.”



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Fox Chase Cancer Center